KR100697983B1 - Novel intermediate, manufacturing method of pioglitazone using it - Google Patents

Abstract

A method for efficiently preparing pioglitazone is provided to obtain the pioglitazone effective as a prophylatic and therapeutic agent of diabetes from a novel intermediate of pioglitazone by removing a protection group therefrom. The method for preparing pioglitazone represented by the formula(1) comprises a step of performing a deprotection reaction on a compound represented by the formula(2) in the presence of an acid catalyst at a temperature of 20-100 deg.C. In the formula(2), Z is a protecting group of thiazolidine-2,4-dione selected from the group consisting of 4-nitrobenzyl, beta-propionitril or trytyl(-C(Ph)3). The compound of the formula(2) is prepared by performing Mitsunobu reaction(SN2) on a compound represented by the formula(3) and a compound represented by the formula(4) using diethyl azodicarboxylate(DEAD) and triphenylphosphine(PPh3).

Description

New intermediate and method for producing pioglitazone using the same {Novel intermediate, manufacturing method of pioglitazone using it}

The present invention relates to a method for preparing pioglitazone (Pioglitazone) represented by the following formula (1), which has low blood sugar and hypoglycemic activity and is effective as an agent for treating and preventing diabetes, and more particularly, a compound represented by the following formula (2) as a novel intermediate for preparing pioglitazone And a protecting group (Z) of thiazolidine-2,4-dione introduced into this intermediate compound in the presence of an acid to efficiently prepare the pioglitazone represented by the following formula (1).

In Formula 2, Z represents a protecting group of thiazolidine-2,4-dione.

   Pioglitazone (pioglitazone) represented by the formula (1) is 5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -benzyl} -thiazolidine-2,4-dione As a thiazolidinedione derivative having a low blood sugar and hypoglycemic activity, it is well known to be useful as an insulin sensitizer and accelerator because it is effective in treating and preventing diabetes.

   Methods for the preparation of thiazolidinedione derivatives and pharmacologically acceptable salts which are practical as antidiabetic drugs are disclosed in EP 0193256A1 and US 4687777.

The preparation method of pioglitazone disclosed in EP 0193256A1 and US 4687777 is a 2- (5-ethyl-2-pyridyl) ethanol and 4-fluoro represented by the following general formula (3), as shown in Scheme 1 below. Rho-1-nitrobenzene was reacted to obtain 4- [2- (5-ethyl-2-pyridyl) -ethoxy] -1-nitrobenzene represented by the following formula (II), followed by palladium on carbon (Pd -C) reduction under a catalyst to obtain a compound represented by the following formula (III), followed by diazotization reaction in aqueous bromic acid solution and merwein arylation by acryl ester under a cupric oxide (Cu ₂ O) catalyst. To obtain a compound represented by the following formula (IV) and to react with thiourea in the presence of sodium acetate in ethanol to obtain a compound represented by the following formula (V), and finally hydrolyzed in an inorganic acid solvent to the formula Blood displayed Article Rita is gaining zone.

   However, the conventional manufacturing method according to Scheme 1 is composed of a multi-step process, and the merbine arylation reaction proceeds to an exothermic reaction in which a large amount of nitrogen is generated, which leads to extremely low yield due to the high risk of byproducts and high byproducts. It is known that there is a lot of problems to apply industrially, because it takes a separate cost for treating this by leaving the waste containing heavy metals as a reactant and using odorous acrylic esters as a reactant.

   In addition, EP 0506273B1 and KR 95-008312 disclose a process of the following Scheme 2 as another process for producing pioglitazone.

   According to the preparation method according to Scheme 2, 2- (5-ethyl-2-pyridine) ethanol represented by the following formula (3) and p-toluenesulfonyl chloride represented by the following formula (VI) in the presence of organic and inorganic bases P-hydroxy after preparing toluene-4-sulfonic acid-2- (5-ethyl-pyridin-2-yl) -ethyl ester represented by the following formula (VII) using benzyltributylammonium chloride as a phase transfer catalyst Reaction with benzaldehyde to give 4- [2- (5-ethylpyridin-2-yl) ethoxy] benzaldehyde, represented by the following formula (VII), followed by 2,4-thia represented by the following formula (VII) Reacting with zolidinedione to form 5-[[4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl] methylene] -2,4-thiazolidinedione represented by the following formula (VII): To obtain a pioglitazone represented by the following formula (1) by performing a high-pressure hydrogen reduction reaction under a carbon-based palladium (Pd-C) catalyst.

