JPWO2012014889A1 - Method for producing phthalonitrile derivative - Google Patents

Abstract

Reacting the compound represented by the formula (I) with bromine in the presence of water and a bromide salt to obtain a compound represented by the formula (II), and a compound represented by the formula (II): A compound of formula (III) comprising step 2 of reacting with a cyanide compound in the presence of a metal cyano complex and / or a 1,3-dicarbonyl compound to obtain a compound of formula (III) A manufacturing method is provided. In the formula, R 1 and R 2 each independently represent a C 1-6 alkyl group.

Description

  The present invention relates to a method for producing a phthalonitrile derivative. More specifically, the present invention relates to an industrial production method of a phthalonitrile derivative useful as a synthesis intermediate of a 2-isoindole derivative that is an excellent thrombin receptor antagonist.

  Recently, a compound having an antagonistic action on the thrombin receptor is expected to exert an excellent action effect in the treatment and prevention of diseases involving thrombin, such as thrombosis, vascular restenosis, deep vein thrombosis, It is effective for the treatment and prevention of pulmonary embolism, cerebral infarction, heart disease, disseminated intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disease, malignant tumor, etc. You can expect. Therefore, provision of a thrombin receptor antagonist that satisfies the points of pharmacological activity, receptor specificity for thrombin receptor, safety, dosage, oral utility, and the like is desired.

Under such circumstances, Patent Document 1 discloses 2-iminopyrrolidine derivatives and salts thereof as thrombin receptor antagonists having excellent thrombin receptor inhibitory activity. Among 2-iminopyrrolidine derivatives and salts thereof, 1- (3-tert-butyl-4-methoxy-5-morpholino-phenyl) -2- (5,6-diethoxy-) represented by the formula (A-1) As a method for producing 7-fluoro-1-imino-1,3-dihydro-2-isoindol-2-yl) -ethanone or a salt thereof, a compound represented by formula (A-2), a compound represented by formula (A- A method of coupling the compound represented by 3) in an N, N-dimethylformamide (DMF) solvent is described.

Furthermore, in Patent Document 1, as a method for producing a compound represented by formula (A-2), a compound represented by formula (B-II) is passed through a compound represented by formula (B-II). And a synthesis method is described. As a specific method of the compound represented by the formula (B-II) from the compound represented by the formula (BI), bromine or N-bromosuccinate in a solvent such as alcohol or acetonitrile under ice-cooled to room temperature conditions. A method in which an acid imide is allowed to act on a compound represented by formula (BI), or a method in which bromine is allowed to act on a compound represented by formula (BI) in the presence of sodium acetate in an acetic acid solvent at room temperature to 80 ° C. Is described.

  However, in this method, when the compound represented by the formula (BI) is o-dibrominated, a side reaction causes an m-dibromo isomer, an excessively brominated tribromo isomer, and a decomposition product due to side reactions. Generated, and it was difficult to obtain the desired o-dibromo compound with high selectivity, and purification was complicated. Furthermore, the production method on an industrial scale, such as requiring a large amount of a solvent such as acetic acid, has problems in terms of work and cost.

  On the other hand, Patent Document 2 describes a method for regioselectively producing a compound represented by the formula (B-II) using 4-bromo-2-fluorophenol as a raw material. However, since four steps are required for the production, a method for simple production in a shorter step has been demanded.

Patent Documents 1 and 3 describe a method for producing a compound represented by the formula (B-III) from a compound represented by the formula (B-II). Specifically, in Patent Document 1, the compound represented by the formula (B-II) and copper cyanide are mixed in a solvent such as dimethylformamide, dimethyl sulfoxide, N-methylpiperidone, hexamethylphosphoric triamide, or a mixed solvent thereof. To obtain a compound represented by the formula (B-III). In Patent Document 3, a compound represented by the formula (B-II) and copper cyanide are combined with 1,3-dimethyl-2- A compound represented by the formula (B-III) is obtained by reacting in an imidazolidinone (hereinafter sometimes referred to as DMI) solvent. However, these methods have a problem that a large amount of by-products are generated and the yield is low, and there is a problem as a manufacturing method on an industrial scale.

International Publication No. 02/085855 Pamphlet International Publication No. 06/018954 Pamphlet International Publication No. 06/018955 Pamphlet

  In order to provide the compound represented by the formula (A-1), which is useful as an excellent thrombin receptor inhibitor, at an industrially low cost, the formula (A-2) which is useful as a synthetic intermediate thereof. It is necessary to produce the compound represented by the industrially superior method at a low cost, and it is required to provide the compound represented by the formula (B-III) as its precursor at a low cost. Yes.

  In view of such circumstances, an object of the present invention is to provide a phthalonitrile derivative, which is a synthetic intermediate thereof, by a more excellent production method for industrial production of a 2-isoindole derivative, which is an excellent thrombin receptor antagonist. There is.

As a result of intensive studies in view of the above circumstances, the present inventors obtained a compound represented by the formula (II) by highly selective o-dibromination of the compound represented by the formula (I). Furthermore, the inventors have found that a phthalonitrile derivative represented by the formula (III) can be efficiently produced by nitrifying with high selectivity, and the present invention has been completed.

