WO1998029373A1 - φ-BROMOALKYLBENZENES AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

φ-Bromoalkylbenzenes reduced having a small content of positional isomer and a process for preparing the same characterized by bringing a bromoalkylbenzene mixture comprising an φ-bromoalkylbenzene and an (φ-1)-bromoalkylbenzene into contact with an acid and then separating the φ-bromoalkylbenzene therefrom. The above compounds are useful as intermediates for medicines and, for example, 4-bromobutylbenzene is an important intermediate for the synthesis of the compound represented by formula (5) and used as a remedy for asthma.

Description

 Specification

 ω-Bromoalkylbenzene and method for producing the same

 Technical field

 The present invention relates to an ω-bromoalkylbenzene having a low regioisomer content, and a method for producing the same.

 Background art

 ω-Bromoalkylbenzene is used as an important intermediate in medicine and pesticides. For example, 4-bromobutylbenzene is an asthma confection of the following formula (5)

Is an important intermediate used in the synthesis of the compound represented by

 As a method for producing ω-bromoalkylbenzene, for example, a method of reacting ω-phenyl-11-alkene with hydrogen bromide as disclosed in Japanese Patent Application Laid-Open No. Hei 7-206732 is known. Have been. However, in this method, at the same time as the generation of ω-bromoalkylbenzene (hereinafter referred to as “ω-bromo compound”), the regioisomer (ω-1) monobromoalkylbenzene (hereinafter “ω-1 bromo compound”) is produced. ) Is 2.4% by weight as a by-product. Since there is almost no difference in boiling point and polarity between them, it is difficult to separate them by distillation or chromatography. Even in the final product, it is difficult to separate the compound derived from the ω-1 bromo compound.Therefore, there are manufacturing problems such as a significant decrease in the efficiency of separation and purification of the final product. The problem has arisen.

 Disclosure of the invention

 An object of the present invention is to provide an ω-bromoalkylbenzene having a low regioisomer content, and a method for producing the same.

The present inventors have conducted intensive studies in order to solve the above-mentioned problems of the prior art, and found that W

When a mixture of regioisomers containing a compound and an ω-1 bromo compound is brought into contact with an acid, the ω-1 bromo compound is selectively cyclized by the Friedel-Crafts reaction, and then the mixed liquid after the reaction is distilled. As a result, the inventors have found that a high-purity ω-bromo compound can be easily obtained, and have completed the present invention.

 Thus, according to the present invention, equation (1)

[In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and η represents an integer of 1 to 5. ]

Formula (2) wherein the content of (ω-1) -bromoalkylbenzene represented by the following formula (2) is 0.50% by weight or less with respect to ω-bromoalkylbenzene represented by the following formula (2):

 [In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and η represents an integer of 1 to 5. ]

Ω-bromoalkylbenzene represented by the formula:

 According to the present invention, the following formula (2)

[In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and η represents an integer of 1 to 5. ]

Formula (1) with ω-bromoalkylbenzene represented by

 [In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and n represents an integer of 1 to 5. A method for producing ω-bromoalkylbenzene, comprising contacting an acid with a benzene mixture and then separating ω-bromoalkylbenzene represented by the formula (2) is provided.

 BEST MODE FOR CARRYING OUT THE INVENTION

ω—Bromoalkylbenzene

 The ω-bromoalkylbenzene of the present invention has the formula (2)

[In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and η represents an integer of 1 to 5. ]

It is represented by

 Examples of the halogen atom in the formula (2) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 The lower alkyl group in the formula (2) is an alkyl group having 1 to 5 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec-butyl group. , N-amyl group and the like.

 The lower alkoxy group in the formula (2) is an alkoxy group having 1 to 5 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and a pentoxy group.

The position of these substituents in the benzene ring in the formula (2) may be any of the ortho, meta, and para positions with respect to the ω-bromoalkyl group, but may be in the meta position. Or para position is preferred.

 N in the formula (2) is an integer of 1 to 5, preferably an integer of 1 to 3, and more preferably 2.

 The ω-bromoalkylbenzene of the present invention is a regioisomer of the formula (1)

[The meaning of each symbol in the formula is the same as in formula (2). )

(Ω-1) -Promoalkylbenzene content is extremely low. The content of (ω-1) monobromoalkylbenzene is 0.50% by weight or less, preferably 0.40% by weight or less, more preferably 0.30% by weight or less based on ω-promoalkylbenzene.

