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WO2004103947A1 - Procede de production d'un compose d'ester carboxylique aromatique a substitution bromomethyle - Google Patents

Procede de production d'un compose d'ester carboxylique aromatique a substitution bromomethyle Download PDF

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Publication number
WO2004103947A1
WO2004103947A1 PCT/JP2003/006249 JP0306249W WO2004103947A1 WO 2004103947 A1 WO2004103947 A1 WO 2004103947A1 JP 0306249 W JP0306249 W JP 0306249W WO 2004103947 A1 WO2004103947 A1 WO 2004103947A1
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WIPO (PCT)
Prior art keywords
compound
bromine
bromomethyl
reaction
oxidizing agent
Prior art date
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Ceased
Application number
PCT/JP2003/006249
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English (en)
Japanese (ja)
Inventor
Seiji Yamada
Ken Ishihara
Toshio Nakamatsu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Chemical Co Ltd filed Critical Sumitomo Chemical Co Ltd
Priority to JP2004572088A priority Critical patent/JPWO2004103947A1/ja
Priority to PCT/JP2003/006249 priority patent/WO2004103947A1/fr
Priority to AU2003234832A priority patent/AU2003234832A1/en
Publication of WO2004103947A1 publication Critical patent/WO2004103947A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms

Definitions

  • the present invention relates to a method for producing a bromomethyl-substituted aromatic carbonate compound such as 4′-bromomethylbiphen-2-ru-carboxylic acid t ⁇ rt-butyl ester, which is useful as an intermediate for the synthesis of pharmaceuticals.
  • Bromomethyl-substituted aromatic carboxylic acid ester compounds are useful as intermediates in the synthesis of pharmaceuticals, for example, compounds having angiotensin II antagonistic activity (JP-A-63-23868). Various methods for producing a bromomethyl-substituted aromatic carboxylic acid ester compound have been reported so far.
  • JP-63 -23868 discloses, in European Patent No. 253310 Pat Contact and Kohyo Publication 2002-542227 Publication, the presence of Azobisu compound, N- flop port succinimide (NBS) or N, N 5
  • NSS N- flop port succinimide
  • N 5 A method for brominating 4, -methylbiphenyl-2-carbonate using a brominating agent such as 5,5-dimethylhydantoin (DDH) has been reported.
  • this method uses an expensive N-promosuccinimide or the like as a brominating agent, which is industrially disadvantageous.
  • Japanese Patent Application Laid-Open No. 10-279533 reports a method for producing a 4′-bromomethylbiphenyl_2-carboxylate compound by reacting with inexpensive bromine as a brominating agent in the presence of a radical initiator.
  • JP-A-11-130 No. 708 discloses a method for producing a bromomethyl-substituted benzoate by a similar method.
  • carboxylic acid esters, particularly tert-butyl esters are hydrolyzed because hydrogen bromide is by-produced.
  • hydrogen bromide produced as a by-product hinders the reaction, and bromine remains in the reaction system, so that the product is colored and further purification is required for industrial use.
  • Japanese Patent Application Publication No. 2001-518904 reports a method of performing bromination with an aqueous solution of hydrobromic acid or bromine in the presence of hydrogen peroxide.
  • carboxylic acid esters particularly tert-butyl esters
  • An object of the present invention is to provide a method capable of industrially producing a bromomethyl-substituted aromatic carboxylic acid ester compound such as tert-butyl 4'-bromomethylbiphenyl-2-carboxylate. It is.
  • the present inventors have conducted intensive research to solve the above-mentioned problems. That is, in the reaction between a methyl-substituted aromatic carboxylic acid ester compound and bromine in the presence of a radical initiator, coexistence of an oxidizing agent immediately converts by-produced hydrogen bromide into bromine. It has been found that the hydrolysis of the carboxylic acid ester by arsenic does not proceed and the reaction proceeds without being inhibited. In addition, the reaction was completed with 0.5 equivalent of bromine, and it was found that a bromomethyl-substituted aromatic carboxylic acid ester compound could be economically produced, and the present invention was completed.
  • the present invention is as follows.
  • R 1 represents a lower alkyl group or an aralkyl group
  • X represents a bond or an aromatic group
  • Y represents a divalent group which cannot react with a bond or bromine.
  • the “lower alkyl group” represented by R 1 includes linear or branched alkyl having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, izopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like, and preferably methyl, ethyl and tert-butyl.
  • the “aralkyl group” represented by R 1 is an aralkyl group having 1 to 8 carbon atoms, for example, For example, benzyl, 1-phenyl, 2-phenethyl and the like can be mentioned, and preferably benzyl and the like can be mentioned.
  • aromatic ring represented by X
  • aromatic hydrocarbon eg, benzene, naphthylene, phenanthrene, etc.
  • aromatic heterocycle eg, pyridine, etc.
  • Preferable examples of X include a bond, benzene, naphthalene and the like.
  • the “group that cannot react with bromine” represented by Y is not particularly limited as long as it is not brominated by bromine.
