WO2006057261A1

WO2006057261A1 - Processes for producing 5-phthalancarbonitrile and citalopram

Info

Publication number: WO2006057261A1
Application number: PCT/JP2005/021496
Authority: WO
Inventors: Nobuhiro Arai; Tadashi Katsura; Tadashi Mizuno
Original assignee: Sumitomo Chemical Company, Limited
Priority date: 2004-11-29
Filing date: 2005-11-17
Publication date: 2006-06-01
Also published as: JP2006176490A

Abstract

A process for producing the compound represented by the formula (II) which comprises reacting the compound represented by the formula (I) with oxalyl chloride; and a process for producing the compound represented by the formula (III) which comprises a step in which the compound represented by the formula (I) is reacted with oxalyl chloride to obtain the compound represented by the formula (II) and a step in which the compound represented by the formula (II) is reacted with a 3-dimethylaminopropyl halide.

Description

5 Method for producing monophthalan carbonitrile and ciroplopram

Technical field

The present invention relates to a method for producing cyloropram, which is an antidepressant, and a 5 monophthalan force lupnitrile compound useful as an intermediate thereof.

Light

Fine

Background art

Formula (III)

Is a compound useful as an antidepressant, and a method represented by the following reaction scheme is known as its production method (for example, JP2002-121161). -A, see WO2001 / 62754-A).

In the dehydration step of the oxime compound represented by the formula (I) in the above reaction scheme, acetic anhydride or thionyl chloride has been conventionally used as a dehydrating agent.

Disclosure of the invention

One object of the present invention is to provide a method for producing citalopram including a dehydration step of an oxime compound, which can be industrially applied even at a relatively low temperature. It is an object of the present invention to provide a method that can be carried out at a high reaction rate and can suppress the coloring of the product in the dehydration step, and further, the color of ciropram obtained in the following step.

The present invention is as follows.

<1> Formula (I)

Comprising reacting a compound of formula (II) with oxalyl chloride

The manufacturing method of the compound represented by these.

<2> The method according to <1>, wherein the reaction is performed in a temperature range of 0 to 50 ° C. <3> The method according to <1> or <2>, wherein the reaction is performed in a mixture of an aromatic hydrocarbon solvent and an aprotic polar solvent.

<4> The method according to <3>, wherein the mixture of the aromatic hydrocarbon and the aprotic polar solvent is a mixture of toluene and 1,3-dimethyl-2-imidazolidinone.

<5> Formula (1)

Is reacted with oxalyl chloride to give a compound of formula (II)

A process comprising obtaining a compound represented by:

Formula (III) including a step comprising reacting the compound represented by Formula (II) with 3-dimethylaminopropyl octalide

The manufacturing method of the compound represented by these.

BEST MODE FOR CARRYING OUT THE INVENTION

First, the process scheme of the production method in the present invention is shown below.

Dehydration process

This step can be performed by reacting compound (I) with oxalyl chloride, and is usually performed in an organic solvent. Specifically, for example, the compound (I) can be dissolved in an organic solvent and oxalyl chloride is added to the solution. Alternatively, the compound (I) may be added to a mixed liquid of oxalyl chloride and an organic solvent. In consideration of the reaction yield, the formation of by-products, etc., a method of adding the compound (I) to a mixed liquid of oxalyl chloride and an organic solvent is preferable.

The starting compound (I) is, for example, disclosed in JP-A No. 2 0 0 2 — 1 2 1 1 6 1 It can be produced according to the method described in the publication. Oxalyl chloride synthesized by a known method or a commercially available product can be used.

The organic solvent is not particularly limited as long as it does not inhibit the reaction. Ethyl acetate; Acetonitrile; Nitroethane; Aromatic hydrocarbon solvents such as toluene and xylene; Black benzene, 1,2-dichlorobenzene, dichloromethane Halogenated hydrocarbon solvents such as: N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2 —Aprotic polar solvents such as imidazolidinone (DM I) and dimethyl sulfoxide (DMS 2 O); and mixed solvents thereof. Among these, a mixed solvent of an aprotic polar solvent and at least one selected from acetonitrile, toluene, xylene, N-methylpyrrolidone, nitroethane, ethyl acetate and aromatic hydrocarbons is preferable. In particular, a mixed solvent of an aromatic hydrocarbon solvent and an aprotic polar solvent allows the reaction to proceed without reducing the stirring ability of the reaction system even at a small amount of solvent and a low reaction temperature. From the viewpoint of, it is particularly preferable. Among them, a mixed solvent of toluene and DM I, a mixed solvent of toluene and DMF, a mixed solvent of toluene and DMA, a mixed solvent of xylene and DM I, a mixed solvent of xylene and DMF, and xylene and DMA A mixed solvent of toluene and DM I is particularly preferable. The preferable mixing ratio (volume ratio) of the mixed solvent of the aromatic hydrocarbon solvent and the aprotic polar solvent is 20 / l to l Z l (aromatic hydrocarbon solvent Z aprotic polar solvent), More preferably, it is from 10 1 to 2/1.