Specific examples of the ω-bromoalkylbenzene of the present invention include 3-bromopropylbenzene, 4-bromobutylbenzene, 5-bromopentylbenzene, 6-bromohexylbenzene, 7-bromoheptylbenzene, and 1-fluoro-3-. (4-bromobutyl) benzene, 1-chloro- 3- (4-bromobutyl) benzene, 1-bromo-3- (4-bromobutyl) benzene, 1-fluoro 4- (4-bromobutyl) benzene, 1-chloro — 4— (4-bromobutyl) benzene, 1-bromo— 4- (4-bromobutyl) benzene, 1-methyl 3- (4-bromobutyl) benzene, 1-ethyl— 3 -— (4-bromobutyl) benzene, 1-Methyl-4- (4-bromobutyl) benzene, 1-ethyl-4 (4-bromobutyl) benzene, 1-methoxy-3- (4-bromobutyl) Benzene, 1-ethoxy-3- (4-bromobutyl) benzene, 1-methoxy-4-1- (4-bromobutyl) benzene, 1-ethoxy-4- (4-bromobutyl) benzene and the like. Among these, 3-bromopropyl benzene, 4-bromobutyl benzene, 5-bromopentyl benzene, 1-chloro mouth 3- (4-bromobutyl) benzene, 1-chloro mouth 4- 4- (4-bromobutyl) benzene, 1 —Methyl_3— (4-bromobutyl) benzene, 1-methyl-4- (4-bromobutyl) benzene, etc. are preferred. Are suitable, and 4-bromobutylbenzene is particularly preferred.

Production method

 The ω-bromoalkylbenzene having a low regioisomer content of the present invention contains ω-bromoalkylbenzene represented by the above formula (2) and (ω-1) monobromoalkylbenzene represented by the above formula (1). Ω-bromoalkylbenzene represented by the formula (2) by contacting an acid with the resulting bromoalkylbenzene mixture, and then separating it.

 (1) Bromoalkylbenzene mixture

 The ratio of ω-bromoalkylbenzene [ω-bromo compound] and (ω-1) monobromoalkylbenzene [(ω-1) promo compound] in the mixture of regioisomers of bromoalkylbenzene in contact with acid is exceptional. Although there is no particular limitation, generally, a compound having a small ratio of the (ω-1) bromo compound is used. A typical bromoalkylbenzene mixture is a product obtained by reacting ω-phenyl-1-argen with hydrogen bromide as described below. In this reaction product, [ω-bromo Compound]: The weight ratio of [(ω-1) bromo compound] is usually 80:20 to 98.5: 1.5, preferably 85:15 to 98.5: 1.5, more preferably 90:90. : 10 to 98.5: It is in the range of 1.5.

 A typical example of the bromoalkyl benzene mixture containing the ω-bromo compound and the (ω-1) bromo compound is represented by the formula (3)

[The meaning of each symbol in the formula is the same as that in formula (2). )

And an ω-bromo compound represented by the above formula (2) obtained by reacting ω-phenyl-1-alkene and hydrogen bromide represented by the formula (1): (Ω-1) monobromo compound.

Specific examples of the ω-phenyl-1-argen represented by the above formula (3) include 3-phenyl_1-propene, 4-phenyl-1-butene, and 5-phenyl-1-pentene. Ten, 6—phenyl 1-hexene, 7—phenyl 11-heptene, 4- (3-fluorophenyl) — 1-butene, 4_ (3-cyclo-phenyl) — 1-butene, 4 -— (3-bromophenyl ) — 1-butene, 4- (4-fluorophenyl) — 1-butene, 4- (4-chlorophenyl) — 1-butene, 4- (4-bromophenyl) 1-butene, 4- (3-methylphenyl) 1 1-butene, 4- (3-ethylphenyl) 1-butene, 4-1-1 (4-methylphenyl) _ 1-butene, 4_ (4-methylphenyl) 1-1-butene, 4-1-1 (3-methoxyphenyl) _ 1-butene And 4- (3-ethoxyphenyl) -1 butene, 4- (4-methoxyphenyl) -1 butene, 4- (4-ethoxyphenyl) -11-butene, and the like. Of these, 3-phenyl 1-propene, 4-phenyl 1-butene, 5-phenyl 1-pentene, 4- (4-chlorophenyl) —1-butene, 4- (3-chloro Mouthphenyl) 1-butene, 4- (4-methylphenyl) -11-butene, 4- (3-methylphenyl) -1-butene and the like are preferred, and 4-phenyl-1-butene is particularly preferred.