(In the formula, R ¹ and R ² each independently represent a C _1-6 alkyl group.)

That is, the present invention provides the following [1] and [2].
[1] Formula (I)

[Wherein, R ¹ and R ² each independently represent a C _1-6 alkyl group. The compound of formula (II) is reacted with bromine in the presence of water and a bromide salt.

[Wherein, R ¹ and R ² each independently represent a C _1-6 alkyl group. Step 1 for obtaining a compound represented by the formula:
A compound represented by the formula (II) is reacted with a cyanide compound in the presence of a metal cyano complex and / or a 1,3-dicarbonyl compound to give a compound of the formula (III)

[Wherein, R ¹ and R ² each independently represent a C _1-6 alkyl group. A step 2 of obtaining a compound represented by the formula:
A process for producing a compound represented by formula (III); and [2] The process according to [1], wherein the step 2 is carried out in the presence of an iodide salt.

  According to the present invention, a phthalonitrile derivative (III) useful as a synthetic intermediate of a thrombin receptor antagonist can be obtained with high yield and high purity by an inexpensive and efficient industrial production method.

  According to the present invention, the selectivity of the bromination step of the compound represented by the formula (I) is improved, and the amount of by-products to be generated can be greatly reduced as compared with the conventional case. improves. Furthermore, the yield of the nitrification step of the compound represented by formula (II) is also improved. Thereby, it is possible to provide a method for producing a phthalonitrile derivative (III) which is more efficient and inexpensive on an industrial scale than the conventional method, and at the same time, a 2-isoindole derivative (A-1) which is an excellent thrombin receptor antagonist. ) Useful industrial production methods.

  Hereinafter, the present invention will be described in detail with reference to definitions of symbols, terms, and the like described in the present specification, embodiments of the present invention, and the like. In addition, this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.

  In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but in the present invention, all geometrical isomers, stereoisomers, rotational isomers and tautomers that can occur in the structure of the compound are included in the present invention. It includes isomers such as isomers and isomer mixtures, and is not limited to the description of formulas for convenience, and may be either isomer or a mixture. In addition, there may be a crystal polymorph, but it is not limited in the same manner, and any single crystal form or a mixture of two or more crystal forms may be used. The compounds according to the present invention include compound salts, anhydrides, hydrates, solvates and the like.

  As used herein, “and / or” is used to mean including both “and” and “or”.

  As used herein, “to” is used to mean a range including numerical values before and after “to”.

[Step 1]

  The method for producing a compound represented by formula (III) according to the present invention is represented by formula (I) by reacting a compound represented by formula (I) with bromine in the presence of water and a bromide salt. Step 1 to obtain a compound. Step 1 is an o-dibromination step.

In the formulas (I) and (II), R ¹ and R ² each independently represent a C _1-6 alkyl group.

The “C _1-6 alkyl group” is a monovalent group derived by removing one arbitrary hydrogen atom from an aliphatic hydrocarbon having 1 to 6 carbon atoms, and is a straight chain having 1 to 6 carbon atoms. A chain or branched alkyl group is meant.

Specific examples of the C _1-6 alkyl group include, for example, methyl group, ethyl group, 1-propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, and 1-butyl. Group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-1-butyl group, 3-methyl-1-butyl group, 2-methyl-2-butyl group, 3 -Methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-methyl- 1-pentyl group, 4-methyl-1-pentyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,3-dimethyl-1-butyl group 3,3-dimethyl-1-butyl group, 2,2-dimethyl-1-butyl group, 2-ethyl-1-butyl group, 3,3-dimethyl-2-butyl group, 2,3-dimethyl-2 -A butyl group etc. are mentioned. As the C _1-6 alkyl group, a methyl group or an ethyl group is preferable, and an ethyl group is more preferable.

  Bromide salts include bromides having a counter cation that is not oxidized by bromine, preferably alkali metal bromides or alkaline earth metal bromides. Specific examples include lithium bromide, sodium bromide, potassium bromide, magnesium bromide, calcium bromide and barium bromide. Sodium bromide is preferred from the viewpoint of cost.

  In step 1, the reaction is performed in the presence of water, but water may be used as a solvent, or water may be added to a solvent other than water. As water, water usually used for the production of pharmaceuticals and pharmaceutical intermediates such as distilled water, ion-exchanged water and pure water can be used. Solvents other than water can be used as long as they do not inhibit the reaction, but those that are particularly stable against bromine and by-produced hydrogen bromide and do not inhibit the phase transfer process. It is preferable to use it. Examples of such solvents include hydrocarbon solvents such as pentane, hexane, and heptane; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; hydrobromic acid and the like. Examples thereof include inorganic acids that do not inhibit the bromination reaction and aqueous solutions thereof, and a plurality of solvents selected from these may be used in an arbitrary ratio.

  In the present invention, it is preferable to use only water without using other solvents because of the reaction rate and low environmental load.

  The bromide salt is usually 0.5 equivalents or more, preferably 0.8 equivalents or more, more preferably 1.0 equivalents per 1 equivalent of bromine used. If the amount is less than this, bromine may not completely dissolve in water, which may adversely affect selectivity. Moreover, it is 10 equivalent or less normally, Preferably it is 5 equivalent or less, More preferably, it is 2 equivalent or less. If more than this, more water is required to dissolve the bromide salt, which can adversely affect productivity.