When a mixed solvent of an aromatic hydrocarbon solvent and an aprotic polar solvent is used, the compound (I) and the aromatic carbonization are mixed in a mixture of aromatic hydrocarbons, aprotic polar solvent and oxalyl chloride. It is preferable to add a mixture of hydrogen solvents. At this time, the amount of the aprotic polar solvent used is preferably 0.2 to 2 times the weight of the oxalyl chloride, and is preferably 0.7 to 1.5 times. It is more preferable that the amount is doubled.

The amount of the organic solvent is usually 0.5 to 50 L, preferably 1 to 20 L, relative to 1 kg of compound (I). However, when using a mixed solvent of an aromatic hydrocarbon and a non-proton polar solvent, usually 5 to 20 L, preferably 1 to about 10 L, per 1 kg of compound (I). Good.

More specifically, when adding a mixture of compound (I) and aromatic hydrocarbons to a mixture of aromatic hydrocarbon solvent, aprotic polar solvent and oxalyl chloride, compound (1) 1 kg In contrast, compound (I) and compound (I) 1 are usually contained in a mixture of 2 to 10 L, preferably 2 to 5 L of aromatic hydrocarbons, aprotic polar solvent and oxalyl chloride. A mode in which usually 1.5 to 10 L, preferably 1.5 to 5 L of a mixture of aromatic hydrocarbons is added dropwise to kg is particularly preferable.

The amount of oxalyl chloride to be used is generally 1-2 mol, preferably 1-1.5 mol, per 1 mol of compound (I).

The reaction temperature is usually 0 to 50 ° C, preferably 10 to 40 ° C. The reaction time is usually 10 minutes to 5 hours, preferably 30 minutes to 2 hours.

After completion of the reaction, the target compound (II) can be isolated by a known method such as extraction, crystallization and concentration after neutralizing the reaction solution. Furthermore, the target compound (II) can be purified by a method such as recrystallization or silica gel column chromatography. Alkylation process

In this step, compound (II) is converted into 3-dimethylaminopropyl halide (eg, 3-dimethylaminopropyl chloride, 3-dimethylaminopropyl fluoride, 3-dimethylaminopropyl chloride). It can be carried out by reacting with Zido etc.).

Specifically, it is performed by the method described in W098-19511-A or US6458975. A method for adding N, N, N, N′-tetramethylethylenediamine to a solution of compound (II) and 1,3-dimethyl-2-imidazolidinone as described in US6458975 The method of adding 1,3-dimethyl-2-imidazolidinone to the solution of (II) and N, N, N, N, —tetramethylethylenediamine is preferred.

This makes it possible to produce compound (III) (sitaguchi plum), which is a useful compound as an antidepressant. EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1 Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (dehydration step)

Charge toluene (55 mL), DMI (7 mL) and 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde (13.6 g, 0.0529 mol) at 20 ± 2 ° C. Oxalyl chloride (7.3g, 0.0575mol, 1.09eq) was added dropwise over 40 minutes and kept at the same temperature for 1 hour. After confirming disappearance of the raw materials by LC analysis, toluene (14 mL) was charged into the reaction mixture, and water (70 mL) was added dropwise at 20 to 25 ° C. After stirring for 30 minutes, the aqueous layer was separated, and the organic layer was washed with 10% soda ash water (70 g) and then with water (70 g). The aqueous layer was separated, anhydrous magnesium sulfate (1.36 g) was added to the organic layer for dehydration, and then the inorganic substance was filtered off and 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5- A strong toluene solution of toluene (90.0 g) was obtained. As a result of evaluating the number of Gardner colors of the reaction solution according to JIS K5400, it was 10. Concentration gave 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-strength lponitrile (ll. 7 g) (yield = 93.7%).

