JP4707350B2 - 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 compound as a pharmaceutical intermediate. 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.

This isoquinoline nuclear chlorinated product is derived from sulfuryl chloride contained in a small amount in thionyl chloride. Therefore, in order to obtain high-purity isoquinoline sulfonyl chloride, it is necessary to remove in advance a trace amount of sulfuryl chloride contained in thionyl chloride. Conventionally, the following methods have been used to remove traces of sulfuryl chloride contained in thionyl chloride:
(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).

Both of these methods must distill thionyl chloride. Therefore, these methods have the disadvantage of high costs due to the time and effort required for the distillation process. Equipment for distillation must also be prepared. In these methods, if thionyl chloride is used for the reaction with isoquinoline sulfonic acid without distillation, the substances added before distillation (for example, phenol, cresol, p-hydroxybenzoic acid, aniline, etc. in method (e)) ) Reacts with the product isoquinoline sulfonyl chloride, forming an ester or amide impurity.
JP-A-10-130200

  An object of the present invention is to provide a method for producing isoquinoline sulfonyl chloride at a relatively low cost while suppressing the generation of isoquinoline nuclei chlorinated products of isoquinoline sulfonic acid.

  The inventor has noted that certain aromatic compounds selectively react with sulfuryl chloride and do not react with isoquinoline sulfonic acid. As a result of intensive studies to produce isoquinoline sulfonyl chloride at a relatively low cost by utilizing this property, the present inventors have completed the present invention.

  That is, the present invention is characterized in that thionyl chloride containing a small amount of sulfuryl chloride, an aromatic compound, and N, N-dimethylformamide are mixed and heated, and then this reaction product is reacted with isoquinoline sulfonic acid. A method for producing isoquinolinesulfonyl chloride is provided.

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

  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 wt% to 1.5 wt%) of sulfuryl chloride.

  Other isoquinoline sulfonic acids, aromatic compounds, and N, N-dimethylformamide used in the method of the present invention may be synthesized using commercially available products.

  The isoquinoline sulfonic acid used as a raw material in the present invention may be one having a sulfone group 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.

  Aromatic compounds that may be added to remove sulfuryl chloride include any as long as they react with sulfuryl chloride and do not react with isoquinoline sulfonic acid.

  Examples of the aromatic compound that may be added include compounds having a benzene ring, a naphthalene ring, an anthracene ring, and a phenanthrene ring. The aromatic compound that may be added includes 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). Aromatic rings substituted with a C1-C4 linear or branched alkyl group substituted with atoms are also included. 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.

  In the method of the present invention, first, thionyl chloride containing a trace amount of sulfuryl chloride, an aromatic compound for removing sulfuryl chloride, and N, N-dimethylformamide are mixed and heated.

  The amount of the aromatic compound added in this step may be equal to or more than the amount corresponding to sulfuryl chloride contained in thionyl chloride. This addition amount is usually about 0.1% to 60% by weight, preferably about 1% to 60% by weight, based on thionyl chloride. Furthermore, when this aromatic compound is a liquid, it can also be used as a solvent. In that case, it is used about 0.5 to 20 times, preferably about 2 to 5 times the isoquinolinesulfonic acid added in the next step.

  The amount of N, N-dimethylformamide added can be easily determined based on the common general technical knowledge in the field according to the amount of isoquinoline sulfonic acid in the next step, the reaction temperature, the reaction time, and the like.

  The treatment temperature of thionyl chloride containing sulfuryl chloride with an aromatic compound is usually about 0 to 75 ° C, preferably about 50 to 70 ° C. The treatment time is usually about 0.5 to 10 hours, preferably about 1 to 4 hours.

  By this treatment, sulfuryl chloride contained in a small amount in thionyl chloride reacts with the aromatic compound to become a chlorinated aromatic compound, and the chlorination reaction of isoquinoline sulfonic acid is substantially not performed in the subsequent steps.

  The reaction product is then reacted with isoquinoline sulfonic acid to selectively chlorinate the sulfonic group of isoquinoline sulfonic acid.

  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.

