JPH06192170A - Production of 4-bromomethylbiphenyl compound - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate for pharmaceuticals on an industrial scale at a low cost by brominating a spe cific compound in a halogenated hydrocarbon solvent in the presence of an azobis compound. CONSTITUTION:The objective compound of formula II is produced by brominating a compound of formula I [R is cyano, carboxyl which may be esterified or amidated or (substituted)tetrazolyl] with a bromination agent (e.g. N-bromosuccinimide) in a halogenated hydrocarbon solvent (preferably methylene chloride) in the presence of an azobis compound [preferably 2,2'-azobis(2,4- dimethylvaleronitrile)].

Description

Detailed Description of the Invention

[0001]

The present invention relates to a general formula useful as a synthetic intermediate for pharmaceuticals.

[0002]

[Chemical 3]

(In the formula, R means cyano, carboxyl which may be esterified or amidated, or tetrazolyl which may be substituted.) A 4-bromomethylbiphenyl compound (hereinafter, referred to as compound ( (I) may be referred to)) as an industrially advantageous production method.

[0004]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 63-23868 discloses a biphenylmethylimidazole compound having an angiotensin II antagonistic effect and useful as an antihypertensive agent or a therapeutic drug for congestive heart failure and the like, and a synthetic intermediate thereof. As compound (I) in the presence of dibenzoyl peroxide in the presence of dibenzoyl peroxide in a carbon tetrachloride solvent as the corresponding 4-
It is described to be produced by brominating a methylbiphenyl compound with N-bromosuccinimide.

[0005]

However, the above method is dangerous because it uses explosive dibenzoyl peroxide and is industrially problematic. Further, 90% of the charged amount remains after the completion of the reaction, and a large amount of alkaline substance is required for the treatment. On the other hand, when it is desired to use a small amount, light irradiation is required, and it is well known that this means is not industrially suitable. Furthermore, although the reaction is an exothermic reaction, it is extremely difficult to control the heat of reaction because it ends in an extremely short time of 15 to 20 minutes. Moreover, the yield is not as high as 60%.

Therefore, there has been a demand for the development of an industrial method for safely producing the desired compound (I) in a high yield under mild conditions.

[0007]

Means for Solving the Problems The inventors of the present invention have made extensive studies to solve the above-mentioned problems, and found that the corresponding 4-methylbiphenyl compound is present in a halogenated hydrocarbon solvent in the presence of an azobis compound. It was found that the compound (I) can be safely produced in a high yield under mild conditions by bromination of the compound, and completed the present invention. That is, the present invention is a halogenated hydrocarbon solvent in the presence of an azobis compound,

[0008]

[Chemical 4]

A compound (I) characterized by brominating a 4-methylbiphenyl compound represented by the formula (wherein R has the same meaning as defined above) (hereinafter sometimes referred to as compound (II)). ) Is a 4-bromomethylbiphenyl compound.

In the present specification, as a substituent of tetrazolyl which may be substituted, about 1 to 3 phenyl groups (the phenyl group is 1 to 3 halogen atoms, alkyl groups, alkoxy groups, hydroxyl groups, 1 to carbon atoms which may be substituted with a nitro group or the like)
Examples thereof include 6 linear or branched alkyl groups.

The carboxyl which may be esterified or amidated is represented by the formula --COOR ¹ or --CONR ² R ³ (wherein R ¹ , R ² and R ³ are hydrogen, hydroxyl group, amino group, Halogen atom,
An alkoxy group having 1 to 4 carbon atoms or a phenyl group having about 1 to 3 carbon atoms (the phenyl group is 1 to 3 halogen atoms,
Optionally substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, etc.) or a straight chain having 1 to 6 carbon atoms or A branched alkyl group is shown. ) And the like.

Compound (I) produced by the method of the present invention
Specific examples of the compound include 4'-bromomethylbiphenyl-2-carbonitrile, 4'-bromomethylbiphenyl-2-carboxylic acid or its methyl, ethyl, isopropyl, tertiary butyl, benzyl or p-nitrobenzyl. Ester, 4'-bromomethylbiphenyl-2
-Carboxamide or its N-methyl, ethyl, isopropyl, tert-butyl, benzyl or p-nitrobenzyl derivative, N-triphenylmethyl-5- (4'-
Bromomethylbiphenyl-2-yl) tetrazole, N
Examples include -tert-butyl-5- (4′-bromomethylbiphenyl-2-yl) tetrazole and the like.