  Bromine is usually 2.0 equivalents or more, preferably 2.2 equivalents or more, more preferably 2.4 equivalents or more with respect to 1 equivalent of the compound represented by the formula (I). When the amount is less than this, a large amount of unreacted intermediate remains, which may reduce the yield. Moreover, it is 3.0 equivalent or less normally, Preferably it is 2.8 equivalent or less, More preferably, it is 2.6 equivalent or less. When the amount is larger than this, excessive bromination may proceed to lower the yield.

  Although the solvent can be used in any amount, it is usually 1 to 10 times the volume, preferably 2 to 7 times the volume of the compound represented by the formula (I), more preferably 3 to 3 times the volume. 5 times volume.

  The reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C, more preferably 0 ° C to 30 ° C. The reaction time is usually 0.5 hours to 10 hours, preferably 1 hour to 5 hours.

  Step 1 is a two-phase reaction of an organic phase and an aqueous phase because the compound represented by the formula (I) and water are not compatible. It is considered that decomposition of the compound represented by the formula (I) can be suppressed because hydrogen bromide as a by-product is absorbed in the aqueous phase.

  In addition, bromine which is hardly soluble in water can be solubilized by the presence of a bromide salt. Thereby, a phase transfer reaction is possible, and it is considered that a bromination (o-dibromination) reaction with extremely high regioselectivity is possible.

  Step 1 is performed, for example, by preparing an aqueous solution of a bromine-bromide salt and adding this dropwise to the liquid compound represented by formula (I). At that time, it is preferable to sufficiently stir and mix so that the transfer of bromine from the aqueous phase to the organic phase and the transfer of by-produced hydrogen bromide from the organic phase to the aqueous phase are performed smoothly.

  After Step 1, it is usually preferable to deactivate bromine with sodium sulfite, sodium thiosulfate or the like, then add an organic solvent such as toluene, xylene, heptane, hexane or the like and wash with water.

  The compound represented by the formula (II) obtained in Step 1 is a liquid or a solid, and in the case of a solid, it may be necessary to add the aforementioned organic solvent in order to effectively perform the phase transfer process.

  The compound represented by the formula (II) can be isolated and purified by known means such as distillation, sublimation, silica gel chromatography, extraction or crystallization, if necessary, and these means can be used in combination. May be. In addition, if purification is not particularly necessary, it can be used in the next reaction as it is.

  Step 1 of the present invention enables a bromination (o-dibromination) reaction with a high reaction rate and high regioselectivity, and can efficiently obtain a compound represented by the high purity formula (II). . In addition, the cleaning process can be simplified as compared with the prior art.

[Step 2]

  The method for producing a compound represented by formula (III) according to the present invention comprises reacting a compound represented by formula (II) with a cyanide compound in the presence of a metal cyano complex and / or a 1,3-dicarbonyl compound. Step 2 to obtain a compound represented by the formula (III). Step 2 is a cyanation step.

In the formulas (II) and (III), R ¹ and R ² are as defined above.

Step 2
(I) a metal cyano complex; and / or (ii) a reaction in the presence of a 1,3-dicarbonyl compound.

  In step 2, the cyanide compound is capable of cyanating the compound represented by formula (II), dissolves to some extent in the reaction solvent used, and does not inhibit the reaction. There is no particular limitation as long as it is, for example, a salt having a cyanide ion such as sodium cyanide, potassium cyanide, copper cyanide, silver cyanide, zinc cyanide as an anion can be used. Further, a plurality of cyan compounds selected from these may be mixed at an arbitrary ratio. Preferably, copper cyanide is preferable because the reaction proceeds smoothly and is inexpensive and easy to handle.

  The cyanide compound is usually 2 equivalents or more, preferably 2.5 equivalents or more, more preferably 3.0 equivalents or more, relative to 1 equivalent of the compound represented by the formula (II). When the amount is less than this, a large amount of unreacted intermediate may remain and the yield may be reduced. Moreover, it is 10 equivalent or less normally, Preferably it is 5 equivalent or less, More preferably, it is 3.5 equivalent or less. When it is more than this, there is a possibility that the load of the process of removing the copper waste is increased.

  The metal cyano complex is not particularly limited as long as it is soluble to some extent in the reaction solvent to be used and does not inhibit the reaction. For example, potassium ferrocyanide, potassium ferricyanide, sodium ferrocyanide, sodium ferricyanide , A complex salt containing a cyano group such as potassium hexacyanocobalt (III), potassium hexacyanochromate (III), potassium hexacyanomanganese (III), etc., and a plurality of metal cyano complexes selected from these can be used. You may mix and use in arbitrary ratios. Among them, an iron cyano complex is preferable because it has a strong side reaction suppressing effect, is inexpensive and has low toxicity, and potassium ferricyanide is particularly preferable. The presence of the metal cyano complex can improve the selectivity of the reaction and can suppress the production of by-products.

