TECHNICAL FIELD

The present invention relates to a production method of a pyrrole compound useful as a pharmaceutical product, particularly an acid secretion inhibitor, a production method of an intermediate used for this method, a novel intermediate and the like.

BACKGROUND OF THE INVENTION

A pyrrole compound having a substituted sulfonyl group at the 1-position (hereinafter to be referred to as a sulfonylpyrrole compound) is useful as an acid secretion inhibitor (proton pump inhibitor), a therapeutic drug for a neoplastic disease or an autoimmune disease (patent documents 1-3).

For example, patent document 2 describes, as a compound having an acid secretion suppressive activity, a compound represented by the formula:


wherein r1is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, wherein the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), r2is an optionally substituted C6-14aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, r3and r4are each a hydrogen atom, or one of r3and r4is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r5is an alkyl group, or a salt thereof.

Patent document 2 describes, as a production method of a sulfonylpyrrole compound, the following method using a pyrrole-3-carboxylate:



Patent document 3 describes the following production method of a sulfonylpyrrole compound:


wherein Q is chlorine, bromine or iodine.

On the other hand, the following method is known as a production method of a 2-halogeno-3-cyanopyrrole compound.

Patent document 4



As a method for producing a 3-cyanopyrrole compound from a 2-halogeno-3-cyanopyrrole compound, the following methods are known.

Non-patent document 1, Non-patent document 2


Non-patent document 3



As a method for producing a 3-formylpyrrole compound from a 3-cyanopyrrole compound, the following methods are known.

Non-patent document 4


Patent document 5



In addition, as a 3-cyanopyrrole compound, the following compounds are known.

Patent document 6


Patent document 7



TABLE 1waxayazaRd3-CN4-Cl5-Cl2-(p-CF3O—C6H5)C2H54-NO22-Br3-Br5-(p-Cl—C6H5)C2H54-NO22-Cl3-Cl5-(3,4-diCl—C6H5)C2H54-NO22-Cl3-Cl5-(p-Br—C6H5)C2H53-CN4-Cl5-Cl2-(p-CF3—C6H5)C2H53-CN4-Cl5-Cl2-(3,4-diCl—C6H5)C2H53-CN4-Cl5-Cl2-(p-Cl—C6H5)C2H54-NO22-(p-Cl—C6H5)5-CF32-(p-Cl—C6H5)C2H53-CN4-Br5-Br2-BrC2H53-CN4-Br5-CF32-(p-Cl—C6H5)C2H53-CN4-Cl5-CF32-(p-Cl—C6H5)C2H54-NO23-(p-Cl—C6H5)5-CF32-(p-Cl—C6H5)C2H53-NO24-(3,4-diCl—C6H5)5-CF32-(p-Cl—C6H5)C2H54-NO23-(m-CN—C6H5)2-CF35-(p-Cl—C6H5)C2H53-CN4-Br5-Br2-(p-CF3—C6H5)C2H53-CN2-Cl4-Cl5-(3,4-diCl—C6H5)C2H53-CN2-Cl4-Br5-(p-Br—C6H5)C2H5
Patent document 8




Patent document 9



Patent document 10



TABLE 2Compound NoQnxbybzb2-53-ClHCNH2-63-ClCH3CNH2-73-ClClCNH2-83-ClBrCNH2-313-ClHCNCH32-323-ClHCNCHO2-573-MeHCNH2-583-MeCH3CNH2-593-MeClCNH2-603-MeBrCNH2-723-MeHCNCH32-733-MeHCNCHO2-923-cyclopropylHCNH2-933-cyclopropylCH3CNH2-943-cyclopropylClCNH2-953-cyclopropylBrCNH2-1083-cyclopropylHCNCH32-1093-cyclopropylHCNCHO

TABLE 3Compound NoQnxbybzb2-1285-cyclopropylHCNH2-1295-cyclopropylCH3CNH2-1305-cyclopropylClCNH2-1315-cyclopropylBrCNH2-1455-cyclopropylHCNCH32-1465-cyclopropylHCNCHO2-1575-EtHCNH2-1585-EtCH3CNH2-1595-EtClCNH2-1605-EtBrCNH2-1755-EtHCNCH,2-1765-EtHCNCHO2-1953-C≡CHHCNH2-1963-C≡CHCH3CNH2-1973-C≡CHClCNH2-1983-C≡CHBrCNH2-2123-C≡CHHCNCH32-2133-C≡CHHCNCHO

In addition, as a 2-mercaptopyrrole derivative, the following compounds are known.

For example, non-patent document 5 describes 2-mercaptopyrrole derivative (A) having a cyano group at the 3-position:


non-patent document 6 describes 2-mercaptopyrrole derivative (B) having a cyano group at the 3-position:


patent document 11 describes 2-mercaptopyrrole derivative (C) having a cyano group at the 3-position:


patent document 12 describes 2-mercaptopyrrole derivative (D) having a cyano group at the 3-position:



As a synthesis method of these 2-mercaptopyrrole derivatives having a cyano group at the 3-position, non-patent document 5 describes, as shown in the following reaction scheme, a synthesis method of mercaptopyrrole derivative (A) by a reaction of a (2-oxoethyl)malononitrile derivative with hydrogen sulfide; however, a desulfurization reaction is not described.



In addition, non-patent document 6 describes, as shown in the following reaction scheme, a synthesis method of 2-mercaptopyrrole derivative (B) having a cyano group at the 3-position is described; however, it is not by a ring closure reaction of a (2-oxoethyl)malononitrile derivative and a sulfur compound. Furthermore, a desulfurization reaction of the obtained 2-mercaptopyrrole derivative is not described.



Moreover, patent document 11 describes, as shown in the following reaction scheme, a synthesis method of 2-mercaptopyrrole derivative (C) having a cyano group at the 3-position; however, it is not by a ring closure reaction of a (2-oxoethyl)malononitrile derivative and a sulfur compound. Furthermore, a desulfurization reaction of the obtained 2-mercaptopyrrole derivative is not described.



Moreover, patent document 12 describes, as shown in the following reaction scheme, a synthesis method of 2-mercaptopyrrole derivative (D) having a cyano group at the 3-position; however, it is not by a ring closure reaction of a (2-oxoethyl)malononitrile derivative and a sulfur compound. In addition, a desulfurization reaction of the obtained 2-mercaptopyrrole derivative is not described.



DOCUMENT LIST

Patent Documents

patent document 1: WO2006/036024patent document 2: WO2007/026916patent document 3: WO2004/103968patent document 4: JP-A-6-9554patent document 5: U.S. Pat. No. 4,904,687patent document 6: EP-A-358047patent document 7: EP-A-491136patent document 8: U.S. Pat. No. 5,359,090patent document 9: U.S. Pat. No. 5,563,279patent document 10: JP-A-10-324687patent document 11: WO2005/040110patent document 12: WO2006/064944

Non-Patent Documents

non-patent document 1: J. Med. Chem., 1995, 38 (12), 2158-2165non-patent document 2: Nucleosides Nucleotides, 1997, 16 (7-9), 941-944non-patent document 3: J. Med. Chem., 1995, 38 (20), 4106-4144non-patent document 4: Can. J. Chem., 1980, 58, 409-411non-patent document 5: Chemistry Heterocyclic Compound, 1992, vol. 2, page 277non-patent document 6: Tetrahedron, 1991, vol. 47, page 8243

SUMMARY OF THE INVENTION

A more efficient production method of a sulfonylpyrrole compound useful as a pharmaceutical product is desired. In addition, provision of an intermediate used for this method is desired.

The present inventors have intensively studied a production method of a sulfonylpyrrole compound useful as an acid secretion inhibitor, particularly a compound represented by the formula (VIII):


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R4is an alkyl group, or a salt thereof. As a result, they have found a novel production method of a sulfonylpyrrole compound, which uses a 3-cyanopyrrole compound. In addition, they have found a novel production method of a 3-cyanopyrrole compound, which is an intermediate, and a novel intermediate, which resulted in the completion of the present invention.

Accordingly, the present invention relates to the following invention.

(1) A method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R4is an alkyl group, or a salt thereof, comprising
(I) reducing a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, and hydrolyzing the reduced product to give a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof,
(II) reacting the obtained compound with a compound represented by the formula
R3—SO2—X  (V)
wherein R3is as defined above and X is a leaving group, or a salt thereof, to give a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, and
(III) reacting the obtained compound with a compound represented by the formula
R4—NH2(VII)
wherein R4is as defined above, or a salt thereof, in the presence of a reducing agent;
(2) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, comprising subjecting a compound represented by the formula


wherein X1is a halogen atom and other symbols are as defined above, or a salt thereof, to dehalogenation;
(3) the production method of the aforementioned (2), wherein the dehalogenation is performed in the presence of a base;
(4) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, comprising reducing a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, and hydrolyzing the reduced product;
(5) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R5is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group or a group represented by —S—R6(R6is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and n is 0, 1 or 2, or a salt thereof, comprising reacting a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula
R5S(O)nH
wherein R5and n are as defined above, or a salt thereof; (6) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, comprising subjecting a compound represented by the formula


wherein R1and R2are as defined above, R5is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group or a group represented by —S—R6(R6is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and n is 0, 1 or 2, or a salt thereof, to a desulfurization reaction;
(7) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R4is an alkyl group, or a salt thereof, comprising
(I) reacting a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula
R5S(O)nH
wherein R5is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group or a group represented by —S—R6(R6is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and n is 0, 1 or 2, or a salt thereof, to give a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, (II) subjecting the obtained compound to a desulfurization reaction to give a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, (III) reacting the obtained compound with a compound represented by the formula
R3—SO2—X  (V)
wherein R3is as defined above, and X is a leaving group, or a salt thereof, to give a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof,
(IV) reducing the obtained compound and hydrolyzing the reduced product to give a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, and
(V) reacting the obtained compound with a compound represented by the formula
R4—NH2(VII)
wherein R4is as defined above, or a salt thereof; (8) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, comprising subjecting a compound represented by the formula