 Although hydrogen bromide gas is generally used as hydrogen bromide, a hydrogen bromide monoacetic acid solution (or a propionic acid solution) or the like can also be used. The amount of hydrogen bromide used is appropriately selected depending on the reaction conditions and the like, but is usually at least equimolar, preferably 1 to 10 mol, more preferably 1 to 1 mol per 1 mol of ω-phenyl-1-alkane. The range is 5 moles.

 The reaction between the ω-phenyl-11-argen compound represented by the formula (3) and hydrogen bromide can be carried out in the presence of a catalyst or using a solvent, if necessary. Examples of the catalyst include various peroxides such as benzoyl peroxide, azobisisobutyronitrile, and t-butyl peroxy peroxide, and the amount of the catalyst used is based on 1 mole of ω-phenyl-2-alkene. Thus, it is usually in the range of 0.001 to 0.5 mol, preferably 0.01 to 0.1 mol.

The reaction temperature is usually in the range of -50 to 50 ° C, and the reaction time is appropriately selected depending on the reaction temperature, but is usually in the range of 5 minutes to 10 hours. The end point of the reaction is confirmed by, for example, GC (gas chromatography) analysis, and the peak of the ω-phenyl-2-alkene compound of the raw material can be 0.5% or less as a guideline of the end point of the reaction. . Anti After completion of the reaction, a regioisomeric mixture of ω-bromoalkylbenzene and (ω-1) -bromoalkylbenzene is obtained from the reaction solution by ordinary separation means such as extraction, liquid separation, washing, drying, and concentration. can get.

 (2) Cyclization reaction

When the above mixture of regioisomers of bromobenzene is brought into contact with an acid, the (ω-1) -bromoalkylbenzene represented by the formula (1) selectively causes a Friedel-Crafts reaction, and the formula (4)

 [The meaning of each symbol in the formula is the same as that of the formula (2). )

Is converted to a cyclized compound represented by

 Examples of the acid used include a Lewis acid and a Bronsted acid, and a Lewis acid is preferably used.

 Examples of Lewis acids include halogens such as aluminum trichloride, iron trichloride, tin tetrachloride, boron trifluoride, zinc dinitride, iron dichloride, titanium tetrachloride, bromomagnesium, antimony fluoride, and mercury chloride. Metal alkoxides such as tetraisopropoxytitanium, triethoxyaluminum, and dimethoxymagnesium; trifluoromethanesulfonates of rare earth metals such as scandium triflate, ytterbium triflate, and ruthenium triflate; trifluoromethanesulfonate methyl ester Sulfonic acid esters such as ρ-toluenesulfonic acid methyl ester; and the like. Among these, metal halides, metal alkoxides, and trifluoromethanesulfonic acid salts of rare earth metals are preferred, and metal halides are more preferred. Among the metal halides, aluminum trichloride and iron trichloride are preferably used, and aluminum trichloride is particularly preferred because of its high activity.

Bronsted acids include hydrohalic acids, carboxylic acids, sulfonic acids, inorganic acids, and solid acids. Examples of hydrohalic acids include hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; examples of carboxylic acids include acetic acid and Examples of sulfonic acids include sulfuric acid, methylsulfonic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, benzenesulfonic acid, and 4-nitrobenzenesulfonic acid. Examples of inorganic acids include: For example, nitric acid, phosphoric acid, and the like.

 Solid acids are metal acid compounds and clay minerals. Specific compounds include, for example, metal acid compounds such as silica, alumina, silica-alumina, silica-magnesia, and zeolite; acid clay, activated clay, montmorillonite And the like; and montmorillonite is particularly preferred. These solid oxides may be used by carrying a heteropolyacid such as phosphotungstic acid or chemolybdic acid.

 Among these brenstead acids, hydrobromic acid and methanesulfonic acid are preferred.

 These acids can be used alone or in combination of two or more. The amount of the acid to be used is generally 0.01 to 1 mol, preferably 0.05 to 0.5 mol, more preferably 0.05 to 0.5 mol, per 1 mol of the bromoalkylbenzene regioisomer mixture. In the range of 1 mole.

 Further, water may be present as a cocatalyst, and the amount thereof is 0.001-1 mol, preferably 0.05-0.1 mol, per 1 mol of the bromoalkylbenzene regioisomer mixture. Range.