  A metal cyano complex is 0.005 equivalent or more normally with respect to 1 equivalent of compounds represented by Formula (II), Preferably it is 0.01 equivalent or more, More preferably, it is 0.03 equivalent or more. When it is less than this, there is a possibility that the effect of suppressing by-products becomes small. Moreover, it is 0.20 equivalent or less normally, Preferably it is 0.15 equivalent or less, More preferably, it is 0.10 equivalent or less. If it is more than this, the reaction rate may be significantly reduced.

  In Step 2, an iodide salt may be present together with the metal cyano complex. By the presence of the iodide salt, effects such as improvement of the reaction rate and suppression of decomposition of the phthalonitrile derivative represented by the formula (III) can be obtained.

  The iodide salt is not particularly limited as long as it is soluble to some extent in the reaction solvent used and does not inhibit the reaction. For example, lithium iodide, sodium iodide, potassium iodide, calcium iodide A salt having an iodide ion such as magnesium iodide, copper iodide, silver iodide or zinc iodide as an anion can be used, and a plurality of iodide salts selected from these can be mixed in an arbitrary ratio. It may be used. Of these, potassium iodide and / or copper iodide are preferred because the reaction proceeds smoothly, is inexpensive and easy to handle.

  When using an iodide salt, it is usually 0.01 equivalent or more, preferably 0.02 equivalent or more, relative to 1 equivalent of the compound represented by the formula (II). If it is less than this, the intended effect may not be obtained. Moreover, it is 0.2 equivalent or less normally, Preferably it is 0.1 equivalent or less. A further improvement effect is not recognized even if it exceeds this.

  In particular, when potassium iodide and cuprous iodide are used as the iodide salt, potassium iodide is 0.02 equivalents or more and 0.04 equivalents or less with respect to 1 equivalent of the compound represented by formula (II). In addition, it is preferable to use 0.005 equivalents or more and 0.02 equivalents or less of cuprous iodide.

  The solvent used in the reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbons such as toluene, benzene, xylene, mesitylene, etc. System solvents: hydrocarbon solvents such as pentane, hexane, heptane; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, 1, Ether solvents such as 2-dimethoxyethane and diethylene glycol dimethyl ether; water-soluble lower alcohol solvents such as methanol, ethanol and propanol; ester solvents such as ethyl acetate; nitrile solvents such as acetonitrile and isobutyronitrile; Amide solvents such as amide, dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone; organic solvents such as carbon disulfide and dimethyl sulfoxide; A plurality of solvents selected from the above may be mixed and used in an arbitrary ratio.

  Preferably, it is an amide solvent because it can suppress the formation of by-products, and more preferably 1,3-dimethyl-2-imidazolidinone.

  Although the reaction solvent can be used in any amount, it is usually 1 to 10 times volume, preferably 2 to 7 times volume, more preferably 3 to the compound represented by formula (II). ˜5 times volume.

  The reaction temperature is usually 20 ° C to 240 ° C, preferably 100 ° C to 160 ° C, more preferably 120 ° C to 140 ° C. The reaction time is usually 5 hours to 40 hours, preferably 10 hours to 30 hours, more preferably 15 hours to 25 hours.

  Examples of 1,3-dicarbonyl compounds include acetic anhydride, propionic anhydride, succinic anhydride, maleic anhydride, phthalic anhydride and other carboxylic anhydrides, succinimide, N-methyl succinimide, phthalimide and other acid imides. , Β-diketones such as acetylacetone, 3,3-dimethyl-2,4-pentanedione, and the like, preferably carboxylic anhydrides, particularly preferably succinic anhydride or succinic anhydride from the viewpoint of the effect of the auxiliary agent and cost Maleic anhydride.

  By the presence of the 1,3-dicarbonyl compound, effects such as suppressing the production of by-products can be obtained. In addition, when N-methylpyrrolidone is used as a solvent, generation of by-products can be suppressed as in the case of using 1,3-dimethyl-2-imidazolidinone.

  The 1,3-dicarbonyl compound is usually at least 0.2 equivalents, preferably at least 0.35 equivalents, more preferably at least 0.5 equivalents relative to 1 equivalent of the compound represented by formula (II). If the amount is less than this, there is a possibility that the effect of suppressing by-products may be reduced. Moreover, it is 3.0 equivalent or less normally, Preferably it is 2.0 equivalent or less, More preferably, it is 1.0 equivalent or less. A further improvement effect is not recognized even if it exceeds this.

  In the above reaction, a compound represented by the formula (II), a cyanide compound, a metal cyano complex and / or a 1,3-dicarbonyl compound, an iodide salt as necessary, and a reaction solvent are mixed in advance and heated. In a solution obtained by dissolving and / or suspending a cyanide compound, a metal cyano complex and / or a 1,3-dicarbonyl compound, and, if necessary, an iodide salt in a reaction solvent in advance, Although the compound represented by (II) may be added, the former method is preferred because it is industrially safe and easy.

  The above reaction may be performed in the presence of a divalent copper compound such as cupric bromide, if necessary. Thereby, it becomes possible to improve the extraction efficiency of the reaction product in the post-treatment.