The brominating agent used in the bromination of the method of the present invention includes bromine-containing organic compounds such as N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, N-bromomaleimide and N-bromosulfonamide. Among these, N-bromosuccinimide or N-bromophthalimide is preferably used. The amount used is about 0.5 to 2 times the molar amount of the starting compound (II).

The azobis compounds used in the present invention have the general formula

[0015]

[Chemical 5]

(In the formula, R ⁴ and R ⁵ are each hydrogen or a hydroxyl group, an amino group, an imino group, a halogen atom or a linear or branched chain which may be substituted with an alkoxy group having 1 to 4 carbon atoms. Or a salt thereof, which represents an alkyl group or R ⁴ and R ⁵ combine to form a ring.

As the azobis compounds of the above formula, 2,
2'-azobisisobutyronitrile, 2,2'-azobis (2,4-dimethylvaleronitrile), 2,2'-azobis (2-methylbutyronitrile), azobisisovaleronitrile, 1,1 '-Azobis (cyclohexanecarbonitrile), 2,2'-azobis (4-methoxy-
2,4-dimethylvaleronitrile), 2,2'-azobis (2-amidinopropane) hydrochloride, dimethyl 2,2 '
-Azobisisobutyrate, etc., preferably azobisnitrile, more preferably 2,2'-azobisisobutyronitrile, 2,2'-azobis (2,4-dimethylvaleronitrile), among which 2,2 '-Azobis (2,4-
Dimethylvaleronitrile) is preferably used. The amount used may be about 0.1 to 3% with respect to the brominating agent, and preferably 2,3 ', 2,2'-azobis (2,2'-azobisisobutyronitrile). In the case of 4-dimethylvaleronitrile), it is 0.1 to 0.3%. The halogenated hydrocarbon solvent used is methylene chloride, chloroform, dichloroethane, carbon tetrachloride, bromochloroethane, bromoethane, etc., with methylene chloride being most suitable.

The reaction is carried out at a temperature under reflux for about 30 minutes to 5 minutes.
Although it will be completed in about a while, the reaction stops when the reflux is stopped. Also, depending on the substance, if the reaction is continued for 5 hours or more,
Bromine is liberated and only brown crystals are obtained.

After completion of the reaction, the desired product can be isolated and purified by a conventional method such as a recrystallization method or a chromatography method.

[0020]

By the method of the present invention, the desired compound (I) can be obtained safely and in high yield under mild conditions. In addition, by carrying out in methylene chloride, the reaction rate is higher than that in carbon tetrachloride.
It becomes slow and control of reaction heat in industrialization becomes extremely easy. The compound (I) obtained by the present invention can be used, for example, as a raw material for synthesizing an angiotensin II antagonist described in JP-A-63-23868.

[0021]

The present invention will be specifically described below with reference to Examples and Comparative Examples, but it goes without saying that the present invention is not limited to these.

Example 1 180 g of methylene chloride, 63.2 g of 4'-methylbiphenyl-2-carbonitrile, 58.8 g of N-bromosuccinimide and 2,2'-azobis in a four-dimensional glass container equipped with a stirrer and a cooler. 90 mg of (2,4-dimethylvaleronitrile) was added and heated, and the mixture was reacted with stirring under reflux at an internal temperature of 45 to 47 ° C for 3 hours. Then, after maintaining the reflux as it is for 1 hour, it was cooled and 200 g of water at an internal temperature of 35 to 38 ° C.
Is added and liquid separation is performed twice to remove succinimide as a by-product of the reaction in the aqueous layer. The methylene chloride layer is gradually cooled to 0 ° C. to precipitate white crystals. The white crystals were filtered off, washed with cold methylene chloride and dried,
4'-Bromomethylbiphenyl-2-carbonitrile 7
1.6 g was obtained. Yield 80.5%

