JP2018070562A - Method for producing 4-fluoroisoquinoline - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing 4-fluoroisoquinoline more simply and in a shorter time compared to heretofore known methods.SOLUTION: Provided is a method for producing 4-fluoroisoquinoline represented by formula (1), where 1-chloro-4-fluoroisoquinoline represented by formula (9a) is reductively decomposed preferably in the presence of a palladium catalyst. Also provided is the method, where 1-chloro-4-fluoroisoquinoline represented by formula (9a) is obtained by treating 1-hydroxyisoquinoline with a fluorinating agent to obtain 4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroxyisoquinoline, which is reacted with a chlorinating agent.SELECTED DRAWING: None

Description

  The present invention relates to a process for producing 4-fluoroisoquinoline, and more particularly, to an economical process for producing 4-fluoroisoquinoline useful as a pharmaceutical intermediate.

  4-Fluoroisoquinoline represented by the following formula (1) is lipasyl (4-fluoro-5-[[2-methyl] of the formula (2), which is a therapeutic agent for glaucoma and ocular hypertension mainly having Rho kinase inhibition. -1,4-diazepan-1-yl] sulfonyl] isoquinoline) (Patent Document 1). Furthermore, this ripaspil (2) is a therapeutic agent for cerebrovascular disorder (Patent Document 2), a therapeutic agent for diseases involving Rho kinase, such as an autoimmune disease therapeutic agent, a cancer cell metastasis inhibitor (Patent Document 3), etc. Development as a new drug is underway.

  As for the above-mentioned 4-fluoroisoquinoline (1), only the production method via 4-bromoisoquinoline of the formula (3) as shown in the following reaction formula is known so far. That is, 4-bromoisoquinoline (3) is reacted with n-butyllithium at −78 ° C. to lithiate, and N-fluorobenzenesulfonimide is allowed to act thereon to obtain 4-fluoroisoquinoline (1) (Patent Document 3). ), 4-bromoisoquinoline (3) is reacted with silver fluoride and potassium fluoride in the presence of a special palladium complex to obtain 4-fluoroisoquinoline (1) and 4-bromoisoquinoline ( 3) is converted to 4-aminoisoquinoline of formula (4), and then 4-fluoroisoquinoline (1) is obtained by utilizing the Balz-Schimann reaction of diazonium salt (5) (Patent Document 4) Non-Patent Document 2).

  However, as mentioned above, although there are several known methods for producing 4-fluoroisoquinoline (1), a special catalyst using a large amount of anhydrous solvent that actually requires a low temperature equipment of -78 ° C. And expensive silver fluoride, the operation when replacing the diazonium salt (5) with fluorine is difficult, the yield range is 0 to 50%, the fluctuation is large, and it is difficult to manufacture a large quantity. As a practical method, it was problematic.

  The present inventor has been studying a method for easily obtaining 4-fluoroisoquinoline (1), which is an alternative to the above method, in a higher yield. As a result, a bromo group or a nitro group is bonded to the benzene ring. When a fluorinating agent is allowed to act on the 1-hydroxyisoquinoline derivative of 6b, c, d), 4-fluoro-3-hydroxy (or methoxy) -1-hydroxydihydro represented by the formula (7b, c, d) It was found that isoquinoline derivatives were reported to be obtained in good yield (Non-patent Document 3, Patent Documents 5, 6, and 7). This fluorine compound is easily dehydrated (or demethanol) by acid treatment to give a 4-fluoro-1-hydroxyisoquinoline derivative (8b, c, d), of which (8b, d) is oxychlorinated. It was found that chlorination with phosphorus converted to the 1-chloro-4-fluoroisoquinoline derivative (9b, d).

  In general, it is said that a chloro group is more susceptible to reduction than a fluoro group substituted on an aromatic ring. Therefore, for example, reduction of the chloro group of the compound (9a) is expected to give 4-fluoroisoquinoline. Therefore, it is expected that 4-fluoroisoquinoline (1) is obtained if the 1-hydroxyisoquinoline (6a) is reduced after fluorination, acid treatment and phosphorus oxychloride treatment.