  After step 2, usually copper by-produced using amines such as ammonia, ethylenediamine and triethylenetetramine, or oxidizing agents such as iron (III) bromide, or cyanide salts such as sodium cyanide and potassium cyanide. After removing the compound, extraction, washing and filtration are preferably performed. For extraction, ethyl acetate, isopropyl acetate, methyl-t-butyl ether (MTBE), diethyl ether, toluene, xylene, heptane, hexane, or the like can be used. For washing, water, an acidic aqueous solution, an alkaline aqueous solution, a saline solution, or the like can be used. Activated carbon, diatomaceous earth, or the like may be used as a filter aid.

  The compound represented by the formula (III) obtained in step 2 is a liquid or a solid, and if necessary, can be isolated and purified by a known means such as distillation, sublimation, silica gel chromatography, extraction or crystallization. In addition, these means may be used in combination. In addition, if purification is not particularly necessary, it can be used in the next reaction as it is.

  Step 2 of the present invention enables a reaction using a solvent that is cheaper and more versatile than known means, and can suppress the formation of by-products, and is therefore represented by the high purity formula (III). A compound can be obtained efficiently. In addition, the cleaning process can be simplified as compared with the prior art.

  In the present invention, amide solvents such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, ammonia, ethylenediamine, triethylenetetramine, etc. It is preferable to wash and filter after adding the reaction liquid obtained at the said process 2 to the solution containing amines and water, and crystallizing the compound represented by Formula (III). As the amide solvent used for isolation and purification, the same solvent as that used in the reaction of Step 2 is preferably used, and 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidone is particularly preferable. As the amines, ethylenediamine is preferable.

  The mixing ratio of the amide solvent, amines and water is usually amide solvent: amines: water (weight ratio) = 1: 1 to 5: 1 equivalent of the compound represented by the formula (II). 2-10, preferably amide solvent: amines: water (weight ratio) = 1: 1.5-3: 3-7.

  This method is preferable as an industrial method because the amount of the cleaning liquid used can be reduced and by-products, impurities, and the like can be efficiently removed.

  Further, in the present invention, a monovalent copper ion stabilizer such as sodium thiosulfate, sodium cyanide or potassium cyanide, an inorganic base such as sodium carbonate, lithium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide or potassium hydroxide It is particularly preferred that the reaction solution obtained in Step 2 above is added to a solution containing the above compound and water to crystallize the compound represented by the formula (III), and then washed and filtered. As a monovalent copper ion stabilizer used at the time of isolation and purification, sodium thiosulfate is preferable from the viewpoint of low toxicity and cost. As the inorganic base, sodium carbonate or lithium carbonate is preferable, and sodium carbonate is particularly preferable from the viewpoint of ease of post-treatment and cost.

  The mixing ratio of the monovalent copper ion stabilizer, inorganic bases and water is usually monovalent copper ion stabilizer: inorganic bases: water (1 equivalent to 1 equivalent of the compound represented by the formula (II)). Mol / mol / weight ratio) = 6-14: 0.5-2: 6-16, preferably monovalent copper ion stabilizer: inorganic base: water (mol / mol / weight ratio) = 8-12: 0.8-1.4: 9-13.

  By this method, the amount of cleaning liquid used can be reduced, and by-products, impurities, and the like can be efficiently removed. Furthermore, since decomposition | disassembly of the compound represented by Formula (III) can be suppressed and the copper stain | pollution | contamination of the equipment by disproportionation of a monovalent copper ion can be avoided, it is preferable as an industrial method.

  The compounds according to the present invention can be produced, for example, by the methods described in the following examples and production examples. However, these are illustrative, and the compound according to the present invention is not limited to the following specific examples in any case.

  In the following examples, the purity and reaction yield of the product are calculated by high performance liquid chromatography (HPLC). As an HPLC column, YMC-Pack Pro C18 RS manufactured by YMC Co., Ltd. (length: 150 mm × inner diameter) 4.6 mm) was used.

Example 1 Production of 1,2-dibromo-4,5-diethoxy-3-fluorobenzene: Step 1

  A glass lining (GL) reaction kettle 1 was charged with 117.0 kg (635 mol) of commercially available 1,2-diethoxy-3-fluorobenzene and 117 L of water and cooled to 0 ° C. A bromine / sodium bromide aqueous solution was prepared by mixing 243.6 kg (1.52 kmol) of bromine, 117.6 kg (1.14 kmol) of sodium bromide, and 351 L of water in the GL reaction kettle 2. The solution was added dropwise at 9 ° C. over 4.5 hours. After completion of dropping, the GL reaction kettle 2 was washed with 18 L of water and added to the GL reaction kettle 1. The temperature of the GL reaction kettle 1 was raised to 29 ° C., and the mixture was further stirred for 1.7 hours to obtain a bromination reaction mixture. In the GL reaction tank 3, 240.1 kg of heptane, 88.9 kg (2.22 kmol) of sodium hydroxide and 356 L of water were mixed to prepare a heptane / sodium hydroxide aqueous solution and cooled to 1 ° C. After the bromination reaction mixture in the GL reaction kettle 1 was dropped into the GL reaction kettle 3 while maintaining the temperature at 25 ° C. or lower, the GL reaction kettle 1 was washed with 79.6 kg of heptane and added to the GL reaction kettle 3. Further, 50.2 kg (202 mol) of sodium thiosulfate pentahydrate was added to the GL reaction kettle 3 while keeping it at 25 ° C. or lower. The resulting reaction mixture was allowed to stand at 25 ° C. and separated to discard the lower layer, and further separated and washed with 468 L of water three times. The obtained heptane solution was filtered with a cartridge filter (TCW-1-CSS; Advantech Toyo Co., Ltd.), washed with 78.0 kg of heptane, and concentrated under reduced pressure at 25 ° C. to 60 ° C. to give a crude yellow oily crude 1, 2-Dibromo-4,5-diethoxy-3-fluorobenzene was obtained. (218.2 kg, purity 94.3% by weight, 601 mol, yield 94.7%)