 To cause the cyclization reaction, the bromoalkylbenzene regioisomer mixture may be brought into contact with an acid, and there is no particular limitation. The reaction temperature is in the range of −50 to + 100 ° C., preferably −20 to 150 ° C., and the reaction time is 5 minutes to 20 hours, preferably 5 minutes to 1 hour. The range is 0 hours.

Separation operation

The cyclized compound formed by cyclization of (ω-1) -bromoalkylbenzene in the above reaction has a large difference in boiling point or polarity from the target compound, ω-bromoalkylbenzene. Can be separated. For example, the boiling point of the target compound, 4-bromobutylbenzene [ω-bromo compound 1 is 24 (TC ^ 6 O mmHg, and 3-bromobutylbenzene [( ω-1) bromo compound] has a boiling point of 230 ° CZ76 O mmHg. Since the boiling point difference between the two is only 10 ° C. at normal pressure, it is very difficult to separate the regioisomer mixture by distillation. On the other hand, the boiling point of 1,2,3,4-tetrahydronaphthylene [cyclized compound], which is a cyclized compound of 3_bromobutylbenzene, is 206 ° CZ76 O mmHg, The boiling point difference is 34 ° C at normal pressure. Therefore, after distilling off the cyclized compound from the acid-treated mixture of the bromoalkylbenzene regioisomers, the target compound can be efficiently obtained.

 Operations such as distillation and chromatography can be performed according to a conventional method. For example, after acid treatment (end of the cyclization reaction), water is added to the reaction system to decompose acidic compounds, extracted with an organic solvent, and the organic phase is washed with water, saturated aqueous sodium hydrogen carbonate, and then saturated brine. Wash. After drying the organic phase with a desiccant, the organic solvent is distilled off and distilled under reduced pressure to obtain the target compound ω-bromoalkylbenzene. The degree of vacuum at the time of distillation is preferably 0.1 to 1 OmmHg. The bath temperature at this time is desirably 180 ° C or lower in order to prevent decomposition of the target substance. Also, for the reasons described above, distillation can be carried out using a simple rectification column. As the rectification tower, for example, various rectification towers such as Hempel, Igruy and Wittma can be used.

 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Reference example (Preparation of a mixture of 4-bromobutylbenzene and 3-bromobutylbenzene)

 4-5.3 1-butene 66.1 g (0.5 mol) was blown with 0.53 mol of hydrogen bromide gas under ice-cooling for 2 hours, and further reacted at the same temperature for 1.5 hours. Was. After the completion of the reaction, water was added, the organic phase was separated, and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The organic phase was dried to obtain 103.1 g of a crude product. At this time, the yield of the crude product based on 4-phenyl-11-butene was 96.7%. According to GC analysis, 45.1-bromobutylbenzene (hereinafter referred to as “4_bromo compound”) in this crude product was 95.1%, and 3-bromobutylbenzene (hereinafter referred to as “3_bromo compound”). ) Had a 2.7% composition.

Example 1 43.2 g (0.193 mol of 4-bromo compound, 0.005 mol of 3-bromo compound) of the crude product obtained in Reference Example was cooled on ice, and iron trichloride was added. 4 g (3.1 mol% of the crude product) was added and reacted at the same temperature for 1.5 hours. After completion of the reaction, water was added to the reaction system, extracted with toluene, and the organic phase was washed with water, washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine. The organic phase was dried, and the solvent was distilled off. Then, the residue was distilled under reduced pressure (with a 30 cm ゥ igulu fractionating column) to obtain 1.3 g of 1,2,3,4-tetrahydronaphylene. 0.01 mol) at 70.0-88.0 ° C./4.5 mmHg, to give 38.9 g (0.183 mol) of a 4-bromo compound. The yield of the 4-bromo compound relative to the above crude product was 90.0%, and no 3-bromo compound was detected. 4 The boiling point of 1-bromobutylbenzene was 100 to 100 ° C./4.5 mmHg.

Incidentally, 1, 2, 3, 4-tetrahydronaphthyl evening Ren ¹ H- NMR (Unit: ppm): 6 (CD CL 3, TMS reference) 7. 1 (m, 4 H , A r -H) 2. 8 (t, 4H, Ar-CH ₂ ~) 1.8 (t, 4 H, Ar-CH _g -CH _g- ) Example 2

 1.0 g of the crude product obtained in Reference Example was ice-cooled, 12.1 mg (1.6 mol%) of iron trichloride was added, and the mixture was reacted at the same temperature for 2 hours. After the reaction, the reaction was carried out in the same manner as in Example 1 to obtain a 4-bromo compound. The 3-bromo compound content in the obtained 4-bromo compound was 0.26%.