  This chlorination reaction is usually carried out at about 0 to 75 ° C., preferably about 50 to 70 ° C., and the reaction time varies depending on the amount of thionyl chloride used, temperature, etc., but is usually 3 to 24 hours. After this chlorination reaction, impurities are removed by appropriately performing steps such as cooling, filtration, washing and drying by methods known to those skilled in the art. The chlorinated aromatic compound generated in the treatment step with the thionyl chloride aromatic compound containing sulfuryl chloride is removed as an impurity in a state of being dissolved in the filtrate in the filtration step. By these steps, high-purity isoquinoline sulfonyl chloride can be obtained.

  Moreover, the nuclear chlorination reaction product in a final product can further be reduced by performing these operation under nitrogen stream.

  According to the present invention, it is possible to produce isoquinoline sulfonyl chloride while suppressing the generation of isoquinoline nucleates of isoquinoline sulfonic acid. Moreover, since the method of the present invention does not require a distillation step in order to remove sulfuryl chloride contained in thionyl chloride, isoquinoline sulfonyl chloride can be produced at a low cost.

  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.

  In the following examples, “part” means “part by weight”.

Comparative Example 1

  82 parts of thionyl chloride, 0.5 part of N, N-dimethylformamide and 10 parts of 5-isoquinolinesulfonic acid were added and reacted at 60 ° C. for 4 hours. After cooling, the precipitated crystals were filtered off and dried to give isoquinolinesulfonyl chloride (yield 61.8%). In HPLC analysis, 0.07% nuclear chlorinated product was found.

  82 parts of thionyl chloride, 0.8 part of toluene and 0.5 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 60.9%). In HPLC analysis, the nuclear chlorinated product was 0.02%.

  41 parts of thionyl chloride, 0.4 part of toluene and 0.3 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, 50 parts of toluene was added, and the precipitated crystals were separated by filtration and dried to obtain isoquinoline sulfonyl chloride (yield 92.5%). In HPLC analysis, the nuclear chlorinated product was 0.02%.

  The same operation as in Example 2 was carried out except that cumene was used in place of toluene in Example 2 to obtain isoquinoline sulfonyl chloride (yield 91.0%). In HPLC analysis, the nuclear chlorinated product was 0.01%.

  The same operation as in Example 2 was carried out except that mesitylene was used in place of toluene in Example 2 to obtain isoquinolinesulfonyl chloride (yield 92.9%). In HPLC analysis, the nuclear chlorinated product was 0.01%.

  The same operation as in Example 2 was carried out except that chlorobenzene was used instead of toluene in Example 2 to obtain isoquinolinesulfonyl chloride (yield 91.6%). In HPLC analysis, the nuclear chlorinated product was 0.02%.

  The same operation as in Example 2 was carried out except that benzyl chloride was used instead of toluene in Example 2 to obtain isoquinoline sulfonyl chloride (yield 92.2%). In HPLC analysis, the nuclear chlorinated product was 0.02%.

  The same operation as in Example 2 was carried out except that the inside of the system was flowed under a nitrogen stream to obtain isoquinoline sulfonyl chloride (yield 93.1%). In HPLC analysis, the nuclear chlorinated product was 0.01%.

  The same operation as in Example 3 was carried out except that the inside of the system was flowed under a nitrogen stream to obtain isoquinoline sulfonyl chloride (yield: 93.3%). In the HPLC analysis, no nuclear chlorinated product was observed.

  87 parts of thionyl chloride, 51 parts of toluene and 0.5 part of N, N-dimethylformamide were mixed and treated at 64 ° C. for 2.5 hours. 20 parts of isoquinoline sulfonic acid was added without distilling this treatment liquid and reacted at 80 ° C. for 26 hours. After cooling, the precipitated crystals were separated by filtration and dried to obtain isoquinoline sulfonyl chloride (yield 95.6%). In the HPLC analysis, no nuclear chlorinated product was observed.

Claims (3)

And thionyl chloride containing sulfuryl chloride,
Benzene, naphthalene, anthracene, phenanthrene, toluene, xylene, ethylbenzene, mesitylene, cumene, chlorobenzene, aromatic compounds selected from the group consisting of dichlorobenzene, and benzyl chloride,
N, and N- dimethylformamide were mixed,
A method for producing 5-isoquinolinesulfonyl chloride , comprising reacting a mixture and then reacting the reaction product with 5-isoquinolinesulfonic acid . The method according to claim 1, wherein the addition amount of the aromatic compound is 0.1 wt% to 60 wt% with respect to thionyl chloride. The method according to claim 1 or 2, wherein the reaction is carried out under a nitrogen stream.