JP2009209106A - Method for producing 2-imino-4-thiazolidinone derivative and 2,4-thiazolidinedione derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a production method whereby 5-[4-[2-äN-methyl-N-(2-pyridyl)amino}ethoxy]benzyl]-2,4-thiazolidinedione (general name: rosiglitazone) can be prepared in a high yield with few steps. <P>SOLUTION: 5-[4-[2-äN-methyl-N-(2-pyridyl)amino}ethoxy]benzyl]-2,4-thiazolidinedione is obtained by: carrying out a condensation reaction of 4-[2-äN-methyl-N-(2-pyridyl)amino}ethoxy]benzaldehyde and 2-imino-4-thiazolidinone to obtain a new compound, i.e. 5-[4-[2-äN-methyl-N-(2-pyridyl)amino}ethoxy]benzylidene]-2-imino-4-thiazolidinone; reducing the new compound to produce 5-[4-[2-äN-methyl-N-(2-pyridyl)amino}ethoxy]benzyl]-2-imino-4-thiazolidinone; and hydrolyzing the resultant compound. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione (generic name: rosiglitazone) represented by the following formula: The present invention relates to a production method and a novel intermediate thereof.

The compound (V) according to the production method of the present invention has an excellent insulin resistance improving action and is a substance useful as a therapeutic agent for diabetes.
As a conventional method for producing the compound (V), 4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzaldehyde is reacted with 2,4-thiazolidione to produce 5--4- [2 A method of obtaining-{N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene} -2-imino-4-thiazolidinone and reducing it is disclosed (Patent Document 1, Patent) Document 2 and Non-Patent Document 1).
However, these methods have a problem of using a large amount of heavy metal catalyst for reduction. In addition, none of the conventional methods is satisfactory in terms of yield.

Japanese Patent No. 2817840 Japanese Patent No. 3723448 Journal of Medicinal Chemistry, Vol. 37, No. 23, p. 3777-3985 (1994).

  An object of the present invention is to treat 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione useful as a therapeutic agent for diabetes in a number of steps. Production method which can be obtained in a small amount and in a high yield, and 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene], which is a useful synthetic intermediate therefor It is to provide 2-imino-4-thiazolidinone and a method for producing the same.

  As a result of intensive studies to solve the above problems, the present inventors have found that a novel compound, 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2- By obtaining imino-4-thiazolidinone and using it as a synthetic intermediate, it was found that the intended purpose could be achieved, and further studies were made to complete the present invention.

で表わされる４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンズアルデヒドと、式（II）

で表わされる２−イミノ−４−チアゾリジノンとを反応させて、式（III）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジリデン〕−２−イミノ−４−チアゾリジノンを製造する方法、
２．式（III）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジリデン〕−２−イミノ−４−チアゾリジノン、
３．式（III）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジリデン〕−２−イミノ−４−チアゾリジノンを還元して、式（IV）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジル〕−２−イミノ−４−チアゾリジノンを製造する方法、
４．式（III）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジリデン〕−２−イミノ−４−チアゾリジノンを還元して、式（IV）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジル〕−２−イミノ−４−チアゾリジノンとし、これを加水分解することにより式（Ｖ）

で表わされる５−〔４−［２−{Ｎ−メチル−Ｎ−（２−ピリジル）アミノ}エトキシ］ベンジル〕−２，４−チアゾリジンジオンを製造する方法、を提供することができる。 That is, according to the present invention,
1. Formula (I)

4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzaldehyde represented by the formula (II)

Is reacted with 2-imino-4-thiazolidinone represented by the formula (III)

A process for producing 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by the formula:
2. Formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by
3. Formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by formula (IV) is reduced.

A process for producing 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone represented by:
4). Formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by formula (IV) is reduced.

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone represented by the formula (V)

A process for producing 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione represented by formula (1) can be provided.

The novel intermediate (III) used in the present invention is easy to reduce the double bond at the benzylidene moiety and can be selectively reduced. Therefore, according to the present invention, it is not necessary to use a large amount of a heavy metal compound that is difficult to treat with a waste liquid.
In addition, by using the novel intermediate (III) in the present invention, the compound (V) can be produced with a small number of steps and with a high yield.