[Comparative Example 1] Step 1
1,2-Dibromo-4,5-diethoxy-3-fluorobenzene was produced in accordance with the method described in Step 7 of Example 7 of International Publication Pamphlet WO02 / 085855.
The GL reaction kettle 1 was charged with 54.95 kg (298 mol) of commercially available 1,2-diethoxy-3-fluorobenzene, 289.11 kg of acetic acid, and 63.70 kg (777 mol) of sodium acetate and adjusted to 25 ° C. While maintaining the internal temperature at 30 ° C. or lower, 124.10 kg (776 mol) of bromine was added dropwise over 2.5 hours, and after completion of the addition, the bromine charging line was washed with 3.74 kg of acetic acid and added to the reaction solution. The reaction mixture was heated to 45 ° C. and further stirred for 6.4 hours. After completion of the reaction, the mixture was cooled to 25 ° C., 150.49 kg of heptane and 442 L of water were added with stirring, and 25.06 kg of sodium pyrosulfite was added while maintaining the internal temperature at 30 ° C. or lower. After stirring and allowing to stand, the upper heptane phase 1 and the lower aqueous phase were separated, and the aqueous phase was fed to the GL reactor 2. 150.53 kg of heptane was added to the aqueous phase of the GL reaction kettle 2 and stirred and allowed to stand, and the aqueous phase was discarded leaving the upper heptane phase 2. After feeding the heptane phase 2 to the GL reaction kettle 1 containing the heptane phase 1, the GL reaction kettle 2 and the liquid feed line were washed with 18.45 kg of heptane and added to the GL reaction kettle 1. The obtained heptane solution in the GL reaction kettle 1 was separated and washed twice with 220.8 kg of 4% aqueous sodium hydroxide solution and three times with 221 L of water. The washed heptane solution was filtered with a cartridge filter (TCW-1-CSS), and the filtration line was washed with 36.65 kg of heptane and concentrated under reduced pressure at 25 ° C. to 60 ° C. to give crude oily crude 1,2- Dibromo-4,5-diethoxy-3-fluorobenzene was obtained. (101.99 kg, purity 85.3% by weight, 254 mol, yield 85.3%)

Example 2 Production of 4,5-diethoxy-3-fluorophthalonitrile: Step 2

  To the GL reaction kettle 1, the crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene obtained in Example 1 (218.2 kg, 94.3% by weight, 601 mol), 1,3-dimethyl- 2-Imidazolidinone 868.9 kg, copper cyanide 167.00 kg (1.86 kmol), potassium ferricyanide 5.95 kg (18.1 mol), potassium iodide 3.00 kg (18.1 mol), and copper iodide 1. After charging 15 kg (6.04 mol) to form a mixture, the reaction kettle was purged with nitrogen. The mixture was heated to 133 ° C. with stirring, stirred for 21.4 hours and then cooled. Prepare a mixed solution of 343.00 kg (2.35 kmol) of triethylenetetramine, 1726 L of water, and 889.75 kg of toluene in the GL reaction vessel 2, and take about 1 hour while keeping the reaction solution in the GL reaction vessel 1 at 30 ° C. And dripped. Further, the GL reaction kettle 1 was washed with 211.65 kg of N-methylpyrrolidone and added to the GL reaction kettle 2. From the resulting reaction mixture, the upper toluene phase 1 and the lower aqueous phase were separated at 25 ° C., and the aqueous phase was further extracted with 533.95 kg of toluene and discarded. The extracted toluene phase was added to toluene phase 1, and the liquid feed line was washed with 17.80 kg of toluene. To the obtained toluene phase, 41.10 kg of diatomaceous earth (made by Showa Chemical Industry Co., Ltd., trade name: Radiolite) was added and stirred, followed by filtration. The filtration residue and the liquid feed line were washed with 533.80 kg of toluene and mixed with the filtrate. did. After separating and discarding the aqueous phase from the obtained toluene solution, an aqueous solution containing 5 wt% ethylenediamine / 5 wt% sodium chloride dissolved in about 825 kg × 2 times, 3.5 wt% hydrochloric acid 823.2 kg, water 825 L × 3 times Liquid separation washing was carried out sequentially. To the toluene phase after washing, a mixture of activated carbon (4.05 kg) / toluene (22.00 kg) was added and stirred, followed by filtration. The reaction kettle and the liquid feed line were washed with 53.45 kg of toluene and mixed with the filtrate. The obtained toluene solution was concentrated under reduced pressure at 50 ° C., and the concentration of 4,5-diethoxy-3-fluorophthalonitrile was adjusted to 38.3% by weight. After concentration, 421.6 kg of heptane was added dropwise to the toluene solution at 50 to 55 ° C. over about 1 hour and cooled to about 5 ° C. over 3.5 hours. The mixture was further stirred at 5 ° C. for 2 hours and then centrifuged. The obtained crystals were washed with a mixed solution of 44.45 kg of toluene / 105.70 kg of heptane, and 112.05 kg of crude 4,5-diethoxy-3-fluorophthalonitrile. Got. The obtained crude crystals were dissolved in 88.9 kg of toluene at 55 ° C., and 70.4 kg of heptane was added dropwise over about 1 hour. The resulting suspension was stirred at 55 ° C. for about 1 hour and then cooled to about 5 ° C. over 4 hours. The mixture was further stirred at 5 ° C. for 2 hours and then centrifuged. The obtained crystals were washed with a mixed solution of 44.6 kg of toluene / 105.7 kg of heptane. The obtained wet body was dried under reduced pressure at 50 ° C. or less to obtain slightly yellow crystalline 4,5-diethoxy-3-fluorophthalonitrile (105.70 kg, HPLC purity 98.0%, yield 75.0). %).