   In addition, EP 0506273B1 and KR 95-008312 disclose 4- [2- (5-ethylpyridin-2-yl) ethoxy represented by the formula (VII), which is synthesized as an intermediate in the preparation method according to Scheme 2 above. ] Method for preparing benzalaldehyde by the method of Scheme 3 below is disclosed. That is, 2- (5-ethyl-2-pyridine) ethanol represented by the following formula (3) and 4-fluorobenzonitrile represented by the following formula (XI) are reacted in the presence of sodium hydride, as shown in the following scheme (3). To obtain 4- [2- (5-ethylpyridin-2-yl) ethoxy] benzonitrile represented by the following formula (XII), a reduction reaction using Raney Ni in formic acid is carried out. 4- [2- (5-ethylpyridin-2-yl) ethoxy] benzaldehyde is obtained as shown by (i).

In addition, WO93 / 13095 discloses a co-substituted, bidentate ligand for a 5-substituted methylene-thiazolidinedione represented by the following formula (VII-a) in the same manner as shown in Scheme 4 below. And a reduction system using a catalyst system composed of a sodium borohydride (NaBH ₄ ) reducing agent.

   In Scheme 4, X is an organic residue as a derivative of thiazolidinedione.

   However, the 5-substituted methylene-thiazolidinedione represented by the formula (VII-a) is synthesized as a reaction intermediate, and the methylene double bond is reduced to reduce the 5-substituted represented by the formula (VII-b). In order to convert to methyl-thiazolidinedione, it is generally technically significant that a palladium on carbon (Pd-C) catalyst and pressurized hydrogen reduction conditions must be maintained to selectively reduce the double bond at the desired position outside the ring. It is tricky and can also cause low yields. In addition, metal catalysts and pressurized hydrogenation methods used in reduction reactions carry various risks in the manufacturing process and require special equipment for smooth processing while treating them.

   As described above, in the typical method of producing a known pioglitazone (pioglitazone), there are many restrictions on mass production of pioglitazone by performing a reduction reaction by synthesizing 5-substituted methylene-thiazolidinedione as a reaction intermediate. Therefore, there is an urgent need for the development of improved synthetic methods that can commercially produce pioglitazone more advantageously.

The present inventors have studied and examined a novel production method of pioglitazone, which can be manufactured in a relatively small production process step industrially and commercially, avoiding the problems of the conventional techniques described above and the technically difficult manufacturing method in the manufacturing process. As a result, the compound represented by Formula 2 was synthesized as an intermediate for synthesizing pioglitazone, and the synthesis of pioglitazone from the intermediate compound was performed by a simple deprotection reaction. .

Therefore, an object of the present invention is to provide a compound represented by the formula (2) as an intermediate for pioglitazone synthesis.

Another object of the present invention is to provide a method for synthesizing pioglitazone by deprotecting a compound represented by Chemical Formula 2.

The present invention is characterized by a compound represented by the following formula (2) which is useful as an intermediate for preparing pioglitazone.

(Formula 2)

In Formula 2, Z represents a protecting group of thiazolidine-2,4-dione.

In addition, the present invention includes a method for preparing a pioglitazone (Pioglitazone) represented by the following formula 1 by the deprotection reaction of the compound represented by the following formula (2), as shown in the following scheme 5.

In Scheme 5, Z represents a protecting group of thiazolidine-2,4-dione.

   Referring to the present invention in more detail as follows.

The present invention has a technical feature in using the compound represented by the formula (2) as an intermediate for producing pioglitazone (Pioglitazone). In a general manufacturing method, a compound containing an out-of-ring double bond represented by Chemical Formula (VII-a) is synthesized as a reaction intermediate, and a selective reduction reaction to the out-of-ring double bond is performed to synthesize pioglitazone, thereby synthesizing a metal catalyst and pressurized hydrogenation. Whereas a special device was needed for the present invention, since the method of removing the protecting group of the thiazolidine-2,4-dione introduced in the compound represented by the formula (2) is applied, it can be said to have great commercial utility.

In the compound represented by Formula 2, the protecting group (Z) of thiazolidine-2,4-dione includes 4-nitrobenzyl group, trityl group (trytyl, -C (Ph) ₃ ), etc. as a general protecting group. Among them, particularly preferred is a trityl group.