wherein m is 0 or 1 and other symbols are as defined above, or a salt thereof, to a desulfurization reaction;
(9) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, or a salt thereof, comprising reacting a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, with a sulfur reagent to give a compound represented by the formula


wherein m is 0 or 1, and other symbols are as defined above, or a salt thereof, and subjecting the obtained compound to a desulfurization reaction;
(10) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R7is a cyano group or a substituted carboxyl group, and R8is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a chlorine atom or a fluorine atom, or a salt thereof, comprising subjecting a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, to a reduction reaction;
(11) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R7is a cyano group or a substituted carboxyl group, and R8is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a chlorine atom or a fluorine atom, or a salt thereof, comprising cyclizing a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof;
(12) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R7is a cyano group or a substituted carboxyl group, and R8is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a chlorine atom or a fluorine atom, or a salt thereof, comprising reducing a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, and cyclizing the reduced product;
(13) a method of producing a compound represented by the formula


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R8is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a chlorine atom or a fluorine atom, or a salt thereof, comprising cyclizing a compound represented by the formula


wherein each symbol is as defined above, or a salt thereof, in the presence of a reducing agent;
(14) a compound represented by the formula


wherein R1ais an aryl group having substituent(s), or a salt thereof;
(15) a compound represented by the formula


wherein R1bis an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R5is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group or a group represented by —S—R6(R6is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and n is 0, 1 or 2 (excluding 2,2′-dithiobis(5-methyl-1H-pyrrole-3-carbonitrile), 2,2′-dithiobis(5-phenyl-1H-pyrrole-3-carbonitrile), 2,2′-dithiobis[5-(4-chlorophenyl)-1H-pyrrole-3-carbonitrile], 2,2′-dithiobis[5-(4-methylphenyl)-1H-pyrrole-3-carbonitrile] and 2,2′-dithiobis[5-(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile]), or a salt thereof.

Effect of the Invention

According to the method of the present invention, since a sulfonylpyrrole compound is obtained in a short step as compared to conventional methods, the sulfonylpyrrole compound can be produced at a low cost.

In addition, as a synthesis method of the above-mentioned intermediate 3-cyanopyrrole compound, a (2-oxoethyl)malononitrile compound is reacted with a sulfur compound to give a 2-mercapto-3-cyanopyrrole compound, which is then subjected to a desulfurization reaction to give the object compound in a high yield. Furthermore, 2-mercapto-3-cyanopyrrole can be used as a novel intermediate for a 3-cyanopyrrole compound.

The present invention relates to a production method of a sulfonylpyrrole compound useful as an acid secretion inhibitor, particularly, a compound represented by the formula (VIII):


wherein R1is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R2is a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a chlorine atom or a fluorine atom, R3is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R4is an alkyl group (hereinafter sometimes to be abbreviated as compound (VIII)) or a salt thereof, a production method of an intermediate therefor and the like. Compound (VIII) or a salt thereof shows a highly strong proton pump inhibitory effect. Since compound (VIII) or a salt thereof inhibits the proton pump (H+/K+-ATPase) activity reversibly and in a K+antagonist inhibitory manner to consequently suppress acid secretion, it is sometimes referred to as a potassium-competitive acid blocker: P-CAB or an acid pump antagonist (APA). Compound (VIII) or a salt thereof rapidly expresses action, and shows maximum efficacy from the initial administration. Furthermore, it is characterized by a small influence of metabolism polymorphisms (dispersion among patients), low cytotoxicity, weak cytochrome P450 (CYP) inhibitory activity and hERG inhibitory activity, and long duration of action. Therefore, compound (VIII) or a salt thereof obtained according to the production method of the present invention is useful as an agent clinically useful for the prophylaxis and/or treatment of peptic ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidal anti-inflammatory agents, ulcer due to postoperative stress etc.); Zollinger-Ellison syndrome; gastritis; erosive esophagitis; symptomatic gastroesophageal reflux disease (symptomatic GERD); Barrett esophagus, functional dyspepsia; gastric cancer; stomach MALT lymphoma; gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress or recurrence of ulcer due to non-steroidal anti-inflammatory agents and the like. Since compound (VIII) or a salt thereof shows low toxicity and is superior in water-solubility, in vivo kinetics and efficacy expression, it is useful as a pharmaceutical composition. Moreover, since compound (VIII) or a salt thereof is stable even under acidic conditions, it can be administered orally as a conventional tablet and the like without being formulated as an enteric-coated preparation. This has a consequence that the preparation of tablet and the like can be made smaller, which is advantageous in that it is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since a sustained release effect afforded by enteric-coated preparations is absent, expression of a gastric acid secretion-suppressive action is rapid, and alleviation of symptoms such as pain and the like is rapid.