[Example 3] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.01 g, 92.4 wt%, 2.95 mmol) prepared in the same manner as in Example 1, N -3 mL of methylpyrrolidone, 0.79 g (8.82 mmol) of copper cyanide and 0.31 g (3.04 mmol) of acetic anhydride were charged, and the system was purged with nitrogen, heated to 130 ° C. and stirred for 17.5 hours. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (70.7%).

[Example 4] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.01 g, 92.4 wt%, 2.95 mmol) prepared in the same manner as in Example 1, N -3 mL of methylpyrrolidone, 0.79 g (8.82 mmol) of copper cyanide and 0.30 g (3.00 mmol) of succinic anhydride were charged, and the system was purged with nitrogen, heated to 130 ° C. and stirred for 17.5 hours. . The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (73.3%).

[Example 5] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.01 g, 92.4 wt%, 2.95 mmol) prepared in the same manner as in Example 1, N -3 mL of methylpyrrolidone, 0.78 g (8.71 mmol) of copper cyanide and 0.29 g (2.96 mmol) of maleic anhydride were charged, and the system was purged with nitrogen, heated to 130 ° C. and stirred for 17.4 hours. . The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (77.5%).

[Example 6] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.00 g, 89.9 wt%, 2.63 mmol) prepared in the same manner as in Comparative Example 1, , 3-dimethyl-2-imidazolidinone 3.6 mL, copper 708 mg (7.91 mmol), potassium ferricyanide 41.3 mg (0.13 mmol), cupric bromide 36.7 mg (0.16 mmol) Then, the system was purged with nitrogen, heated to 130 ° C., and stirred for 16.2 hours. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (71.9%).

[Example 7] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (0.98 g, 89.9 wt%, 2.58 mmol) prepared in the same manner as in Comparative Example 1, , 3-dimethyl-2-imidazolidinone 3.6 mL, copper 707 mg (7.89 mmol), potassium ferricyanide 46.2 mg (0.14 mmol), potassium iodide 42.4 mg (0.26 mmol), and iodide Copper (47.4 mg, 0.25 mmol) was charged, and the system was purged with nitrogen. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (75.6%).

[Example 8] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (0.99 g, 89.9 wt%, 2.60 mmol) prepared in the same manner as in Comparative Example 1, , 3-dimethyl-2-imidazolidinone 3.6 mL, copper cyanide 714 mg (7.97 mmol), potassium ferrocyanide trihydrate 59.8 mg (0.14 mmol), potassium iodide 45.6 mg (0.27 mmol) And 48.1 mg (0.25 mmol) of copper iodide were added, and the system was purged with nitrogen, then heated to 130 ° C. and stirred for 16.0 hours. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (68.0%).

[Example 9] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.00 g, 92.4 wt%, 2.92 mmol) prepared in the same manner as in Example 1, N -3 mL of methylpyrrolidone, 0.79 g (8.82 mmol) of copper cyanide and 0.34 g (98 wt%, 2.95 mmol) of N-methylsuccinimide were charged, and the system was purged with nitrogen. Stir for 2 hours. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (64.1%).

[Example 10] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.00 g, 92.4 wt%, 2.92 mmol) prepared in the same manner as in Example 1, N -3 mL of methylpyrrolidone, 0.79 g (8.82 mmol) of copper cyanide and 0.38 g (2.96 mmol) of 3,3-dimethyl-2,4-pentanedione were charged. The temperature was raised and the mixture was stirred for 17.5 hours. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (49.9%).