  • Y is not particularly limited as long as it is not brominated by bromine.
  • one 0—, — C ( 0) —, one CONH—, — S 0 2 — or a group formed by removing any two hydrogen atoms on the aromatic group exemplified by X (eg, p, m or o-phenylene, pyridylene, etc.).
  • X eg, p, m or o-phenylene, pyridylene, etc.
  • Preferred examples of Y include a bond.
  • the synthesis scheme of the production method of the present invention is as follows.
  • Oxidizing agent The present invention is achieved by, for example, reacting compound (I) with bromine in a solvent in the presence of a radical initiator and an oxidizing agent.
  • the order of addition of the reagents is not particularly limited. However, from the viewpoint of operability, bromine or a solution thereof (preferably radical-initiated (At the same time as the agent or its solution). Further, in order to make the reaction proceed smoothly, it is preferable to carry out the reaction mixture with stirring.
  • the compound (I) used in the present invention is not limited as long as it can be defined by the above-mentioned symbols, and examples thereof include toluic acid esters in which benzoic acid is substituted by a methyl group, and phenyl such as biphenyl carboxylic acid.
  • Examples include 4′-methylbiphenyl-2-capronic acid ester bonded to benzoic acid through a group, but it is possible to use it as a synthetic intermediate of a compound having angiotensin II antagonistic action.
  • Methyl biphenyl-12-carboxylic acid tert-butyl ester is preferred.
  • the compound (I) as a raw material in the present invention for example, 4-methylbiphenyl-12-carboxylic acid ester, can be produced by a known method, for example, the method described in JP-A-2000-26372. Can be.
  • the amount of bromine used is 0.4 to 0.7 mol, preferably 0.45 to 0.60 mol, more preferably 0.48 to 1 mol of compound (I) as a raw material. ⁇ 0.53 mol.
  • the amount of bromine used is less than 0.4 mol per 1 mol of the compound (I), unreacted raw materials tend to remain easily. Tends to increase.
  • a radical initiator such as an azobis compound or a peroxide is used.
  • azobis compounds 2,2'-azobis (4-methoxy-1,2,4-dimethylvaleronitrile), 2,2, -azobisisobutyronitrile, 2,2, -azobis (2 —Methylbutyronitrile), 2,2, —azobis (2,4-dimethylvaleronitrile);
  • peroxides include dibenzoyl peroxide, ditert_butyl peroxide and the like, and preferably 2, 2 ′ —Azobis (2-methylbutyronitrile) and 2,2,1-azobis (2,4-dimethylvalero nitrile).
  • the amount of the radical initiator to be used is 0.1 to 10 mol%, preferably 1 to 4 mol%, relative to compound (I).
  • the amount of the radical initiator used is less than 0.1 mol% with respect to the compound (I)
  • the reaction tends to be slow, and when it exceeds 10 mol%, the effect corresponding thereto becomes small, It tends to be industrially disadvantageous.
  • oxidizing agents which are relatively safe to handle, for example, bromates such as sodium bromate and bromic acid rim; chlorates such as sodium chlorate and potassium chlorate And preferably sodium bromate.
  • the amount of the oxidizing agent used may be a theoretical amount necessary for regenerating hydrogen bromide by-produced into bromine or a slight excess thereof, and is 9 to 30 moles relative to compound (I). %, Preferably 20 to 30 mol%.
  • the amount of the oxidizing agent is less than 9 mol% based on the compound (I)
  • bromine is not sufficiently regenerated and the yield tends to decrease. The corresponding effect is reduced and tends to be industrially disadvantageous.
  • Examples of the solvent used in the present invention include aliphatic esters, alkanes having 5 to 7 carbon atoms or halogenated hydrocarbons. Specific examples include methyl acetate, ethyl acetate, methyl propionate, ethyl propionate, and hexane. , Heptane, cyclohexane, methylene chloride, ethylene dichloride, carbon tetrachloride, monochlorobenzene, o-dichlorobenzene, and promobenzene. Of these, aliphatic esters are preferred, and especially ethyl acetate is preferred.
  • the amount of the solvent to be used is generally 0.5 to 20-fold weight, preferably 1 to 20-fold weight, more preferably 1 to 15-fold weight, relative to compound (I). If it is less than this range, the stirring efficiency tends to be poor, and if it is more than this range, the reaction tends to be slow and disadvantageously disadvantageous.
  • the amount of water is 1 to 4 times the weight of the oxidizing agent used, preferably 2 to 3.5 times the weight. If the amount of water is less than 1 times the weight of the oxidizing agent used, the oxidizing agent does not dissolve sufficiently, and the reaction selectivity tends to decrease. If the amount of water exceeds 4 times the weight, the volumetric efficiency is poor. Productivity tends to decrease.
  • the reaction temperature varies depending on the radical initiator and the like, but is usually 30 to 70 ° C, preferably 40 to 60 ° C. If it is lower than this range, the reaction tends to be slow, and if it is higher than this range, the radical initiator tends to be unstable, and it tends to be industrially meaningless.
  • the reaction time is also appropriately determined according to the various reaction conditions described above (for example, about 3 to 10 hours).