Example 2 In the same manner as in Example 1, 900 mg of 2,2'-azobisisobutyronitrile was used in place of 2,2'-azobis (2,4-dimethylvaleronitrile), and a similar reaction treatment was carried out to obtain white. 70.5 g of 4′-bromomethylbiphenyl-2-carbonitrile was obtained. Yield 79.2%

Example 3 In place of 4'-methylbiphenyl-2-carbonitrile in Example 1, 69.4 g of 4'-methylbiphenyl-2-carboxylic acid was used, and a similar reaction treatment was carried out to obtain white 4 '-Bromomethylbiphenyl-2-carboxylic acid 7
6.6 g was obtained. Yield 80.5%

Example 4 In Example 3, the solvent was carbon tetrachloride and the internal temperature was 77 to 7.
When carried out at the reflux temperature of 8 ° C., the reaction was completed in 1 hour. As a result of the same treatment, 71.9 g of white 4′-bromomethylbiphenyl-2-carboxylic acid crystal was obtained. Yield 75.5%

Example 5 In place of 4'-methylbiphenyl-2-carbonitrile in Example 1, 69.1 g of 4'-methylbiphenyl-2-carboxylic acid amide was used, and a similar reaction treatment was carried out to give a white product. 57.4 g of 4'-bromomethyl biphenyl-2-carboxylic acid amide was obtained. Yield 60.5%

Example 6 15 g of methylene chloride, 3.0 g of N-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) tetrazole and N-bromosuccinimide in a four-diameter glass container equipped with a stirrer and a condenser. 1.13 g and 2,2′-azobis (2,4-dimethylvaleronitrile) 1.7 mg were put and heated, and the mixture was stirred and reacted under reflux at an internal temperature of 42 ° C. for 11.5 hours (the reaction was slow and the starting material was reduced to 5 hours). Remains about half). After completion of the reaction, the reaction mixture was cooled to room temperature, and then 15 ml of water was added to perform liquid separation, which was repeated twice. The solvent was distilled off to obtain 3.51 g of a yellow solid. This solid was dissolved in 30 ml of a methylene chloride-ethyl acetate (1: 1) mixed solution, and then about 1
Concentrated to / 3. The mixture was stirred under ice cooling to precipitate white crystals. The white crystals were filtered off, washed with 5 ml of ethyl acetate and dried to give N-triphenylmethyl-5-
2.93 g (yield 83.8%) of (4'-bromomethylbiphenyl-2-yl) tetrazole was obtained. Melting point 137
~ 138 ° C

NMR δ (90 MHz, CDCl ₃ ): 4.37 (2H, s, CH ₂ ),
6.83-8.20 (23H, m, Ar)

Example 7 10 g of methylene chloride, 0.92 g of N-tert-butyl-5- (4'-methylbiphenyl-2-yl) tetrazole and N-bromosuccinimide were placed in a four-diameter glass container equipped with a stirrer and a condenser. 0.57 g and 2,2′-azobis (2,4-dimethylvaleronitrile) 0.8 mg were put and heated, and the mixture was reacted under stirring at reflux of an internal temperature of 42 ° C. for 23 hours (the reaction was slow and most of the reaction took 5 hours). Raw materials remain).
After completion of the reaction, the operation of cooling to room temperature and adding 20 ml of water to carry out liquid separation was performed twice. The solvent was distilled off to obtain 1.49 g of an orange solid. This solid was dissolved in 30 ml of a mixed solution of methylene chloride-ethyl acetate-hexane (1: 1: 1) and then concentrated to about 1/10. Hexane (1 ml) was added and the mixture was stirred under ice cooling to precipitate pale yellow crystals. The pale yellow crystals were filtered off, washed with 3 ml of ethyl acetate and dried to give 0.88 g of N-tert-butyl-5- (4′-bromomethylbiphenyl-2-yl) tetrazole (yield 75.3%). ) Got. Melting point 117.5-118.5 ° C

NMR δ (90 MHz, CDCl ₃ ): 1.65 (9H, s, Me), 4.
50 (2H, s, CH ₂ ), 7.32-8.02 (8H, m, Ar)

