JP2000007607A - Production of 7-(2-fluorophenyl)-1-benzosuberone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently and inexpensively obtain 7-(2-fluorophenyl)-1- benzosuberone useful as an intermediate for production of immunosuppressant by reacting a specific benzosuberone compound with a specific fluorobenzene derivative in the presence of a metal such as zinc and a nickel halide, etc. SOLUTION: (A) A benzosuberone derivative of formula I (X1 is a halogen) (e.g. 7-bromo-1-benzosuberone) is reacted with (B) a fluorobenzene derivative of formula II (X2 is a halogen) (e.g. 1-fluoro-2-iodobenzene) in the presence of one or more kinds of metals (preferably zinc) selected from zinc, manganese, aluminum, magnesium, sodium and calcium, nickel halide (preferably nickel chloride) and triarylphosphine (preferably triphenylphosphine) in a solvent such as dimethylformamide to provide the objective compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 6,7-dihydro-10-fluoro-3- (2-fluorophenyl) -5H-benzo [6,7] cyclohepta [1,2- useful as an immunosuppressant. b] A method for producing quinoline-8-carboxylic acid and a compound useful as an intermediate for the production thereof.

[0002]

[0002] International Publication WO93 / 22286 discloses the use of the following compound (hereinafter sometimes referred to as compound (IV) in the present specification) as an immunosuppressant.

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As a method for producing compound (IV), compound (I)
And 5-fluoroisatin (V) with Bitinger-Borsch (Pf
A method of condensation by an itzinger-Borsche reaction is known (International Publication WO93 / 22286).

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The compound (I) used as an intermediate for the production of the compound (IV) in this method is obtained by converting 5- [4- (2-fluorophenyl) phenyl] pentanoic acid (VI) into polyphosphoric acid in 110%.
After heating to 8 ° C. to give 8- (2-fluorophenyl) benzosuberone (VII), compound (VII) was treated with triethylsilane in trifluoroacetic acid to give 7- (2-fluorophenyl) -1H-2, Converted to 3,4,5-tetrahydrobenzocycloheptene (compound (VIII)), and then reacted with compound (VIII) and chromic acid in a mixed solvent of propionic acid and acetic acid to produce it through three steps (WO 93/22286).

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The compound (VI) used as a raw material for the production in the above production method is obtained by reacting 2-fluorobiphenyl and glutaric anhydride in dichloroethane in the presence of aluminum trichloride to give 3- [4- (2 After obtaining [-fluorophenyl) benzoyl] butanoic acid, the compound is reacted with triethylsilane in trifluoroacetic acid, or
After reacting 2-fluorobiphenyl and ethyl 4- (chloroformyl) butanoate in dichloroethane in the presence of aluminum trichloride to obtain ethyl 3- [4- (2-fluorophenyl) benzoyl] butanoate, This compound is treated with triethylsilane in trifluoroacetic acid to convert it to ethyl 5- [4- (2-fluorophenyl) phenyl] pentanoate, and the ester is further treated with potassium hydroxide or potassium hydroxide in a dioxane-water mixed solvent. It can be produced by treating with an alkali such as sodium hydroxide (WO93 / 222).
86).

However, these production methods using compound (VI) as a raw material for production are not always satisfactory as industrial production methods because the yield is low and the reaction operation is complicated. Therefore, development of a method for producing compound (I) without using compound (VI) has been required.

The following scheme is used as a method for producing compound (I):

Embedded image And a catalytic amount of tetrakis (triphenylphosphine) palladium with compound (IX) (wherein Y represents a bromine atom, iodine atom, or trifluorosulfonyloxy group) and orthofluorophenyltributyltin (compound (X)) And a reaction method in the presence of silver oxide in a dimethylformamide solvent is also known (WO 93/222).
86). However, this method is not an advantageous method for industrial implementation because a large amount of heavy metal is discharged, and the disposal thereof requires a lot of cost.

On the other hand, a method of forming a carbon-carbon bond between the same molecules or within a molecule using nickel is known [J. Am.
Chem. Soc. 93, 5908, 1971; Tetrahedron Lett., 35,
8985, 1994]. As an example of applying this reaction to two different molecules to form a carbon-carbon bond, there is a method in which aryl bromide and aryl chloride are cross-coupled in the presence of nickel chloride, triphenylphosphine, and zinc. It is known (Synlett, 371, 1994). Also, J. Org. Ch
em., 54, 4844, 1989 discloses the cross-coupling of aryl halide compounds using nickel.