  • the compound (II) such as 4'-bromomethylbiphenyl-l--2-carboxylic acid tert-butyl ester obtained by the above reaction is isolated and purified from the reaction mixture, but the method is not particularly limited. For example, after removing inorganic salts by filtration or the like as usual, if necessary, the solvent can be distilled off and recrystallized with another suitable solvent. It is preferable to perform isolation and purification.
  • the reaction solution is added by adding an aqueous alkaline solution (for example, an aqueous solution of sodium hydroxide, an aqueous solution of sodium carbonate, an aqueous solution of sodium hydrogen carbonate, etc.).
  • an aqueous alkaline solution for example, an aqueous solution of sodium hydroxide, an aqueous solution of sodium carbonate, an aqueous solution of sodium hydrogen carbonate, etc.
  • the bromination reaction is terminated by adjusting the pH to a range of 2 to 6 or by separating and washing the aqueous layer after completion of the reaction.
  • the organic layer is separated, and the solvent is concentrated under reduced pressure to such an extent that the compound (II) does not precipitate (0.5 to 1 times the weight of the compound (II)), and if necessary, the precipitated inorganic salt is removed by filtration or the like.
  • a poor solvent for compound (II) for example, a hydrocarbon-based solvent such as heptane or hexane
  • a seed crystal may be added for smooth crystallization. After filtering the precipitated crystals, the compound (II) can be isolated and purified by washing the filtrate and drying under reduced pressure.
  • the compound (II) obtained by the present invention for example, tert-butyl 4'-bromomethylbiphenyl-2-carboxylate, can be prepared by the method described in Drug of the Future 1997, 22 (10), 1112-1116.
  • a biphenylmethylimidazole compound useful as a pharmaceutical described in JP-A-63-23868 can be derived.
  • Ethyl acetate (169.1 g) and 4-methylbiphenyl-2-carboxylate t ⁇ rt monobutyl ester (100 g, 0.373 mol 1) were added to the reaction vessel, and the mixture was added to about 5 ml. Dissolved at 0 ° C. Then, a solution of sodium bromate (1.4.5 g, 0.093mo1) dissolved in 33.16 g of water was added. 2,2,1-Azobis (2-methyltyltyronitrile) (2.75 g, 0.0143mo1) was dissolved in ethyl acetate (20.52 g), and 4.31 g of the solution was dissolved. Was added into the reaction vessel.
  • bromine (31.33 g, 0.196mo 1) and the remainder of 2,2'-azobis (2-methylbutyronitrile) in ethyl acetate were added dropwise over 5 hours. did. It was kept at the same temperature for 1 hour. Then, ⁇ was adjusted to 5 to 7 by adding a 20% aqueous sodium hydroxide solution, and the mixture was allowed to stand and separated. The solution was concentrated and dehydrated at 50 to 70 ° C under a reduced pressure of 40 to 6 OKPa. When the water content of the concentrate reached 0.2%, the weight of the content was 250. Celite (2.38 g) was filtered through a pre-filter and washed with ethyl acetate (39.02 g).
  • the content of the filtrate was concentrated to 201 g, and heptane (122.78 g) was added dropwise at 60 to 70 ° C.
  • the mixture was cooled to 43 ° C over 2 hours, seed crystals (0.095 g) of 4′-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester were added, and the mixture was stirred at about 43 ° C for 2 hours.
  • the mixture was cooled to 25 to 35 ° C for about 5 hours and further to 0 to 5 ° C over 3 hours, and aged at 0 to -5 ° C for 5 hours.
  • the coexistence of sodium bromate as an oxidizing agent enables the conversion of the bromine from 0.5 equivalent to a slight excess with respect to the compound (I) as a raw material. It has been found that bromination can be performed with the amount used.
  • the production method of the present invention is a method capable of producing a bromomethyl-substituted aromatic carboxylic acid ester compound [compound (II)] more industrially than conventional methods.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de production d'un composé d'ester carboxylique aromatique à substitution bromométhyle représenté par la formule (II) et caractérisé en ce qu'il consiste à faire réagir un composé représenté par la formule (I) avec un brome, en présence d'un initiateur à radical libre et d'un agent oxydant. (Dans les formules, R1 représente un alkyle inférieur ou un aralkyle ; X désigne une liaison ou un noyau aromatique ; et Y représente une liaison ou un groupe divalent non réactif avec le brome.). Le procédé selon l'invention permet de produire, de manière plus efficace que des techniques classiques, au niveau industriel, un composé d'ester carboxylique aromatique à substitution bromométhyle représenté par la formule (II), utile comme intermédiaire dans des médicaments, par exemple, un composé possédant une activité antagoniste de l'angiotensine II.
PCT/JP2003/006249 2003-05-20 2003-05-20 Procede de production d'un compose d'ester carboxylique aromatique a substitution bromomethyle Ceased WO2004103947A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2004572088A JPWO2004103947A1 (ja) 2003-05-20 2003-05-20 ブロモメチル置換芳香族カルボン酸エステル化合物の製造方法
PCT/JP2003/006249 WO2004103947A1 (fr) 2003-05-20 2003-05-20 Procede de production d'un compose d'ester carboxylique aromatique a substitution bromomethyle
AU2003234832A AU2003234832A1 (en) 2003-05-20 2003-05-20 Process for producing bromomethyl-substituted aromatic carboxylic ester compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2003/006249 WO2004103947A1 (fr) 2003-05-20 2003-05-20 Procede de production d'un compose d'ester carboxylique aromatique a substitution bromomethyle