Example 8 In Example 1, the solvent was carbon tetrachloride and the internal temperature was 80 to 8
When the reaction was carried out at a reflux temperature of 2 ° C., the reaction time was 15 minutes, and the same treatment as described below was performed to obtain white crystals of 4′-bromomethylbiphenyl-2-carbonitrile. Yield 75%

Example 9 In Example 1, the solvent was chloroform and the internal temperature was 64 to
When it is carried out at a reflux temperature of 65 ° C., the reaction is completed in 30 minutes,
As a result of the same treatment, 64.5 g of white 4'-bromomethylbiphenyl-2-carbonitrile was obtained. Yield 72.5%

Example 10 When the solvent in Example 1 was bromochloromethane and the internal temperature was 71 to 74 ° C. at the reflux temperature, the reaction was completed in 50 minutes. As a result of the same treatment, 62.7 g of white 4′-bromomethylbiphenyl-2-carbonitrile crystals were obtained. Yield 70.5%

Example 11 In Example 1, the solvent was bromoethane and the internal temperature was from 41 to 41.
When performed at a reflux temperature of 43 ° C., the reaction time is 4 hours, and
As a result of the same treatment, 67.2 g of white 4′-bromomethylbiphenyl-2-carbonitrile was obtained. Yield 70.2%

Example 12 Using N-bromoacetamide instead of N-bromosuccinimide as the brominating agent in Example 1,
The same reaction treatment was performed to obtain white 4'-bromomethylbiphenyl-2-carbonitrile.

Example 13 Instead of N-bromosuccinimide as the brominating agent in Example 1, 76.2 g of N-bromophthalimide was used.
In the same manner as above, followed by cooling to an internal temperature of 35 to
The operation of adding 200 g of a 0.2% aqueous sodium hydroxide solution at 38 ° C. and performing liquid separation is performed twice to remove the phthalimide as a reaction by-product in the aqueous layer. Then, the same treatment as in Example 1 was carried out to obtain 66.4 g of white 4′-bromomethylbiphenyl-2-carbonitrile. Yield 79.6%

Example 14 Carbon tetrachloride was used as the solvent in Example 1, 76.2 g of N-bromophthalimide was used as the brominating agent instead of N-bromosuccinimide, and the internal temperature was 77-78 ° C at the reflux temperature. When carried out, the reaction was completed in 1 hour. Less than,
The same treatment as in Example 13 was performed to obtain 63.6 g of white 4′-bromomethylbiphenyl-2-carbonitrile.
Yield 71.5%

Comparative Example 1 Instead of 2,2'-azobis (2,4-dimethylvaleronitrile) in Example 5, dibenzoyl peroxide was used in double amount as used in JP-A-63-23868. 2.8 g was used and the reaction was carried out in carbon tetrachloride having an internal temperature of 80 to 82 ° C. under reflux, the reaction was completed in 15 minutes, and the same treatment as described below was performed. As a result, white 4′-bromomethylbiphenyl-2 was obtained. -Carbonitrile 58.9 g crystals were obtained. Yield 65.5%

Comparative Example 2 In Comparative Example 1, the amount of dibenzoyl peroxide was adjusted to 3
When the amount is 78 mg and infrared irradiation is also used, the reaction is 20
Finished in minutes. As a result of similar processing, white 4'-
Bromomethylbiphenyl-2-carbonitrile 57.9
g crystals were obtained. Yield 65.1%. The reaction did not occur without infrared irradiation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 255/50 9357-4H C07D 257/04 7433-4C // C07C 69/76 A 9279-4H

Claims (5)

[Claims] 1. A compound represented by the general formula: ## STR1 ## in a halogenated hydrocarbon solvent in the presence of an azobis compound. (Wherein R means cyano, carboxyl which may be esterified or amidated, or tetrazolyl which may be substituted). The compound represented by the general formula: 2] (In the formula, R has the same meaning as above) 4-
Process for producing bromomethylbiphenyl compound. 2. The method according to claim 1, wherein the halogenated hydrocarbon solvent is methylene chloride. 3. The method according to claim 1, wherein N-bromosuccinimide or N-bromophthalimide is used as the brominating agent. 4. The method according to claim 1, wherein the azobis compound is 2,2′-azobis (2,4-dimethylvaleronitrile). 5. The method of claim 1, wherein R is cyano.