Melting point 96_98 ° C;

IR (KBr) v = 3050 (w), 2867 (m), 2228 (s), 1603 (s), 1510 (s), 1224 (s), 1157 (m), 1048 (s), 1031 (s) , 832 (8) 0 ^-1 ;

_{1H-NMR (CDC1 3, 400MHz} ) d = 5.21 (lH, d, J = 13Hz), 5.34 (1H, d, J = 13Hz), 6.16 (1H, s), 7.06 (2H, t, J = 9Hz), 7.10 (1H, d, J = 8Hz), 7.27 (2H, dd, J = 9Hz, J = 5Hz), 7.55 (1H, d, J = 8Hz), 7.60 (1H, s) ppm. Example 2 Synthesis of 1- (4'-fluorophenyl) -l, 3-dihydroisobenzofuran-5-carbonitrile (dehydration step)

Toluene (27 mL), DMI (7 mL) and oxalyl chloride (7.3 g, 0.0575 mol, 1.09 eq) were charged, and 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran- at 30 ± 2 ° C A mixed slurry solution of 5-carbaldehyde (13.6 g, 0.0529 mol) and toluene (34 mL) was added dropwise over 40 minutes, and kept at that temperature for 30 minutes. After confirming disappearance of the raw material by LC analysis, water (70 mL) was added dropwise to the reaction mixture at 20 to 25 ° C. After stirring for 30 minutes, the aqueous layer was separated, and the organic layer was washed with 10% soda ash water (70 g) and then with water (70 g). After the aqueous layer was separated, a toluene solution (75.3 g) of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-streptolitol was obtained. Concentration gave 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-streptolitol (12.3 g) (yield = 97.8%). Example 3 Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (dehydration step)

Toluene (129mL), DMI (26mL) and oxalyl chloride (27.9g) were charged, and 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde oxime at 25 ± 5 ° C A mixed slurry solution of (51.5 g) and toluene (103 mL) was added dropwise over 52 minutes, washed with toluene (26 mL), and kept at that temperature for 30 minutes. After confirming disappearance of the raw materials by LC analysis, water (257 mL) was added dropwise to the reaction mixture at 20 to 30 ° C. After stirring for 30 minutes, the aqueous layer was separated, and the organic layer was mixed with soda ash (10.3 g), average salt (25.7 g) and water (232 mL), then mixed with average salt (25.7 g) and water (232 mL). Washed with solution. After separation of the aqueous layer, anhydrous magnesium sulfate (5.1 g) was added to the organic layer, and the mixture was stirred at 28 ° C for 1 hour. Magnesium sulfate is filtered off, washed with toluene (26 mL), and 1- (4'-fluorophenyl) -1,3-di- A toluene solution (278.5 g) of hydroisobenzofuran-5-carbonitryl was obtained. According to LC quantitative analysis, the content of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-streptolitol was 15.4%. Example 4 (Hue comparison)

Toluene (12 mL), DMI (1.5 mL) and 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-strength rubydede oxime (3.0 g) were charged and oxalyl chloride was added at 30 ± 2 ° C. (1.88 g) was added dropwise over 30 minutes, and the mixture was kept at the same temperature for 30 minutes. After confirming disappearance of the raw material by LC analysis, the number of Gardner colors of the reaction solution was measured according to JIS K5400, and was 10. Comparative Example 1 (Hue Comparison)

Charge toluene (10 mL), 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde (2.6 g), and add thionyl chloride (1.3 mL) at 80 ± 2 ° C. The solution was added dropwise over 10 minutes and kept at the same temperature for 1 hour. After confirming disappearance of the raw material by LC analysis, the number of guard donor colors of the reaction solution was measured in accordance with JIS K5400. Comparative Example 2

Toluene (10 mL;), 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde Aged xime (2.6 g) was charged, and thionyl chloride (1.3 mL) was added dropwise over 10 minutes and kept at the same temperature for 1 hour. After confirming the disappearance of the raw materials by LC analysis, the Gardner color number of the reaction solution was evaluated according to JIS K5400.