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WO2004103947A1 true WO2004103947A1 (fr) 2004-12-02

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AU (1) AU2003234832A1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109796338A (zh) * 2019-01-15 2019-05-24 深圳市第二人民医院 奥扎格雷中间体对溴甲基肉桂酸酯的合成方法
US10981861B1 (en) 2019-10-25 2021-04-20 Chang Sha Jia Qiao Biotech Co., Ltd. Bromination method for m-diamide compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6133468A (en) * 1997-07-30 2000-10-17 Basf Aktiengesellschaft Method for preparing substituted benzyl bromides
US6214999B1 (en) * 1997-11-17 2001-04-10 Sanofi-Synthelabo Method for preparing bromomenthyl-biphenyl derivatives
WO2003106406A1 (fr) * 2002-06-12 2003-12-24 住化ファインケム株式会社 Procede de production de 4'-bromomethyl-2-cyanobiphenyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6133468A (en) * 1997-07-30 2000-10-17 Basf Aktiengesellschaft Method for preparing substituted benzyl bromides
US6214999B1 (en) * 1997-11-17 2001-04-10 Sanofi-Synthelabo Method for preparing bromomenthyl-biphenyl derivatives
WO2003106406A1 (fr) * 2002-06-12 2003-12-24 住化ファインケム株式会社 Procede de production de 4'-bromomethyl-2-cyanobiphenyle

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109796338A (zh) * 2019-01-15 2019-05-24 深圳市第二人民医院 奥扎格雷中间体对溴甲基肉桂酸酯的合成方法
CN109796338B (zh) * 2019-01-15 2022-05-06 深圳市第二人民医院 奥扎格雷中间体对溴甲基肉桂酸酯的合成方法
US10981861B1 (en) 2019-10-25 2021-04-20 Chang Sha Jia Qiao Biotech Co., Ltd. Bromination method for m-diamide compounds
JP2021066720A (ja) * 2019-10-25 2021-04-30 長沙嘉橋生物科技有限公司 ｍ−ジアミド化合物の臭素化方法

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AU2003234832A1 (en) 2004-12-13
JPWO2004103947A1 (ja) 2006-07-20

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