[Example 11] Step 2
Crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (426.97 kg, 96.4 wt%, 1.20 kmol) prepared in the same manner as in Example 1 in the GL reaction kettle 1, N-methyl After charging 1274.75 kg of pyrrolidone, 324.00 kg (3.62 kmol) of copper cyanide, 31.70 kg (96.3 mol) of potassium ferricyanide, and 59.10 kg (603 mol) of maleic anhydride, the inside of the reaction kettle was purged with nitrogen. . The mixture was heated to 133 ° C. with stirring, stirred for 21.2 hours, and then cooled to obtain a reaction solution. A mixture of ethylenediamine 738.6 kg, water 1644 L, and N-methylpyrrolidone 411.7 kg was prepared in the GL reaction kettle 2 and dropped over about 1 hour while keeping the reaction temperature of the GL reaction kettle 1 at an internal temperature of 30 ° C. did. The GL reaction kettle 1 was washed with 207.45 kg of N-methylpyrrolidone and added, and the resulting reaction mixture was stirred at 25 ° C. for 1 hour and then centrifuged. The isolate was washed with 1644.2 kg of a 6.4 wt% aqueous sodium thiosulfate solution and 3288 L of water. The washed crude crystals were dissolved in 1693 kg of toluene, and a mixture of activated carbon 8.25 kg / toluene 89.1 kg and diatomaceous earth (product name: Radiolite) 16.40 kg were added and further stirred for 1 hour. . The resulting mixture was filtered under pressure and washed with 356.75 kg of toluene. After separating and discarding the aqueous phase from the obtained toluene solution, 1645 L of water was added for separation and washing. After adding a mixture of activated carbon 8.25 kg / toluene 107 kg to this toluene solution, the mixture was stirred for about 1 hour, filtered, and washed with 357.65 kg of toluene. The obtained toluene solution was concentrated under reduced pressure at 50 ° C., and the concentration of 4,5-diethoxy-3-fluorophthalonitrile was adjusted to 37.7% by weight. After concentration, 846.05 kg of heptane was added dropwise to the toluene solution at 55 ° C. or less over 1 hour, and the mixture was cooled to around 5 ° C. over 4.7 hours. The mixture was further stirred at 5 ° C. for 2 hours and then centrifuged, and the separated product was washed with a mixed solution of 88.6 kg of toluene / 212.0 kg of heptane. The obtained wet substance was dried under reduced pressure at 25 to 50 ° C. to obtain white crystalline 4,5-diethoxy-3-fluorophthalonitrile (213.75 kg, HPLC purity 98.2%, yield 75.8). %).

[Comparative Example 2] Step 2
In a test tube reactor, crude 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (1.01 g, 92.4 wt%, 2.95 mmol) prepared in the same manner as in Example 1, N -3 mL of methylpyrrolidone and 0.79 g (8.82 mmol) of copper cyanide were charged, the inside of the system was purged with nitrogen, heated to 130 ° C., and stirred for 17.5 hours. The reaction yield of 4,5-diethoxy-3-fluorophthalonitrile was calculated from the HPLC analysis result (31.5%).

[Reference Example 1] Preparation Example 1 of International Publication Pamphlet WO 2006/018955
1,2-dibromo-4,5-diethoxy-3-fluorobenzene (137.0 g, 0.401 mol, content 81%), copper cyanide (107.5 g, 1,200 mol) and 1,3-dimethyl-2 -A mixture of imidazolidinone (600 mL) was purged with nitrogen under reduced pressure, and then heated and stirred at 130 ° C for 17 hours and 140 ° C for 4 hours under a nitrogen atmosphere.
After cooling the reaction solution to room temperature, N, N-dimethylformamide (600 mL), toluene (1.2 L) and concentrated aqueous ammonia (1.2 L) were added to separate the solution, and the resulting organic layer was subjected to N, N- Dimethylformamide (411 mL) and concentrated aqueous ammonia (800 mL) were added for washing. Further, the organic layer was washed with 25% ethylenediamine water (1.2 L), 1N hydrochloric acid (1.2 L), and water (1.2 L) in this order. After filtration through activated carbon, the solution was concentrated under reduced pressure at 50 ° C. to obtain a yellow sherbet-like residue. Toluene (100 mL) and n-heptane (100 mL) were added and dissolved by heating at 60 ° C. After cooling and stirring at 10 ° C. or lower, the precipitated crystals were collected by filtration. Toluene (50 mL) and n-heptane (50 mL) were added to the obtained crystals, dissolved by heating at 90 ° C., and then stirred at room temperature to precipitate crystals. After cooling to 10 ° C. or lower, the crystals were collected by filtration and dried under reduced pressure at 50 ° C. to obtain 51.5 g (yield: 55%) of the title compound as white crystals.

Claims (2)

Formula (I)

[Wherein, R ¹ and R ² each independently represent a C _1-6 alkyl group. The compound of formula (II) is reacted with bromine in the presence of water and a bromide salt.

[Wherein, R ¹ and R ² each independently represent a C _1-6 alkyl group. Step 1 for obtaining a compound represented by the formula:
A compound represented by the formula (II) is reacted with a cyanide compound in the presence of a metal cyano complex and / or a 1,3-dicarbonyl compound to give a compound of the formula (III)

[Wherein, R ¹ and R ² each independently represent a C _1-6 alkyl group. A step 2 of obtaining a compound represented by the formula:
A method for producing a compound represented by formula (III).   The production method according to claim 1, wherein the step 2 is performed in the presence of an iodide salt.