  In the present invention, the condensation reaction for producing compound (III) from compound (I) and compound (II) is usually carried out in a suitable solvent in the presence of a suitable base. Suitable solvents include alcohols (eg, methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, etc.), ethers (eg, , Tetrahydrofuran, dioxane, dimethoxyethane, etc.), benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, acetonitrile, pyridine, acetic acid or the like, or water or water and a mixed solvent thereof is used. On the other hand, suitable bases include amines (eg, ammonia, methylamine, ethylamine, n-butylamine, pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropylamine, triethylamine, etc.), sodium alkoxide (eg, sodium methoxide, Sodium ethoxide), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate, potassium acetate, or acetic acid and other carboxylic acids and amines (e.g., ammonia, methylamine, ethylamine, n-butylamine, pyrrolidine, piperidine, morpholine, Salts with piperazine, diethylamine, diisopropylamine, triethylamine, etc.) are used. These bases may be mixed and used at an appropriate ratio. Compound (II) is generally used in an amount of 1 to 4 mol, preferably 1 to 2.5 mol, per 1 mol of compound (I). The amount of the base to be used is 0.05 to 1.5 mol, preferably 0.3 to 1.0 mol, per 1 mol of compound (I). This condensation reaction is usually performed at room temperature to reflux temperature, preferably 60 ° C. to reflux temperature, and the reaction time is usually 0.5 to 50 hours.

Compound (III) has a cis isomer (Z isomer) and a trans isomer (E isomer) depending on the configuration at the benzylidene carbon-carbon double bond site.
Compound (III) also has tautomers as found in 2-imino-4-thiazolidinone and its similar compounds.

Next, compound (IV) can be produced by reducing compound (III) obtained as described above. This reduction reaction is usually carried out by catalytic reduction in a suitable solvent in the presence of a suitable catalyst. Suitable solvents include hydrocarbons (eg, hexane, heptane, octane, nonane, decane, benzene, toluene, xylene, etc.), ethers (eg, dioxane, dimethoxyethane, tetrahydrofuran, etc.), organic acids (eg, , Formic acid, acetic acid, propionic acid, butanoic acid, etc.), N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, or a mixed solvent thereof. On the other hand, as the catalyst, a catalyst based on a so-called heterogeneous transition metal supported or not (for example, palladium black, palladium carbon, palladium hydroxide carbon, palladium-barium sulfate, palladium-barium carbonate, Platinum oxide, platinum-carbon, rhodium carbon, ruthenium carbon, Raney nickel, etc.) are used. The reaction temperature in the reduction reaction is usually 0 to 200 ° C, preferably room temperature to 80 ° C. The reaction time in the reduction reaction is usually 0.5 to 100 hours, preferably 1 to 48 hours. Although the reduction reaction proceeds even at normal pressure, it is preferably carried out under a pressure of 15.0 MPa or less, and further 0.2 to 1.0 MPa in order to promote the reaction. In addition, the reduction reaction is carried out with inorganic acids (eg, hydrogen chloride, hydrogen bromide, sulfuric acid, etc.), organic acids (eg, alkyl sulfonic acids such as methanesulfonic acid and ethanesulfonic acid, aromatics such as benzenesulfonic acid, toluenesulfonic acid, etc. It may be carried out in the presence of sulfonic acids and the like. The amount of acids used at this time is usually 0.5 to 10 times mol, preferably 0.5 to 3.0 times mol, of the compound (III).
Compound (IV) has crystal polymorphs and can be isolated as different crystal forms.
Further, the produced compound (IV) may be led to a hydrolysis step for obtaining a compound (V) in the next step without isolation.

Next, the hydrolysis reaction of the compound (IV) obtained as described above can be carried out by a usual method without any particular difficulty. For example, the hydrolysis reaction of compound (IV) is usually carried out in a suitable solvent in the presence of a suitable mineral acid or a suitable organic acid. Suitable solvents include, for example, alcohols (eg, methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, etc.), ethers ( Eg, tetrahydrofuran, dioxane, dimethoxyethane, etc.), organic acids (eg, formic acid, acetic acid, propionic acid, butanoic acid, etc.), solvents such as benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, acetonitrile, etc. Alternatively, water or water and a mixed solvent thereof are used. On the other hand, hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like are used as suitable mineral acids. Furthermore, organic acids (eg, alkyl sulfonic acids such as methane sulfonic acid and ethane sulfonic acid, aromatic sulfonic acids such as benzene sulfonic acid and toluene sulfonic acid, etc.), and these mineral acids or organic acids are mixed in an appropriate ratio. May be used. This hydrolysis reaction is usually carried out at 20 ° C. to reflux temperature, preferably 50 ° C. to 120 ° C., and the reaction time is usually 0.5 to 20 hours.
The compound (V) or the hydrochloride of the compound (V) or its maleate can be obtained by a conventional separation and purification method (eg, concentration, neutralization, hydrochloric acid chloride, crystallization, extraction, recrystallization, chromatography, etc.). It can be separated and purified.

