JP2002069030A - Method for producing sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate having anti-inflammatory and analgesic action in good yield and simple To provide a manufacturing method for manufacturing. [Solution] (Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a lower alkyl, etc., and R ³ represents a hydrogen atom, a lower alkyl, etc.) The present invention provides a compound represented by the formula (I): $ 4
-[(2-oxocyclopentyl) methyl] phenyl}
Propionic acid is converted into sodium with a base represented by the formula (III) in the presence of a solvent represented by the formula (II) and water,
From the reaction solution, sodium 2 represented by the formula (IV)
Sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate characterized by crystallizing-{4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate Provide a method of manufacturing a product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate (generic name: loxoprofen sodium) having anti-inflammatory and analgesic effects.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 58-4699 discloses a method for producing sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate.
{4-[(2-Oxocyclopentyl) methyl] phenyl} propionic acid is dissolved in an aqueous sodium hydroxide solution, stirred, acidified with hydrochloric acid, extracted with ether, and the extract is washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off, the obtained residue was dissolved in ethanol, and an aqueous sodium hydroxide solution was added dropwise to the ethanol solution under ice-cooling. After stirring, the solvent was distilled off. A method of recrystallization with ether is disclosed.

Further, as a method for producing sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate, Journal of Medicinal Chemistry (J. Med. Chem.),
7, p. 212 (1984) describes 2- {4-[(2-
Oxocyclopentyl) methyl] phenyl} propionic acid was dissolved in ethanol, aqueous sodium hydroxide was added to the solution, sodium chloride was added, the solvent was distilled off from the reaction solution, and the obtained residue was recrystallized from ethyl acetate. It discloses a method for converting the data.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide sodium 2- {4-[(2
[Oxocyclopentyl) methyl] phenyl} propionate dihydrate in a high yield and easily.

[0005]

According to the present invention, there is provided a compound of the formula (I)

[0006]

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The 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid represented by the formula (II)

[0008]

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Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom or lower alkyl, or R ¹ and R ² together with an adjacent carbon atom represent cycloalkyl. In the presence of the solvent and water represented by the formula (I)
II)

[0010]

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Wherein R ³ represents a hydrogen atom, a lower alkyl, an aryl, a lower alkenyl or an aralkyl, and then sodium chloride with a base represented by the formula (IV)

[0012]

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Sodium 2- ナ ト リ ウ ム 4-
Crystallizing [(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate, sodium 2- {4-[(2-oxocyclopentyl)
Methyl] phenyl} propionate dihydrate is provided. Among them, R ¹ and R ² are preferably the same or different and are lower alkyl, and R ³ is preferably a hydrogen atom or lower alkyl.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of each group in the formula, examples of the lower alkyl include straight or branched ones having 2 to 8 carbon atoms, such as methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl, heptyl, octyl and the like.

Examples of the cycloalkyl include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the aryl include those having 6 to 14 carbon atoms, such as phenyl, naphthyl,
And anthryl.

Examples of the lower alkenyl include straight-chain or branched-chain C 2 -C 6, for example, vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl and the like. Aralkyl has 7 to 7 carbon atoms.
15, for example, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 9-fluorenylmethyl and the like.

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

[0018]

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The sodium 2- represented by the formula (IV)
{4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate is obtained by converting 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid represented by the formula (I) into a compound represented by the formula The compound can be produced by subjecting a base represented by the formula (III) to sodium chloride in the presence of the solvent represented by the formula (II) and then crystallizing the reaction solution.

The starting material, 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid, is prepared by a known method [Japanese Patent Laid-Open No. 10-265433, Japanese Patent Publication No.
No. 4699, Japanese Patent Application Laid-Open No. 62-161740, and Journal of Medicinal Chemistry (J. Me.
d. Chem. ), 27, p. 212 (1984)
Etc.] or according to it.

The sodium chloride is represented by the formula (I) 2
The reaction is preferably carried out in the presence of preferably 1 to 100 equivalents, more preferably 2 to 50 equivalents of water, based on-{4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid. The base represented by the formula (III) is preferably 0.5 to 1.5 to the 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid represented by the formula (I). Equivalent, more preferably 0.9 to
1.0 equivalent is used. Preferred specific examples of the base represented by the formula (III) include sodium hydroxide, sodium methoxide, sodium ethoxide and the like.

The amount of the solvent represented by the formula (II) is not particularly limited.
The amount is preferably 1 to 100 times (weight) with respect to [(2-oxocyclopentyl) methyl] phenyl} propionic acid. Preferred specific examples of the solvent represented by the formula (II) include acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.

Solvents other than the solvent represented by the formula (II) may be used. Specific examples thereof include esters such as ethyl formate, ethyl acetate, isopropyl acetate and isobutyl acetate, methanol, ethanol and isopropanol. Alcohols such as ethylene glycol, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, amides such as dimethylformamide, dimethylacetamide, carbamates such as ethyl carbamate, propyl carbamate, acetonitrile, nitriles such as propionitrile, Pentane, hexane, heptane, octane, cyclohexane,
Halogen-substituted or unsubstituted aliphatic hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, halogen-substituted or unsubstituted aromatic hydrocarbons such as benzene, toluene, xylene, naphthalene, chlorobenzene, bromobenzene, and dichlorobenzene, and triethylamine , Diisopropylamine, amines such as piperidine, urea, thiourea, sulfolane, dimethylsulfide, dimethylsulfoxide, ethylthiocarbamate, ethyldithiocarbamate, methanesulfonamide, pyridine, quinoline,
Indole, benzofuran, benzothiophene and the like can be mentioned, and these can be used alone or in combination. In this case, it is preferable that the solvent represented by the formula (II) be contained in 50% or more (volume) in all the solvents.
% (Volume) or more is more preferable.

In the production method of the present invention, 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid represented by the formula (I) is usually added to the solvent represented by the formula (II). After dissolution, an aqueous solution of a base represented by the formula (III) is added to this solution, but the method and order of addition of the solvent represented by the formula (II) and the base represented by the formula (III) are limited. Not done.

Usually, the sodium chloride is preferably 20
C. to 100.degree. C., for 5 minutes to 48 hours, more preferably 20 minutes
C. to 60.degree. C. for 30 minutes to 12 hours, and if necessary, the solution is cooled to preferably -30.degree. C. to 15.degree. C., more preferably -20.degree. Crystals can be obtained. The target crystals obtained by crystallization are usually separated by filtration, but if necessary, the crystals may be washed with a solvent represented by the formula (II).

In the production method of the present invention, since the solvent for sodium chloride and the solvent for crystallization are the same, an operation for changing the solvent from the solvent for sodium chloride to the solvent for crystallization (evaporation of solvent, etc.)
This is a method suitable for industrial production, which can produce the target product in a higher yield without the necessity.

[0027]

EXAMPLES Example 1: Sodium 2- {4-[(2-
(Oxocyclopentyl) methyl] phenyl} propionate dihydrate 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid obtained in Reference Example 2 (100.
0 g, 406 mmol) was dissolved in 600 mL of acetone and heated to 52 ° C. Here, 11.7 mol /
L of sodium hydroxide aqueous solution (33.3 mL, 390 mL)
mmol) and stirred for 1 hour, after which the reaction was cooled to 5 ° C. The precipitated crystals were collected by suction filtration, washed with acetone, and dried at 30 ° C. and normal pressure to obtain sodium 2- {4-
[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate (119.0 g, 96% yield)
I got ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.2
8 (2H, d, J = 8.1 Hz), 7.08 (2H,
d, J = 8.1 Hz), 3.36 (1H, q, J = 7.
1 Hz), 3.12 (1H, dd, J = 12.8,3.
1 Hz), 1.88 to 2.52 (6H, m), 1.68
To 1.84 (1H, m), 1.49 to 1.62 (1H,
m), 1.32 (3H, d, J = 7.1 Hz) IR (KBr, cm ^-1 ): 3371, 1732, 155
1,1408,1153,725 Moisture value (Karl Fischer method): 11.8% (theoretical value 11.8%) Elemental analysis: C ₁₅ H ₁₇ NaO ₃ .2H ₂ O (molecular weight: 30)
4.32) theory: C; 59.20, H; 6.96 Found: C; 59.28, H; 7.01 EI-MS: 269 (M + + 1-2H 2 O)

Reference Example 1: 2- [4- (1-ethoxycarbonyl-2-oxocyclopentyl) methylphenyl]
Ethyl propionate 2-ethoxycarbonylcyclopentanone (182.5
g, 1.16 mol) and tetraethylammonium chloride (18.2 g, 0.11 mol) were added to toluene (3.3 L) at room temperature, and potassium carbonate (304 g, 2.2 mol) was added thereto. In addition, the mixture was suspended and stirred. Thereafter, ethyl 2- (4-chloromethylphenyl) propionate (255.2 g, 1.1 mol) was added, and the resulting mixture was stirred at 80 ° C. for 3 hours. After the completion of the reaction, a substance insoluble in the reaction solvent was removed by filtration, washed with water, and the solvent was distilled off, whereby 434 g of an oily crude product was obtained (367.5 g of the target substance, yield: 97%).
I got

The obtained crude product was subjected to silica gel column chromatography to measure physicochemical data to purify the target compound. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.19
(2H, d, J = 8.2 Hz), 7.09 (2H, d,
J = 8.2 Hz), 4.03 to 4.21 (4H, m),
3.66 (1H, q, J = 7.2 Hz), 3.19 (1
H, d, J = 13.8 Hz), 3.07 (1H, d, J)
= 13.8 Hz), 2.32 to 2.45 (2H, m),
1.84 to 2.10 (3H, m), 1.53 to 1.68
(1H, m), 1.47 (3H, d, J = 7.2H
z), 1.25 (3H, t, J = 7.1 Hz), 1.2
0 (3H, t, J = 7.1 Hz) IR (neat, cm ^-1 ): 2980, 1732, 15
15, 1161, 1025, 861 EI-MS: 346 (M ⁺ )

Reference Example 2: 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid 2- [4- (1-ethoxycarbonyl-2-oxocyclopentyl) methylphenyl obtained in Reference Example 1 141.8 g of an oil containing ethyl propionate (120.0 g, 346 mol) was added to 6 mol / L hydrochloric acid (1.2 L) at room temperature, and the mixture was heated under reflux for 8 hours. After extraction with toluene, the extract was treated with a 1 mol / L aqueous sodium hydroxide solution to transfer the target substance to the aqueous layer, and then the aqueous layer was acidified with hydrochloric acid and extracted again with toluene. The extract was washed with water and the solvent was distilled off to obtain 95.0 g of a slightly yellow oily crude product (content of the desired product: 73.8 g, yield: 87%). The obtained crude product is isopropyl acetate at room temperature.
Dissolved in 80 mL and cooled to 5 ° C. The precipitated crystals were collected by filtration and dried under reduced pressure at 60 ° C. to give 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionic acid.
65.7 g (77% yield) were obtained.

The physicochemical data of the obtained target compound is as follows. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.23
(2H, d, J = 8.2 Hz), 7.12 (2H, d,
J = 8.2 Hz), 3.70 (1H, q, J = 7.2H)
z), 3.12 (1H, dd, J = 13.8, 4.0H
z), 2.50 (1H, dd, J = 13.8, 9.6H
z), 2.29 to 2.39 (2H, m), 2.04 to
2.27 (2H, m), 1.91 to 2.01 (1H,
m), 1.65 to 1.80 (1H, m), 1.49 to
1.60 (1H, m), 1.49 (3H, d, J = 7.
2 Hz) IR (KBr, cm ^-1 ): 3377, 1733, 170
1,1166,850 EI-MS: 246 (M ⁺ )

[0032]

Industrial Applicability According to the present invention, there is provided a process for producing sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate having anti-inflammatory and analgesic effects in good yield and with ease. Provided.

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Claims (3)

[Claims] 1. A compound of the formula (I) 2- {4-[(2-oxocyclopentyl) represented by
Methyl] phenyl} propionic acid is converted to a compound of formula (II) Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom or lower alkyl, or R ¹ and R ² together with an adjacent carbon atom represent cycloalkyl. Formula (III) in the presence of a solvent and water (Wherein, R ³ represents a hydrogen atom, lower alkyl, aryl, lower alkenyl or aralkyl) after sodium salification with a base represented by the formula (IV): Sodium 2- {4-[(2-oxocyclopentyl) methyl] phenyl} propionate 2
Sodium 2-, characterized by crystallizing hydrate
A method for producing {4-[(2-oxocyclopentyl) methyl] phenyl} propionate dihydrate. 2. The process according to claim 1, wherein R ¹ and R ² are the same or different and are lower alkyl. 3. The method according to claim 1, wherein R ³ is a hydrogen atom or lower alkyl.