[0009]

An object of the present invention is to provide a method for efficiently and inexpensively producing a compound (IV) useful as an immunosuppressant and a compound (I) usable as an intermediate for the production thereof. Is to do. It is also an object of the present invention to provide a production method having the above-mentioned characteristics, which is capable of producing a high-quality target compound suitable for a raw material for producing a pharmaceutical on an industrial scale.

[0010]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and found that 7-bromo-1-benzosuberone and 1-fluoro-2-iodobenzene were converted to a metal such as zinc. , Nickel halides and triarylphosphines give high quality compounds when reacted
It has been found that (I) can be produced efficiently and at low cost. The present invention has been completed based on the above findings.

That is, the present invention provides the following formula (I):

Embedded image A method for producing 7- (2-fluorophenyl) -1-benzosuberone represented by the following formula (II):

Embedded image (Wherein X ¹ represents a halogen atom) and a benzosuberone derivative (preferably 7-bromo-1-benzosuberone) represented by the following formula (III):

Embedded image (Wherein X ² represents a halogen atom) and a fluorobenzene derivative (preferably 1-fluoro-2-iodobenzene) from the group consisting of zinc, manganese, aluminum, magnesium, sodium and calcium A method is provided that comprises reacting in the presence of one or more selected metals, nickel halides, and triarylphosphines.

The process of the present invention preferably comprises the following formula (I
It can be carried out as one step of the method for producing the compound represented by V).

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According to a preferred embodiment of the present invention, the above method wherein the metal is zinc and the triarylphosphine is triphenylphosphine; one or more salts selected from the group consisting of metal halide salts and sulfonates Wherein the metal halide is sodium iodide; and wherein the nickel halide is nickel chloride.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the compounds represented by the above formulas (II) and (III), X ¹ and X ² each independently represent a halogen atom, wherein the halogen atom is a fluorine atom, a chlorine atom, Either a bromine atom or an iodine atom may be used. Of these, X ¹ is a bromine atom;
Preferably, ² is an iodine atom. The benzosuberone derivative represented by the formula (II), for example, 7-bromo-1-benzosuberone can be obtained by a known method (for example, J. Org. Chem., 27, 7).
0, 1962) or a method analogous thereto. In addition, a fluorobenzene derivative represented by the formula (III), for example, 1-fluoro-2-iodobenzene, can be easily obtained as a commercial product (for example, available as a reagent from Aldrich: 21,940- 1).

The type of nickel halide used in the method of the present invention is not particularly limited. For example, nickel chloride, nickel bromide and the like can be used, and anhydrous nickel chloride can be particularly preferably used. The amount of nickel halide used can be about 10 equivalents to the compound (II) from the catalytic amount, but the catalytic amount is
Those skilled in the art can appropriately select a solvent according to conditions such as the type of solvent, reaction temperature, and reaction time. The method of the present invention generally comprises the step of reacting a compound (N) in the presence of at least one metal selected from the group consisting of zinc, manganese, aluminum, magnesium, sodium and calcium, nickel halide, and triarylphosphine. II) in a solvent 1
The reaction is carried out by reacting with 1010 equivalents of compound (III). The reaction is completed in a temperature range of usually from 60 ° C. to the boiling point of the reaction solvent in about 0.5 to 24 hours.

The type of the solvent is not particularly limited as long as it is inactive in the above reaction, and examples thereof include alcohols such as methanol, ethanol and propanol; Aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride, chloroform and ethylene dichloride; ester solvents such as ethyl acetate and butyl acetate; aprotic solvents such as dimethylformamide and dimethyl sulfoxide; These may be used, and two or more of these may be used in combination. The amount of the solvent to be used is about 1 to 100 times the weight of compound (II).

The triarylphosphine can be used in an amount of about 1 to 10 equivalents to the compound (II). As the triarylphosphine, for example, triphenylphosphine, tri (o-tolyl) phosphine, or the like, preferably triphenylphosphine can be used. As at least one metal selected from the group consisting of zinc, manganese, aluminum, magnesium, sodium, and calcium, it is preferable to use zinc alone. The amount of zinc is about 1 to 20 equivalents relative to compound (II).

In carrying out the method of the present invention, it is preferable to add one or more salts selected from the group consisting of metal halide salts and sulfonates to the reaction system. As the metal halide salt, for example, sodium iodide can be used, and as the sodium sulfonate, sodium sulfonate can be used. Among these, it is preferable to use a metal halide salt, especially sodium iodide. When sodium iodide is used, it can be used in an amount of about 1 to 10 equivalents based on compound (II). The method of the present invention generally employs a carbon-carbon bond forming method using nickel [J. Am. Chem. S.
oc. 93, 5908, 1971; Tetrahedron Lett., 35, 8985, 19
94].

Further, the compound (I) and 5-fluoroisatin are mixed with each other under alkaline conditions such as potassium hydroxide and sodium hydroxide in an ethanol-water mixed solvent, usually at room temperature to 100 ° C.
The compound (IV) can be obtained by reacting at 12 ° C. for 12 to 72 hours. 5-Fluoroisatin can be obtained by purchasing from Aldrich or the like.

[0020]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Example 1: 7- (2-fluorophenyl) -1-benzosuberone [compound (I)] 7-bromo-1-benzosuberone 523 mg (2.19 mmol) and 1
To a solution of 1.27 mL (10.9 mmol) of -fluoro-2-iodobenzene in dimethylformamide (DMF) (10 mL) was added anhydrous nickel chloride (320 mg, 2.47 mmol) and triphenylphosphine.
3.11 g (11.9 mmol), sodium iodide 371 mg (2.48
mmol) and 1.53 g (23.4 mmol) of zinc at 80 ° C.
Stir for 40 minutes. After allowing the reaction mixture to cool to room temperature,
(250 mL) and add ethyl acetate (500 mL + 300 mL + 200 m
L). The obtained organic layer was washed with water (150 mL).
And saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure is subjected to silica gel column chromatography (elution solvent;
Hexane / ethyl acetate = 20: 1 → 15: 1 → 10: 1 → 5: 1) to give 317 mg of compound (I) (57% yield). The ¹ H-NMR data of the obtained compound is described in International Publication No. WO93 / 22286.
It was consistent with the description.

Example 2 10-Fluoro-3- (2-fluorophenyl) -6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b]
Quinoline-8-carboxylic acid [Compound (IV)] Compound (I) 0.62 g (2.4 mmol) and 5-fluoroisatin
Dissolve 0.41 g (2.4 mmol) in ethanol (4 mL),
Water (2 mL) containing 0.67 g (12 mmol) of potassium hydroxide was added. After heating under reflux for 50 hours, the solvent was distilled off, ether was added to the residue, and the mixture was extracted with water. Hydrochloric acid was added to the aqueous layer, and the precipitated crystals were collected by filtration and washed with ether. The obtained crystals were recrystallized from dimethylformamide-water to give 445 mg (46% yield) of the title compound. Mp:> 300 ° C. Elemental analysis _{(%): C 26 H 17} F 2 NO 2 · 0.4H 2 O Calculated: C 73.49%,
H 4.39%, N 3.43% Found: C 73.55%, H 4.04%, N 3.3
4% IR (KBr) cm ^-1 : 2940, 2860, 1730, 1625, 1500, 1480,
1240 NMR (DMSO-d ₆ ) δ (ppm): 8.24-8.19 (1H, m), 7.87 (1H, d, J
= 8Hz), 7.79-7.32 (8H, m), 2.89-2.61 (4H, m), 2.26-2.21
(2H, m) MS (m / e): 401 (M ⁺ ), 356

[0022]

According to the method of the present invention, compound (IV) useful as an immunosuppressant and compound (I) useful as an intermediate for the production thereof can be efficiently and inexpensively produced.

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Claims (6)

[Claims] (1) The following formula (I): A method for producing 7- (2-fluorophenyl) -1-benzosuberone represented by the following formula (II): (Wherein X ¹ represents a halogen atom) and a benzosuberone derivative represented by the following formula (III): (Wherein, X ² represents a halogen atom) and a fluorobenzene derivative represented by the formula: one or more metals selected from the group consisting of zinc, manganese, aluminum, magnesium, sodium and calcium, and nickel halides And reacting in the presence of a triarylphosphine. 2. The following formula (IV): A method for producing a compound represented by the following formula (II): (Wherein X ¹ is as defined above) and a benzosuberonic acid derivative represented by the following formula (III): (Wherein X ² has the same meaning as described above), and zinc, manganese, aluminum,
By reacting in the presence of one or more metals selected from the group consisting of magnesium, sodium and calcium, nickel halides and triarylphosphines, the following formula (I): A method comprising producing 7- (2-fluorophenyl) -1-benzosuberone represented by the formula: 3. The method according to claim 1, wherein the metal is zinc and the triarylphosphine is triphenylphosphine. 4. The method according to claim 1, wherein the reaction is carried out in the presence of one or more salts selected from the group consisting of metal halide salts and sulfonates. 5. The method according to claim 4, wherein the metal halide salt is sodium iodide. 6. The method according to claim 1, wherein the nickel halide is nickel chloride.