4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzaldehyde (compound (I)) and 2-imino-4-thiazolidinone (compound (II)) used in Example 1
Were prepared according to the methods described in the following documents.
Compound (I): International Publication No. 07/017095 Pamphlet Compound (II): Organic Synthesis, Volume 3 (Org. Synth., Coll. Vol. 3) p.751-752.

Example 1 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone (III)
2-Imino-4-thiazolidinone (16.1 g) was suspended in methanol (670 mL) and 4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzaldehyde (32.3 g) and piperidine were suspended. The mixture to which (10.7 g) was added was heated to reflux with stirring for 24 hours. After cooling to room temperature and stirring overnight, the precipitated crystals were collected by filtration and washed with methanol. The obtained crystals were dried to give 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone crystals (41.5 g: Yield 93%) was obtained.
mp 221 to 223 ° C. (decomposition point)
IR (paste method) cm ⁻¹ : 3178, 1670, 1605, 1503, 1426, 1286, 1252, 820, 767, 731, 722, 527, 501
¹ H-NMR (DMSO-d ₆ : TMS) δ ppm: 3.08 (3H, s), 3.93 (2H, t), 4.21 (2H, t), 6.58 (1H, m), 6.65 (1H, d), 7.10 (2H, d), 7.51 (2H, d), 7.50 (1H, m), 7.56 (1H, s), 8.09 (1H M), 9.25 (1H, bs)
MS m / z [(M + 1) ⁺ ]: 355

Example 2 5- [4- [2- {N-Methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone (IV)
To a solution of methanesulfonic acid (12.1 g) in formic acid (110 mL) was added 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone ( 20.2 g) and 10% palladium carbon (containing 50% water) (7.5 g) was added to the mixture and subjected to a catalytic reduction reaction at 40 to 45 ° C. for 8 hours under a hydrogen pressure of 0.4 MPa to 0.8 MPa. I did it. After completion of the reaction, the catalyst was removed by filtration, and the catalyst was further washed with ethanol. The filtrate and washings were combined and concentrated, and the residue was dissolved by heating in 50% aqueous ethanol (80 mL). Next, the mixture was neutralized with 28% aqueous ammonia to cause crystallization, and the suspension was further heated and stirred. Then, the precipitated crystals were collected by filtration and washed with water. Thereafter, by drying, pale yellowish white crystals of 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone (19.2 g) : Yield 94.5%).
mp 189-191 ° C
IR (paste method) cm ⁻¹ : 3227, 1665, 1606, 1508, 1426, 1294, 1249, 1145, 821, 765, 745, 731, 720, 490
¹ H-NMR (DMSO-d ₆ : TMS) δ ppm: 2.84 (1H, dd), 3.07 (3H, s), 3.29 (1H, dd), 3.89 (2H, t), 4.10 (2H, t), 4.54 (1H, dd), 6.56 (1H, m), 6.64 (1H, d), 6.85 (2H, d), 7.12 (2H) D), 7.50 (1H, m), 8.08 (1H, m), 8.71 (1H, s), 8.94 (1H, s)
MS m / z [(M + 1) ⁺ ]: 357

Example 3 5- [4- [2- {N-Methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone (IV) (alternative method)
To a solution of methanesulfonic acid (9.82 g) in formic acid (100 mL) was added 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone ( 18.1 g) was dissolved, and a mixture obtained by adding 10% palladium carbon (containing 50% water) (3.4 g) was subjected to a catalytic reduction reaction at 40 ° C. for 8 hours under a hydrogen pressure of 0.5 MPa to 0.8 MPa. . After completion of the reaction, the catalyst was removed by filtration, and the catalyst was further washed with ethanol. The filtrate and washings were combined and concentrated, and the residue was dissolved by heating in 50% aqueous ethanol (80 mL). Next, the mixture was neutralized with 28% aqueous ammonia for crystallization, and the suspension was further heated and stirred, and then the crystals were collected by filtration and washed with water. Thereafter, by drying, pale yellow crystals of 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone (16.8 g: Yield 92.3%) was obtained.
The data of mp, IR, ¹ H-NMR and MS were consistent with the data of Example 2.