  So far, reduction of 1-chloro group by reductive decomposition of 1-chloroisoquinoline derivative is, for example, sodium borohydride-tetramethylethylenediamine-palladium complex system (non-patent document 4), tin-acetic acid-hydrochloric acid system (patent document 8). ), Phosphorus-hydroiodic acid-acetic acid system (Patent Document 9), hydrogen-palladium charcoal-sodium acetate system (Non-Patent Document 5), and the like.

  However, the synthesis of 4-fluoroisoquinoline (1) and its derivatives by reduction of 1-chloro-4-fluoroisoquinoline (9a) and its derivatives has not been reported so far. The reason for this is that although the chloro group is generally more susceptible to reduction than the fluoro group bonded to the aromatic ring, the reactivity of the chloro group may be reduced due to the influence of the fluoro group bonded to the same heterocyclic ring. In order to obtain 4-fluoroisoquinoline (1), there was a problem in selectively reducing only the 1-chloro group of 1-chloro-4-fluoroisoquinoline (9a).

WO 2012/026529 WO 99/20620, 97/28130 WO 2008/105442; 2008/105058 IN 2005MU00436 WO 2013/184734 WO 2014/097041 WO 2014/201073 WO 2010/127855; US 2005/0113576 WO 2010/045401 WO 2103/092979, 2007/053346

J. Am. Chem. Soc., 136, 3792 (2014) J. Am. Chem. Soc., 64, 783 (1942); 73, 687 (1951). Tetrahedron Lett., 48, 7371 (2007) J. Molecular Catalysis A, 393, 191 (2014) Bioorg. Med. Chem., 28, 1701 (2015) Synthesis, 47, 3583 (2015) J. Org. Chem., 10, 429 (1945) Drug Journal, 80, 1637 (1960) Indian J. Chem., 16B, 1019 (1978) J. Org. Chem., 16, 800 (1951)

  Therefore, an object of the present invention is to provide a method capable of producing 4-fluoroisoquinoline easily and in a short time as compared with conventionally known methods.

  Based on the findings described above, the present inventors, after allowing a fluorinating agent to act on 1-hydroxyisoquinoline (6a), convert the 1-hydroxy group to a 1-chloro group, and reduce and remove it. Focusing on the possibility of producing 4-fluoroisoquinoline (1) by a new route and intensively studying to solve the above problems, 1-hydroxyisoquinoline (6a) can be obtained by using a specific reduction method. From this, it was found that 4-fluoroisoquinoline (1) can be efficiently produced, and the present invention was completed.

で表される１−クロロ−４−フルオロイソキノリンを還元分解することを特徴とする次の式（１）

で表される４−フルオロイソキノリン（１）の製法である。 That is, the present invention
The following formula (9a)

1-chloro-4-fluoroisoquinoline represented by the following formula (1)

It is a manufacturing method of 4-fluoroisoquinoline (1) represented by these.

で表される１−ヒドロキシイソキノリンを、フッ素化剤で処理して、式（７ａ）

で表される４−フルオロ−１−ヒドロキシ−３−メトキシ−３，４−ジヒドロイソキノリンとし、次いでこれを塩素化剤と反応させることにより得られたものを使用する上記の４−フルオロイソキノリン（１）の製法である。 In addition, the present invention provides the above formula (6a) as 1-chloro-4-fluoroisoquinoline (9a).

1-hydroxyisoquinoline represented by formula (7a) is treated with a fluorinating agent.

4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline represented by the following, and then obtained by reacting it with a chlorinating agent, the above 4-fluoroisoquinoline (1 ).