After cooling, the reaction mixture was concentrated and recrystallized with heptane to obtain 1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-streptolitol (2.0 g) (yield) = ₈ 4%). Example 5 Synthesis of l- (3-dimethylaminopropyl) -1- (4'-fluorophenyl) -1,3-dihydroisobenzofuran-5-powered Luponitoryl (Shibaguchi Plum) Process)

1- (4′-fluorophenyl) -1,3- obtained in the same manner as in Example 1 in a suspension in which 60% sodium hydride (0.92 g) was dispersed in tetrahydrofuran (THF, 30 mL). A solution of dihydroisobenzofuran-5-streptolitol (4.80 g) in THF (10 mL) was added dropwise at 40-50 ° C. After stirring at the same temperature for 30 minutes, a solution of 3-dimethylaminopropyl chloride (3.2 g) in toluene (20 mL) was added dropwise and stirred for 10 minutes.

Thereafter, dimethyl sulfoxide (30 mL) was further added dropwise, and the mixture was stirred at 65 to 70 ° C. for 3 hours. The reaction mixture was poured into ice water (200 mL) and extracted three times with toluene (60 mL). The organic layer was extracted twice with 20% aqueous acetic acid (60 mL). After neutralizing the aqueous layer, it was extracted twice with toluene (60 mL). After washing the organic layer with water, anhydrous potassium carbonate (2g) and silica gel (2g) were added, stirred and filtered, and the solvent was distilled off to give a viscous oily 1- (3-dimethylaminopropyl)- 1- (4'-Fluorophenyl) -1,3-dihydroisobenzofuran-5-strength l-ponitrile (Citaguchi plum base, 3.37 g) was obtained (yield = 51.6%).

¹ H-NMR (CDC1 ₃ , 400 MHz) d = 1.26 to .52 (2H, m), 2.11 to 2.26 (4H, m), 2.13 (6H, s), 5.15 (1H, d, J = 13 Hz), 5.19 (1H, d, J = 13Hz), 7.00 (2H, t, J = 9Hz), 7.41 (1H, d, J = 8Hz), 7.43 (2H, dd, J = 9Hz, J = 5Hz), 7.50 (1H , S), 7.59 (1H, d, J = 8 Hz) ppm. The melting point of the crystal obtained by converting this to hydrobromide by a conventional method was 184 to 186 ° C. Example 6 Synthesis of 1- (3-Dimethylaminopropyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-strength Lupitryl (Shiguchiguchi Plum) Process)

1- (4′-fluoropheny) obtained in the same manner as in Example 4 in a mixed solvent of 1,3-dimethyl-2-imidazolidinone (540 mL) and toluene (240 mL). ) -1,3-dihydrobenzofuran-5-strength lponitrile (120 g), 3- (dimethylamino) propyl chloride (82 g) and 60 wt% sodium hydride (24 g) were mixed, and the internal temperature was 60 The reaction was performed at ° C. After completion of the reaction, the reaction solution was added to 700 g of 5 wt% hydrochloric acid, allowed to stand, and then separated into an organic layer and an aqueous layer. The aqueous layer was neutralized with 160 g of a 25 wt% aqueous sodium hydroxide solution, and extracted twice with toluene (using 600 mL for the first time and 240 mL for the second time). After washing the organic layer with water, 48 g of anhydrous potassium carbonate and 18 g of silica gel were added, stirred and filtered, and the solvent was distilled off to give a viscous oily 1- (3-dimethylaminopropyl) -1- (4,- 51 g of fluorophenyl) -1,3-dihydroisobenzofuran-5-powered lupnitryl (Pitaba plum base) was obtained. (Yield = 93%) According to the present invention, the dehydration reaction of the oxime compound can be performed at a relatively low temperature of about room temperature, and the coloring of the product in the reaction can be suppressed. Therefore, the present invention is suitable for implementation of a method for producing citalopram including a dehydration step of an oxime compound on an industrial scale.

Claims

Claim Formula (I)

Comprising reacting a compound of formula (II) with oxalyl chloride

The manufacturing method of the compound represented by these.

2. The method according to claim 1, wherein the reaction is carried out in the temperature range of 0 to 50 ° C.

3. The method according to claim 1, wherein the reaction is carried out in a mixture of an aromatic hydrocarbon solvent and an aprotic polar solvent.

4. The method according to claim 3, wherein the mixture of the aromatic hydrocarbon and the aprotic polar solvent is a mixture of toluene 'and 1,3-dimethyl-2-imidazolidinone.

5. Formula (I)

The compound represented by the formula (II) is reacted with oxalyl chloride.

A process comprising obtaining a compound represented by:

The manufacturing method of the compound represented by these.