In the case of introducing a trityl group as a protecting group of thiazolidine-2,4-dione, triethylmethyl chloride is used to give triethyl in an organic solvent such as dichloromethane, dimethylformamide, and chloroform. It can be carried out in the presence of an organic base such as amine, diethylamine, trimethylamine or inorganic base such as Na ₂ CO ₃ , NaCO ₃ .

In addition, the deprotection reaction of the protecting group of thiazolidine-2,4-dione may be performed using an acid catalyst in an organic solvent or a mixed solvent of water and an organic solvent. In this case, the acid catalyst may be selected from inorganic acids containing hydrochloric acid and sulfuric acid, or organic acids including formic acid and acetic acid. Water is used as the reaction solvent, or hydrocarbons such as nucleic acid, toluene, xylene, halogenated hydrocarbons such as chloroform and dichloromethane, alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, Using an organic solvent selected from dimethyl sulfoxide, sulfoxides such as sulfolane, acetates such as ethyl acetate, isopropyl acetate, amides such as dimethylformamide, dimethylacetamide, and nitriles such as acetonitrile; Or a mixed solvent of water and an organic solvent can be used. The reaction temperature is in the range of 20 ° C to 100 ° C, preferably 50 ° C to 80 ° C.

In addition, the compound represented by the formula (2) as an intermediate for synthesizing pioglitazone characterized by the present invention can be prepared by the method shown in the following Scheme 6. That is, 2- (5-ethyl-pyridin-2-yl) -ethanol represented by the following formula (3) and 5-((4-substitutedphenyl) methyl) -1,3-thiazolidine represented by the following formula (4) It can be prepared by reacting a -2,4-dione compound.

In Scheme 6, Y represents Cl or OH, and Z represents a protecting group of thiazolidine-2,4-dione.

In performing the preparation method according to Scheme 6, the reaction of the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 4 wherein Y = OH is diethyl azodicarboxylate (DEAD) in a common inert organic solvent. ) and by triphenylphosphine (PPh _3), and proceeds to S _N 2 reactions (Mitsunobu reaction), this reaction can be found in the literature [Mitsunobu, O .; Yamada , M. Bull . Chem . Soc . Jpn . 1967, 40, 2380., Mitsunobu , O. Synthesis 1981, 1. ( Review )] .

In addition, in performing the preparation method according to Scheme 6, the reaction of the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 4 wherein Y = Cl is performed in the presence of a base, and trimethylamine and diethylamine are used as bases. Organic bases such as trimethylamine, or inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium phosphate. As the reaction solvent, the above-mentioned organic solvents, for example, hydrocarbons such as hexane, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran , Dimethyl sulfoxide, sulfoxides such as sulfolane, ethyl acetate, acetates such as isopropyl acetate, dimethylformamide, amides such as dimethylacetamide, and nitriles such as acetonitrile. have. The coupling reaction temperature is in the range of room temperature to the reflux temperature of the reactants, and it is particularly preferable to reflux the reactants.

In addition, the compound represented by Formula 4, wherein Y = Cl, may be used by chlorination reaction of the compound represented by Formula 4, wherein Y = OH. The chlorination reaction can be carried out in a solvent such as benzene, toluene, xylene, dimethylformamide by halogenating agent such as thionyl chloride (SOCl ₂ ).

Particularly preferred is a compound represented by the formula (4) wherein Y = Cl in preparing the formula (2).

The present invention as described above will be described in more detail by the following examples.

Example 1 Preparation of 5- (4-chloro-benzyl) -3-trityl-thiazolidine-2,4-dione

   12.5 g of 5- (4-hydroxy-benzyl) -3-trityl-thiazolidine-2,4-dione was added to 50 ml of toluene, and 3.83 g of thionyl chloride was cooled and stirred at 0 ° C to 4 ° C. Equivalent weight) was added dropwise. It was refluxed after the addition. The volatile addition product was distilled under reduced pressure to yield 9.74 g of 5- (4-chloro-benzyl) -3-trityl-thiazolidine-2,4-dione.

¹ H NMR (DMSO, δ) 2.81-3.25 (2H), 4.13-4.16 (1H), 7.11-7.14 (3H), 7.17-7.20 (6H), 7.28 (2H), 7.41-7.45 (6H), 7.62 ( 2H)

Example 2 Preparation of 5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -benzyl} -3-trityl-thiazolidine-2,4-dione

2.5 g of 2- (5-ethyl-pyridin-2-yl) -ethanol and 1.67 g of triethylamine were added to 100 ml of tetrahydrofuran, followed by stirring at room temperature for 30 minutes. After stirring, 7.54 g of 5- (4-chloro-benzyl) -3-trityl-thiazolidine-2,4-dione was added and refluxed. After slowly cooling to room temperature and filtering, the filtrate was concentrated by distillation under reduced pressure. The mixture was washed with water and ethyl acetate, and then the organic phase was extracted, dried over anhydrous Na ₂ SO ₄ , and distilled under reduced pressure to obtain 5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy]- 8.53 g of benzyl} -3-trityl-thiazolidine-2,4-dione was obtained.

¹ H NMR (DMSO, δ) 1.03-1.06 (3H), 2.45-2.47 (2H), 2.81-3.25 (2H), 2.88-2.92 (2H), 4.14 (1H), 4.37-4.41 (2H), 6.83 ( 1H), 7.04-7.07 (2H), 7.12-7.14 (5H), 7.17-7.20 (6H), 7.35 (1H), 7.41-7.45 (6H), 8.38 (1H)

Example 3 Preparation of 5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -benzyl} -thiazolidine-2,4-dione

5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -benzyl} -3-trityl-thiazolidine-2 in 120 mL of 75% acetic acid aqueous solution (V / V), 9 g of 4-dione was added and stirred at about 80 ° C for 3 hours. After stirring was neutralized with NaHCO ₃ and extracted with dichloromethane. The extract was dried over MgSO ₄ , and the organic solvent was concentrated by distillation under reduced pressure. The residue obtained was recrystallized from dimethylformamide and water to obtain 4.45 g of 5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -benzyl} -thiazolidine-2,4-dione. Got it.

¹ H NMR (DMSO, δ) 1.05-1.10 (3H), 2.40-2.55 (2H), 2.87-2.95 (2H), 2.80-3.25 (2H), 4.20 (1H), 4.30-4.45 (2H), 6.85 ( 1H), 7.05 (2H), 7.15-7.20 (2H), 7.34 (1H), 7.37 (1H), 8.40 (1H)

The present invention is characterized by a method for efficiently producing a pioglitazone (Pioglitazone) using the compound represented by the formula (2) as an intermediate, is particularly useful for commercial production of pioglitazone.

Claims (6)

   Compound represented by the following formula (2) used as an intermediate for producing pioglitazone (Pioglitazone): (Formula 2)

In Formula 2, Z represents a protecting group of thiazolidine-2,4-dione selected from 4-nitrobenzyl group or trityl group.    Deprotection reaction of the compound represented by the following formula (2) at a temperature range of 20 ℃ to 100 ℃ under an acid catalyst, to prepare a pioglitazone (Pioglitazone) represented by the following formula (1): (Formula 2)

(Formula 1)

In Formula 2, Z represents a protecting group of thiazolidine-2,4-dione selected from 4-nitrobenzyl group or trityl group. delete The method of claim 2, wherein the protecting group of thiazolidine-2,4-dione is a trityl group (trytyl, -C (Ph) ₃ ).    The compound of claim 2, wherein 2- (5-ethyl-pyridin-2-yl) -ethanol represented by the following formula (3) and Y = OH, 5-((4-substitutedphenyl) methyl) -1,3-thia represented by the following formula (4) 2,4dione compound of diethyl azodicarboxylate characterized in that that produced by S _N 2 reactions (Mitsunobu reaction) using (DEAD) and triphenylphosphine (PPh _3): (Formula 3)

(Formula 4)

(Formula 2)

In the above formula, Y represents OH; Z represents a protecting group of thiazolidine-2,4-dione selected from 4-nitrobenzyl group or trityl group.     The compound of claim 2, wherein    2- (5-ethyl-pyridin-2-yl) -ethanol represented by the following formula (3) and Y = Cl, and 5-((4-substitutedphenyl) methyl) -1,3-thia represented by the following formula (4) A process for preparing a zolidine-2,4-dione compound in the presence of a base by combining the reaction at room temperature to the reflux temperature of the reactants: (Formula 3)

(Formula 4)

(Formula 2)

In the above formula, Y represents Cl; Z represents a protecting group of thiazolidine-2,4-dione selected from 4-nitrobenzyl group or trityl group.