で表される１−ヒドロキシイソキノリンを、フッ素化剤で処理して、式（７ａ）

で表される４−フルオロ−１−ヒドロキシ−３−メトキシ−３，４−ジヒドロイソキノリンとし、次いでこれを酸処理して式（８ａ）

で表される４−フルオロ−１−ヒドロキシイソキノリンとし、更にこれを塩素化剤と反応させることにより得られたものを使用する前記４−フルオロイソキノリン（１）の製法である。 Furthermore, the present invention relates to the formula (6a) as the 1-chloro-4-fluoroisoquinoline.

1-hydroxyisoquinoline represented by formula (7a) is treated with a fluorinating agent.

4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline represented by formula (8a)

The 4-fluoroisoquinoline (1) is produced using 4-fluoro-1-hydroxyisoquinoline represented by the following formula, and further obtained by reacting it with a chlorinating agent.

Furthermore, the present invention provides 4-fluoro-1-hydroxyisoquinoline represented by formula (8a) and 1-chloro-4-fluoroisoquinoline represented by formula (9a), which are used as an intermediate in the above reaction. is there.

  According to the present invention, without using production equipment such as cryogenic equipment, anhydrous solvents, special catalysts, expensive silver fluoride, etc. 1) can be produced at a very high conversion, and the production of other by-products is suppressed.

  Therefore, the method of the present invention can produce 4-fluoroisoquinoline (1), which is particularly useful as an intermediate for pharmaceuticals, safely and economically.

The 4-fluoroisoquinoline (1) of the present invention can be prepared from 1-hydroxyisoquinoline (6a) according to the following reaction formula.

  Among these, 1-hydroxyisoquinoline (6a) to 1-chloro-4-fluoroisoquinoline (9a) can be synthesized according to the prior art (Non-patent Document 3, Patent Documents 5, 6, and 7). That is, 1-hydroxyisoquinoline (6a) is fluoroetherified with fluorinating reagent in acetonitrile containing methanol to obtain a mixture of stereoisomers of (7a), which is acid-treated to give 4-fluoro-1-hydroxy. It can be formed as isoquinoline (8a), and the 1-hydroxy group of (8a) can be chlorinated with phosphorus oxychloride or the like to give 1-chloro-4-fluoroisoquinoline (9a).

  In addition, when the fluoroether (7a) is reacted with phosphorus oxychloride or the like according to the prior art (Non-patent Document 3), it can be directly converted to 1-chloro-4-fluoroisoquinoline (9a).

  The starting material 1-hydroxyisoquinoline (6a) can be prepared, for example, according to a known method (Patent Document 10, Non-Patent Documents 6, 7, 8, 9, 10, etc.).

  The fluorinating agent used for fluorination of 1-hydroxyisoquinoline (6a) is an electrophilic fluorinating agent, and examples thereof include hypofluorite reagents and N-fluoro reagents. Among them, the hypofluorite reagent trifluoromethyl hypofluorite, acetyl hypofluorite, trifluoroacetyl hypofluorite, N-fluoro reagent 1-fluoropyridinium triflate, N-fluorobenzenesulfonimide (NSFI), 1- Chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octanebistetrafluoroborate (Selectfluor ™), N-fluoro-orthobenzenedisulfonimide (NFOBSI) A commercially available electrophilic fluorinating agent such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2], which is an N-fluoro reagent, is more preferable. Octanebistetrafluoroborate (Selec It is a fluoro (trade name)).

  The amount of the fluorinating agent varies slightly depending on the type of the fluorinating agent. For example, when Selectfluor (trade name) is used, it is 1 to 2 moles compared to the compound (6a) serving as a substrate, preferably 1.05-1.5 moles.

  Furthermore, good results can be obtained by using methanol mixed with acetonitrile as a solvent for the fluoroetherification reaction.

  The reaction temperature of the fluoroetherification reaction is −10 to 50 ° C., preferably 0 to 35 ° C.

  Conversion of the obtained fluoroether (7a) to 1-chloro-4-fluoroisoquinoline (9a) can be carried out by using a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phenylphosphonic dichloride alone, or In particular, phosphorus oxychloride is effective, and the reaction temperature is from room temperature to 120 ° C, preferably from room temperature to 80 ° C.

  When the reaction temperature in the conversion reaction from fluoroether (7a) to 1-chloro-4-fluoroisoquinoline (9a) is low (for example, 47 ° C. or lower), in addition to (9a), 4-fluoro- 1-Hydroxyisoquinoline (8a) is produced as a by-product, but all further converge to 1-chloro-4-fluoroisoquinoline (9a) when the reaction is further performed.

  The reductive decomposition reaction of 1-chloro-4-fluoroisoquinoline (9a) of the present invention can be carried out by using a palladium-based catalyst such as palladium on charcoal or palladium black as a reductive decomposition catalyst, or a nickel-based catalyst such as Raney nickel. It has been found that the use of palladium charcoal is most efficient.

  As described above, since synthesis of 4-fluoroisoquinoline (1) by reductive decomposition of (9a) has not been reported so far, 1-chloro-4-fluoro can be obtained by using a palladium-based catalyst or a nickel-based catalyst. The finding that only the chloro group of isoquinoline (9a) is selectively and efficiently reduced and decomposed can be said to be novel.

  As the solvent for the above reductive decomposition reaction, alcohols such as methanol, ethanol, propanol, isopropanol, ethyl acetate, or the like can be used alone or a mixture thereof. The reaction temperature is 0 to 80 ° C., preferably 5 to 5 ° C. 30 ° C.

  As a hydrogen source for this reductive decomposition reaction, ammonium formate, sodium formate, and hydrazine can be used in addition to hydrogen gas. However, when industrializing, ammonium formate that reduces the risk of explosion and can be reduced by general equipment, By using sodium formate as a hydrogen source, the substrate can be effectively reduced and decomposed. When hydrogen gas is used, the reaction pressure may be increased, but is preferably atmospheric pressure.

  In addition, when supplying molecular hydrogen into a reaction vessel, after supplying sufficient molecular hydrogen in advance, the reaction may be performed in a closed system or may be performed by continuously circulating molecular hydrogen. Good.

  Since 4-fluoroisoquinoline (1) obtained as described above has few impurities and reaction by-products, the treatment after the reaction can be performed by a usual method.

  The 4-fluoroisoquinoline (1) produced by the present invention as described above contains about 1 to 15% of isoquinoline, but can be purified as necessary to have higher purity. Examples of the purification means include conventional separation means, for example, separation means such as distillation and column chromatography, or a separation means that combines these. The target compound (1) can be easily separated and purified from the remaining raw materials and by-products.

  In the present invention, the conversion rate of each step from the raw material compound (6a) to the target compound (1) is very high, and the by-product of other by-products is remarkably suppressed, so the efficiency is very high. Very expensive.

  The 4-fluoroisoquinoline (1) obtained as described above is obtained by, for example, sulfonating the 5-position thereof into a compound (9e), which is further chemically converted to give an amino acid represented by the formula (2). A sulfonylisoquinoline compound can be used, but this compound is a Rho kinase inhibitor (Patent Documents 1, 2, and 3) used as a therapeutic agent for glaucoma and ocular hypertension. Is expected to be.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these Examples. In the following examples, the reaction and product were traced by high performance liquid chromatography (HPLC), and the production rate and purity were indicated by area percentage (area%). The separation column was Inertsil ODS-2 (5 μm, 4.6 × 150 mm; manufactured by GL Sciences), and the UV wavelength of the detector was measured at 220 nm. Elution is performed at a flow rate of 1 mL / min, water (0.1% phosphoric acid) is used as the liquid A as the solvent, and acetonitrile is used as the liquid B. The liquid was a linear gradient of 80 to 30% by volume, and liquid B was performed at 30% by volume from 25 to 35 minutes.

Example 1
Synthesis of 4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline (7a):
According to a prior art document (Non-patent Document 3), a suspension of 1-hydroxyisoquinoline (6a) (290 mg) in acetonitrile (15 mL) and methanol (2 mL) in a nitrogen atmosphere was added to Selectfluor (trade name) ( 1062 mg) and stirred at room temperature for 2.5 hours. The reaction mixture was ice-cooled, diluted with ethyl acetate, water was added thereto, and the mixture was stirred. The aqueous layer was removed, and the organic layer was washed with water, sodium bicarbonate water and 20% brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a brown caramel-like 4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline (7a) mixture (about 2: 1) (313 mg). This was used in the next reaction without purification.

IR (KBr): 3220, 1697 cm- ¹ .
HPLC: 12.1 min (62.6 area%), LC / MS: m / z 196
(M ⁺ +1).
HPLC: 13.0 min (30.1 area%), LC / MS: m / z 196
(M ⁺ +1).

Example 2
Synthesis of 4-fluoro-1-hydroxyisoquinoline (8a):
To a solution of the mixture (100 mg) obtained in Example 1 (100 mg) in dichloromethane (2 mL) was added 4M hydrochloric acid / ethyl acetate solution (0.4 mL), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and a water-methanol (10: 1) solution was added to the resulting solid, followed by neutralization with 7% aqueous sodium bicarbonate. After stirring at room temperature for 1 hour, the solid was filtered to obtain a light brown powder. This was washed with a water-methanol (10: 1) solution and then dried to obtain 4-fluoro-1-hydroxyisoquinoline (8a) (68 mg).

HPLC: 14.6 min (99.2 area%).
¹ H-NMR (CDCl ₃ ): 7.16 (1H, d; 3-H), 7.62 (1H,
dt), 7.79 (1H, dt) 7.82 (1H, dd; 5-H), 8.4
3 (1H, dt; 8-H), 11.62 (1H, br; NH).
IR (KBr): 3158, 1652 cm ⁻¹ .
MS: m / z 163 (M ^<+> ), 136 (M ^<+>- 27).

Example 3
Synthesis of 1-chloro-4-fluoroisoquinoline (9a):
Phosphorous oxychloride (1 mL) was added to (8a) (120 mg) obtained in Example 2, and the mixture was heated and stirred at 66 to 68 ° C. for 2.5 hours. The reaction mixture was worked up according to US Pat. No. 6,057,097 to give light gray powder 1-chloro-4-fluoroisoquinoline (9a) (129 mg).

HPLC: 27.0 minutes (99.0 area%).
¹ H-NMR (CDCl ₃ ): 7.77 (1H, dt), 7.85 (1H, dt),
8.11 (1H, dd; 5-H), 8.16 (1H, d; 3-H), 8.33
(1H, ddd; 8-H).
IR (KBr): 1315, 1260, 763 cm ⁻¹ .
MS: m / z 183, 181 (M ^<+> ), 146 (M ^<+> -Cl).

Example 4
Synthesis of 1-chloro-4-fluoroisoquinoline (9a):
It carried out according to a prior art document (nonpatent literature 3). A solution of (7a) mixture (310 mg) obtained in Example 1 in dichloromethane (3 mL) was cooled to 1 ° C., and phosphorus oxychloride (1.0 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature overnight, then phosphorus oxychloride (1.0 mL) was added, and the mixture was heated at 47 ° C. for 1 hr. Solvent and phosphorus oxychloride were distilled off under reduced pressure. After treatment according to Patent Document 7, a mixture (257 mg) of (8a) and (9a) was obtained as a pale red powder.

HPLC: 14.6 minutes (32.5 area%), 27.0 minutes (66.7 area%).
LC / MS: m / z 164 (M ⁺ +1) (HPLC: 14.6 min),
m / z 182 (M ⁺⁺ 1) (HPLC: 27.0 min).

  Phosphorus oxychloride (1.5 mL) was added to the resulting mixture (256 mg) of (8a) and (9a), and the mixture was heated and stirred at 65 to 67 ° C. for 2 hours. The reaction mixture was worked up according to Patent Document 7 to give 1-chloro-4-fluoroisoquinoline (9a) (253 mg).

      HPLC: 27.0 minutes (99.0 area%).

Example 5
Synthesis of 1-chloro-4-fluoroisoquinoline (9a):
It carried out according to a prior art document (patent document 7). Phosphorous oxychloride (1.5 mL) was added to the mixture (310 mg) obtained in Example 1 (7a) and heated and stirred at 65 to 67 ° C. for 3.5 hours. The reaction mixture was worked up according to US Pat.

      HPLC: 27.0 minutes (98.4 area%).

Example 6
Synthesis of 4-fluoroisoquinoline (1) by H ₂ / Pd—C reductive decomposition of 1-chloro-4-fluoroisoquinoline (9a):
To a solution of 1-chloro-4-fluoroisoquinoline (9a) (55 mg) obtained in the method of Example 3 in ethanol (2 mL) was added 10% Pd charcoal (26 mg; containing water 54%), and 1 atm. The mixture was stirred in a hydrogen atmosphere at room temperature until reductive decomposition was completed (5 to 15 hours). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-water to remove the aqueous layer, and the organic layer was washed with 20% brine and dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, a mixture (33 mg) of 4-fluoroisoquinoline (1) and isoquinoline was obtained as a colorless oil.

HPLC: 4-fluoroisoquinoline (1): 13.8 min (78.2 area%),
Isoquinoline: 3.6 minutes (11.1 area%).

Example 7
1-chloro-4-fluoro-isoquinoline of _{(9a) HCO 2 NH 4 /} Pd-C
Synthesis of 4-fluoroisoquinoline (1) by reductive decomposition:
To a solution of 1-chloro-4-fluoroisoquinoline (9a) (55 mg) obtained in the method of Example 3 in ethanol (5 mL) was added 10% Pd charcoal (26 mg; containing water 54%) and ammonium formate (70 mg). And stirred at room temperature for 2 hours under a nitrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-water to remove the aqueous layer, and the organic layer was washed with 20% brine and dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, a mixture (31 mg) of 4-fluoroisoquinoline (1) and isoquinoline was obtained as a colorless oil.

HPLC: 13.8 min (79.6 area%),
3.6 minutes (19.1 area%),
HPLC (254 nm): 13.8 min (80.0 area%),
3.6 minutes (15.0 area%).

The compound (1) obtained by the method of the present invention is useful as a pharmaceutical intermediate as described above. In addition, the compounds of the formula (8a) and the formula (9a) which are the raw materials of the compound (1) are also useful as pharmaceutical intermediates.

Claims (6)

The following formula (9a)

1-chloro-4-fluoroisoquinoline represented by the following formula (1)

The manufacturing method of 4-fluoroisoquinoline (1) represented by these. Formula (9a)

1-chloro-4-fluoroisoquinoline represented by the formula (6a)

1-hydroxyisoquinoline represented by formula (7a) is treated with a fluorinating agent.

4-Fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline represented by the formula: 4-fluoroisoquinoline according to claim 1, which is obtained by reacting this with a chlorinating agent. The production method of (1). Formula (9a)

1-chloro-4-fluoroisoquinoline represented by the formula (6a)

1-hydroxyisoquinoline represented by formula (7a) is treated with a fluorinating agent.

4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline represented by formula (8a)

The process for producing 4-fluoroisoquinoline (1) according to claim 1, which is obtained by reacting with a chlorinating agent.   The process for producing 4-fluoroisoquinoline (1) according to any one of claims 1 to 3, wherein the reductive decomposition is carried out in the presence of a palladium catalyst. 4-Fluoro-1-hydroxyisoquinoline represented by the formula (8a).

1-chloro-4-fluoroisoquinoline represented by the formula (9a).