Example 3

 To 2.0 g of the crude product obtained in the Reference Example, 2 Omg of aluminum trichloride (1.6 mol%) was added under ice-cooling, and the mixture was reacted at the same temperature for 25 minutes. After the reaction, the reaction was carried out in the same manner as in Example 1 to obtain a 4-bromo compound. No 3-bromo compound was detected in the obtained 4-bromo compound.

Comparative Example 1

The crude product obtained in the reference example 5 5. Og was distilled under reduced pressure (30 cm Widariu fractionator) to give the 4-monobromo compound (102 to 103 ° C / 4 mmHg) 28 8 g were obtained. The recovery of the 4-monobromo compound with respect to the crude product was 52.4%, and the content of the 3-bromo compound was 1.37%. The obtained 4-bromo compound is Redistillation was carried out under the same conditions as above, but the content of the 3-bromo compound was almost the same as before distillation.

Claims

The scope of the claims  1. Equation (1)

 [In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and n represents an integer of 1 to 5. ] Formula (2) in which the content of (ω-1) -bromoalkylbenzene represented by the following formula is not more than 0.50 wt% with respect to ω-bromoalkylbenzene represented by the following formula (2).

[In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and η represents an integer of 1 to 5. ] Ω-Promoalkylbenzene represented by  2. The ω-pro according to claim 1, wherein the content of (ω-1) -bromoalkylbenzene is 0.40% by weight or less based on ω-bromoalkylbenzene. 3. The ω-pro according to claim 1, wherein the content of (ω-1) -promoalkylbenzene is 0.30% by weight or less based on ω-bromoalkylbenzene. 4. The ω-bromoalkylbenzene according to any one of claims 1 to 3, wherein η in the formulas (1) and (2) is an integer of 1 to 3.  5. The ω-bromoalkylbenzene according to any one of claims 1 to 3, wherein η in the formulas (1) and (2) is an integer of 2. 6. Equation (2)

 [In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and n represents an integer of 1 to 5. ] Formula (1) with ω-bromoalkylbenzene represented by

 [In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and n represents an integer of 1 to 5. ] Contacting an acid with a bromoalkylbenzene mixture containing (ω-1) -promoalkylbenzene represented by the following formula, and then separating the ω-bromoalkylbenzene represented by the formula (2): Method for producing ω-bromoalkylbenzene.  7. The method according to claim 6, wherein η in the formulas (1) and (2) is an integer of 1 to 3.  8. The method according to claim 6, wherein η in the formulas (1) and (2) is 2.  9. The ratio of ω-promoalkylbenzene and (ω_1) -bromoalkylbenzene in the bromoalkylbenzene mixture contacted with an acid is in the range of 80:20 to 98.5: 1.5. 9. The production method according to any one of paragraphs 8.  10. The ratio of ω-promoalkylbenzene and (ω-1) -bromoalkylbenzene in the bromoalkylbenzene mixture contacted with acid is 85: 15 ~ 98.5: The production method according to any one of claims 6 to 8, which is in the range of 1.5. 1 1. As the acid, use at least one selected from 0.001 to 1 mole of Lewis acid and Brensted acid with respect to 1 mole of the bromoalkylbenzene mixture. The production method according to any one of claims 6 to 10.  12. The production method according to any one of claims 6 to 10, wherein a Lewis acid is used as the acid.  13. The method according to claim 12, wherein after the contact treatment with an acid, water is added to the reaction system to decompose the acid, and the desired ω-bromoalkylbenzene is obtained from the extract using an organic solvent. .  1 4. The bromoalkylbenzene mixture contacted with an acid is represented by the formula (3)

[In the formula, R represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and η represents an integer of 1 to 5. ] Ω-Phenyl-1 represented by the formula (1) which is obtained by reacting monoargen with hydrogen bromide and which is by-produced with the ω-bromoalkylbenzene represented by the formula (2) 1) The production method according to any one of claims 6 to 13, which is a reaction product containing monobromoalkylbenzene.  15. The method according to claim 14, wherein η in the formula (3) is an integer of 1 to 3.  16. The method according to claim 14, wherein η in the formula (3) is 2.  1 7. The reaction of ω-Feuniru 1 —alkene and hydrogen bromide represented by the formula (3) is peroxidized to 0.001 to 5 times the molar amount of the ω-Feuniru-1-alkene. The method according to any one of claims 14 to 16, which is carried out in the presence of a catalyst comprising a substance.