Example 4 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione (V) and its maleate salt (1) 5- [ A mixed solution of 4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone (18.5 g) and dilute hydrochloric acid aqueous solution (150 mL) was refluxed for 10 hours. . After concentration under reduced pressure, water (50 mL) was added to the residue for dissolution, and 28% aqueous ammonia (22 mL) was added dropwise to neutralize the solution, which was then made alkaline. The precipitated oil was dissolved in ethyl acetate (300 mL), and the organic layer was separated. The separated organic layer was washed with 5% brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl. ] -2,4-thiazolidinedione was obtained.
mp 151-153 ° C
IR (paste method) cm ⁻¹ : 2666, 1693, 1610, 1508, 1428, 1248, 1171, 1041, 995, 812, 773, 719, 664, 530
¹ H-NMR (DMSO-d ₆ : TMS) δ ppm: 3.05 (1H, dd), 3.07 (3H, s), 3.29 (1H, dd), 3.90 (2H, t), 4.11 (2H, t), 4.86 (1H, dd), 6.57 (1H, m), 6.63 (1H, d), 6.88 (2H, d), 7.14 (2H) D), 7.50 (1H, m), 8.08 (1H, m)
MS m / z [(M + 1) ⁺ ]: 358
(2) 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione obtained above is dissolved in ethanol (120 ml), Maleic acid (5.8 g) was added and dissolved. Subsequently, the mixture was filtered with activated carbon (2 g, and the filtrate was cooled and stirred for crystallization. The crystals were collected by filtration and dried to give 5- [4- [2- {N-methyl- N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione A slightly yellowish white crystal (21.4 g: yield 87.1%) of maleic acid (rosiglitazone maleate) was obtained.
HPLC purity: 99.5%
mp127-128 ° C
IR (paste method) cm ⁻¹ : 3129, 2774, 1756, 1707, 1640, 1615, 1542, 1513, 1350, 1245, 1163, 865, 764, 717, 662, 579, 525
¹ H-NMR (DMSO-d ₆ : TMS) δ ppm: 3.06 (1H, dd), 3.13 (3H, s), 3.29 (1H, dd), 3.94 (2H, t), 4.14 (2H, t), 4.86 (1H, dd), 6.21 (2H, s), 6.69 (1H, t), 6.86 (2H, d), 6.87 (1H) , T), 7.14 (2H, d), 7.66 (1H, m), 8.05 (1H, m)
MS m / z: 358 [(M + 1) ⁺ ] (as rosiglitazone)
MS m / z: 356 [(M-1) ⁻ ] (as rosiglitazone), 115 [(M−1) ⁻ ] (as maleic acid)

Example 5 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione (V) hydrochloride 5- [4- [2- A mixed solution of {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone (14 g) and dilute aqueous hydrochloric acid (112 mL) was refluxed for 10 hours. After cooling, ethanol (10 mL) and activated carbon (2 g) were added to the reaction solution, heated and stirred, and filtered. The filtrate was cooled and stirred for crystallization, and the crystals were collected by filtration, washed with water, and then washed with ethyl acetate. Thereafter, by drying, the fine salt of 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione hydrochloride (rosiglitazone hydrochloride) Yellowish white crystals (14.8 g: yield 95.6%) were obtained.
HPLC purity: 99.5%
mp 136-138 ° C
IR (paste method) cm ⁻¹ : 3388, 2736, 1752, 1702, 1642, 1609, 1544, 1512, 1250, 1152, 829, 769, 712, 661, 539, 508.
¹ H-NMR (DMSO-d ₆ : TMS) δ ppm: 3.06 (1H, dd), 3.29 (1H, dd), 3.32 (3H, s), 4.11 (2H, t), 4.22 (2H, t), 4.88 (1H, dd), 6.83 (2H, d), 6.95 (1H, t), 7.15 (2H, d), 7.34 (1H) D), 8.00 (2H, m)
MS m / z: 358 [(M + 1) ⁺ ] (as rosiglitazone)

According to the present invention, from the known compound 4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzaldehyde (I), the novel compound 5- [4- [2- {N-methyl] Via 5-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone (III), 5- [4- [2- {N-methyl-N- ( 2-Pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione (V) can be advantageously produced industrially.

Claims (4)

Formula (I)

4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzaldehyde represented by the formula (II)

Is reacted with 2-imino-4-thiazolidinone represented by the formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by the formula: Formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by Formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by formula (IV) is reduced.

A process for producing 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone represented by the formula: Formula (III)

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzylidene] -2-imino-4-thiazolidinone represented by formula (IV) is reduced.

5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2-imino-4-thiazolidinone represented by the formula (V)

A process for producing 5- [4- [2- {N-methyl-N- (2-pyridyl) amino} ethoxy] benzyl] -2,4-thiazolidinedione represented by the formula: