JP4707355B2 - Process for producing isoquinolinesulfonyl chloride - Google Patents

Description

  The present invention relates to a method for producing isoquinolinesulfonyl chloride.

  Isoquinoline sulfonyl chloride is an important intermediate in pharmaceuticals such as fasudil hydrochloride. Isoquinoline sulfonyl chloride can be produced by reacting isoquinoline sulfonic acid with thionyl chloride and chlorinating the sulfonic group. However, in this method, not only the target compound but also a compound in which the isoquinoline nucleus of isoquinoline sulfonic acid is chlorinated (hereinafter referred to as isoquinoline nucleus chlorinated product) is produced. In the pharmaceutical field, the presence of such impurities, even in trace amounts, has a great influence on the pharmacological effect of the product. Since this isoquinoline nuclear chlorinated product differs from the intended isoquinoline sulfonyl chloride in only a small part of the structure, it is difficult to remove only the isoquinoline nuclear chlorinated product from these mixtures.

It is known that this isoquinoline nuclear chlorinated product is derived from sulfuryl chloride contained in a small amount in thionyl chloride. Therefore, conventionally, in order to obtain high-purity isoquinoline sulfonyl chloride, a method of previously removing a trace amount of sulfuryl chloride contained in thionyl chloride has been used exclusively. As a method for removing sulfuryl chloride in advance, for example, the following method has been used:
(A) A method of adding triphenyl phosphite and distilling;
(B) Method of adding sulfur and distilling;
(C) Method of adding diterpene and distilling;
(D) A method of adding linseed oil and distilling;
(E) A method in which one compound selected from the group consisting of phenol, cresol, p-hydroxybenzoic acid and aniline is added, heated and mixed, and then distilled (Patent Document 1).

However, the removal of sulfuryl chloride contained in thionyl chloride by these methods cannot completely control the formation of isoquinoline nuclear chlorinated products.
JP-A-10-130200

  An object of the present invention is to provide a method for producing isoquinoline sulfonyl chloride while completely suppressing the generation of isoquinoline nucleoside of isoquinoline sulfonic acid.

  The present inventor has found that a specific chelating agent suppresses the generation of isoquinoline nuclear chlorinated products. The present inventor has also found that a trace amount of metal present in the system affects the chlorination of aromatic nuclei. Based on these new findings, the present inventor has intensively studied to produce isoquinoline sulfonyl chloride while completely suppressing the generation of nuclear chlorinated products. As a result, the present invention has been completed.

  That is, the present invention provides a method for producing isoquinoline sulfonyl chloride, characterized by reacting thionyl chloride and isoquinoline sulfonic acid in the presence of a chelating agent.

  Hereinafter, the method of the present invention will be described in detail.

  In the present specification, the units “part” and “%” are based on weight.

  A commercially available product is used for thionyl chloride used in the method of the present invention. Commercially available thionyl chloride usually contains a trace amount (about 0.1% to 1.5%) of sulfuryl chloride. In the present specification, thionyl chloride means thionyl chloride containing a trace amount of sulfuryl chloride unless otherwise specified. Commercially available thionyl chloride usually contains iron, aluminum and the like on the order of ppm or less.

  In addition, the isoquinoline sulfonic acid used in the method of the present invention may be one in which a sulfone group is bonded to any carbon atom among the carbon atoms of the isoquinoline nucleus. The isoquinoline sulfonic acid may be one having a sulfone group bonded to two or more carbon atoms. Commercially available or synthetic isoquinoline sulfonic acids usually contain iron on the order of ppm.

  Examples of the chelating reagent used in the method of the present invention include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid, triethylenetetraminehexaacetic acid, 1,3-propanediaminetetraacetic acid, ethylenediaminediol hydroxyphenylacetic acid, ethylenediaminediacetic acid, and ethylenediamine. Examples include dipropionic acid, hydroxyethylethylenediaminetriacetic acid, dihydroxyethylethylenediaminediacetic acid, diaminopropanetetraacetic acid, hydroxyethyliminodiacetic acid, nitrilotriacetic acid, transcyclohexanediaminetetraacetic acid, and L-glutamic acid diacetic acid.

  In the method of the present invention, thionyl chloride and isoquinoline sulfonic acid are first reacted in the presence of a chelating agent.

  The amount of isoquinoline sulfonic acid used for the chlorination reaction is usually about 0.05 to 0.5 times, preferably about 0.1 to 0.3 times that of thionyl chloride.

  In this reaction solution, metal ions such as iron ions and aluminum ions derived from commercially available thionyl chloride and isoquinoline sulfonic acid reagents are present. These metal ions catalyze the nuclear chlorination reaction of isoquinoline sulfonic acid. In this step, these metal ions are chelated by the chelating agent and do not affect the production of the nuclear chlorinated product. Accordingly, thionyl chloride selectively chlorinates the sulfone group of isoquinoline sulfonic acid.

  Here, if necessary, the chlorination reaction can be promoted by using a catalyst (N, N-dimethylformamide or the like) known in the art.

  The amount of chelating reagent used varies depending on the amount of metal contained in the raw material, but is usually about 1 ppm to 5%, preferably about 10 ppm to 0.5% with respect to thionyl chloride.

  Accordingly, the chelating agents used in the present invention are effective even in amounts much smaller than the amount of agents conventionally required to remove sulfuryl chloride.

  The reaction temperature of thionyl chloride and isoquinoline sulfonic acid is usually about 0 to 75 ° C, preferably about 50 to 70 ° C.

  This reaction time is usually about 0.5 to 10 hours, preferably about 1 to 4 hours.

  In the method of the present invention, “in the presence of a chelating agent” means that the chelating agent, thionyl chloride, and isoquinoline sulfonic acid are mixed and reacted, and the chelating agent and thionyl chloride are mixed and reacted in advance. Later, both the reaction product is added to isoquinoline sulfonic acid and allowed to react.

  In addition, the method of the present invention can be combined with the prior removal of a trace amount of sulfuryl chloride contained in thionyl chloride by a conventional method (for example, any one of the methods (i) to (e) above). In this case, isoquinoline sulfonyl chloride can be produced with a smaller amount of the chelating reagent while completely suppressing the nuclear chlorinated product.

  Furthermore, in the method of the present invention, a specific aromatic compound and thionyl chloride are mixed, and the mixture is reacted with heating to combine with a step of removing a trace amount of sulfuryl chloride contained in thionyl chloride. However, it is possible to produce isoquinoline sulfonyl chloride while completely suppressing nuclear chlorination with a smaller addition amount of the chelating reagent.

  Here, the specific aromatic compound used for removing a trace amount of sulfuryl chloride includes any compound as long as it reacts with sulfuryl chloride and does not react with isoquinoline sulfonic acid. Examples of the aromatic compound include compounds having a benzene ring, a naphthalene ring, an anthracene ring, and a phenanthrene ring. The aromatic compound is substituted with 1 to 3 substituents that do not react with isoquinolinesulfonyl chloride (for example, a linear or branched alkyl group having 1 to 4 carbon atoms, a halogen atom, or a halogen atom). And an aromatic ring substituted with a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of these compounds include aromatic hydrocarbons such as benzene, naphthalene, anthracene and phenanthrene, aromatic hydrocarbons substituted with alkyl groups such as toluene, xylene, ethylbenzene, mesitylene and cumene, chlorobenzene, dichlorobenzene and benzyl chloride. Is done.

  The addition amount of these aromatic compounds should just be more than the quantity corresponding to the sulfuryl chloride contained in thionyl chloride. This addition amount is usually about 0.1% to 60%, preferably about 1% to 60%, with respect to thionyl chloride.

  In this case, thionyl chloride, these aromatic compounds, and a chelating agent are mixed, and usually at room temperature or a temperature of about 0 ° C. to 75 ° C., preferably about 50 ° C. to 70 ° C., usually 0.5 hours to 10 hours. The treatment is preferably performed for about 1 to 4 hours. The treatment liquid can be used as it is as a chlorinating agent for chlorination of the sulfo group of isoquinoline sulfonic acid without any operation such as distillation.

  After this chlorination reaction, isoquinoline sulfonyl chloride containing no isoquinoline nucleus chlorinated product can be obtained by appropriately performing steps such as cooling, filtration, washing and drying by a known method.

  According to the present invention, it is possible to produce isoquinoline sulfonyl chloride while completely suppressing the generation of isoquinoline nucleoside of isoquinoline sulfonic acid.

  Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples. However, the present invention is not limited by these descriptions.

Comparative Example 1

  51.2 parts of thionyl chloride, 10.0 parts of 5-isoquinolinesulfonic acid and 0.33 part of N, N-dimethylformamide were mixed and reacted at 60 ° C. for 4 hours. After cooling, 48.5 parts of toluene was added and the precipitated crystals were filtered off and dried to give isoquinolinesulfonyl chloride (yield 93.8%). In HPLC analysis, 0.071% nuclear chlorinated product was found.

Comparative Example 2

  A mixture of 132 parts of thionyl chloride, 0.5 parts of N, N-dimethylformamide and 5.2 parts of phenol was heated and stirred at 78 ° C. for 4 hours. Thereafter, distillation was performed to obtain purified thionyl chloride. To 82 parts of this thionyl chloride, 0.5 part of N, N-dimethylformamide and 10 parts of 5-isoquinolinesulfonic acid were added and reacted at 60 ° C. for 6 hours. After cooling, the precipitated crystals were filtered off and dried to obtain isoquinoline sulfonyl chloride (yield 63.5%). In HPLC analysis, 0.003% nuclear chlorinated product was found.

  51.2 parts of thionyl chloride, 0.05 part of EDTA, 10.0 parts of 5-isoquinolinesulfonic acid and 0.33 part of N, N-dimethylformamide were mixed and reacted at 60 ° C. for 4 hours. After cooling, 48.5 parts of toluene was added and the precipitated crystals were filtered off and dried to give isoquinolinesulfonyl chloride (yield 93.0%). In the HPLC analysis, no nuclear chlorinated product was observed.

  41.2 parts of thionyl chloride, 1.6 parts of cumene, 0.01 part of EDTA and 0.28 part of N, N-dimethylformamide were mixed and treated at 60 ° C. for 2.5 hours. 10 parts of 5-isoquinoline sulfonic acid was added without distilling this processing liquid, and it was made to react at 60 degreeC for 6 hours. After cooling, toluene was added and the precipitated crystals were filtered off and dried to obtain isoquinolinesulfonyl chloride (yield 89.2%). In the HPLC analysis, no nuclear chlorinated product was observed.

  51.2 parts of thionyl chloride, 2.0 parts of cumene, 0.013 part of EDTA and 0.37 part of N, N-dimethylformamide were mixed and treated at 60 ° C. for 2.5 hours. 10 parts of 5-isoquinoline sulfonic acid was added without distilling this processing liquid, and it was made to react at 60 degreeC for 4 hours. After cooling, the precipitated crystals were filtered off and dried to obtain isoquinoline sulfonyl chloride (yield 87.3%). In the HPLC analysis, no nuclear chlorinated product was observed.

  19 parts of the filtrate obtained in Example 3 were mixed with 33 parts of 1.5% thionyl chloride, 1.3 parts of cumene, 0.008 part of EDTA, and 0.21 part of N, N-dimethylformamide. Processed for 5 hours. 10 parts of 5-isoquinolinesulfonic acid was added without distilling this treatment liquid, and the mixture was reacted at 60 ° C. for 9 hours. After cooling, the precipitated crystals were filtered off and dried to give isoquinoline sulfonyl chloride (yield 89.3%). In the HPLC analysis, no nuclear chlorinated product was observed.

  The same operation as in Example 1 was performed, except that ethylenediaminedioltohydroxyphenylacetic acid was used instead of EDTA. In the HPLC analysis, no nuclear chlorinated product was observed.

  The same operation as in Example 1 was performed except that hydroxyethyliminodiacetic acid was used instead of EDTA. In the HPLC analysis, no nuclear chlorinated product was observed.

  The same operation as in Example 1 was performed except that L-glutamic acid diacetic acid was used instead of EDTA. In the HPLC analysis, no nuclear chlorinated product was observed.

  The same operation as in Example 2 was performed, except that benzene was used instead of cumene. In the HPLC analysis, no nuclear chlorinated product was observed.

The same operation as in Example 2 was performed, except that chlorobenzene was used instead of cumene. In the HPLC analysis, no nuclear chlorinated product was observed.

Claims (3)

A method for producing 5-isoquinolinesulfonyl chloride , comprising reacting thionyl chloride with 5-isoquinolinesulfonic acid in the presence of a chelating agent for chelating metal ions . In the presence of a chelating agent that chelates metal ions ,
Thionyl chloride ,
Mixing with an aromatic compound selected from the group consisting of benzene, naphthalene, anthracene, phenanthrene, toluene, xylene, ethylbenzene, mesitylene, cumene, chlorobenzene, dichlorobenzene, and benzyl chloride ;
A method for producing 5-isoquinolinesulfonyl chloride , comprising reacting a mixture and then reacting the reaction product with 5-isoquinolinesulfonic acid . The chelating agent is EDTA, diethylenetriaminepentaacetic acid, triethylenetetraminehexaacetic acid, 1,3-propanediaminetetraacetic acid, ethylenediaminedioltohydroxyphenylacetic acid, ethylenediaminediacetic acid, ethylenediaminedipropionic acid, hydroxyethylethylenediaminetriacetic acid, dihydroxyethyl. 3. Either one of claim 1 or claim 2 selected from the group consisting of ethylenediaminediacetic acid, diaminopropanetetraacetic acid, hydroxyethyliminodiacetic acid, nitrilotriacetic acid, transcyclohexanediaminetetraacetic acid, L-glutamic acid diacetic acid. the method of.