KR810001744B1 - Process for preparing benzin.midazolinone derivatives - Google Patents

Abstract

Benzimidazolinone derivs. (I) and acid addition salts were prepd. Thus, formula(2) was condensed with formula(3) to give formula(4), and formula(4) condensed with formula(5) to give formula(6) in the presence of sodium amide. And then, formula(6) was reduced to give title compds. The title compds. are used as antiemetic.

Description

Method for preparing benzimidazolinone derivatives

The present invention relates to a benzimidazolinone derivative represented by the following structural formula (1) and a novel production method thereof.

This product has a pronounced antitiemetic effect and is known to be particularly effective for indigestion and vomiting. A number of patents exist for a conventional method for preparing similar compounds and the like, and some of them are as follows.

Firstly, according to Belgian patent no.

Production methods such as these are known.

Secondly, according to US Patent No. 3196157, the following manufacturing method is described.

(Wherein n is 2-5, R ₁ is hydrogen, hydroxy, cyano, carbamoyl, lower alkylcarbonyl, R ₂ is aryl, R ₃ is aryl or arylmethylene, R ₄ is hydrogen, Lower alkyl, lower alkylcarbonyl, lower alkoxy lower alkyl.

Third) According to US Pat. No. 3,89,707, the following manufacturing method is described.

In the above formula, Ar ₁ and Ar ₂ are phenyl, halophenyl, and the like, R ₁ , R ₂ are hydrogen, halo, lower alkyl and the like, R ₃ is hydrogen, methyl L is hydrogen, lower alkyl, phenyl lower alkyl and the like.

Fourth) In addition to this, a preparation method for a preparation having a structure and effect similar to the object of the present invention is disclosed in Korean Patent No. 5010,7594, US Patent Nos. , French Patent No. 3695M, German Laid-Open Patent No. 2632870, and many others, including Japanese Patent Laid-Open Nos. 48-92378 and 51-13780.

In particular, according to US Pat. No. 3191645 and US Pat. No. 417702, methods for preparing compounds having the general formula (M) are known.

Wherein R ₁ is halo, lower alkyl and trifluoro methyl, R ₂ is hydrogen, halo, lower alkyl and trifluoro methyl and R ₃ is hydrogen and methyl when R ₃ is methyl and R ₃ is 2 of the piperidine nucleus. In the 3-position and L is hydrogen, lower alkyl, lower alkyloxy carbonyl-lower alkyl, lower alkylcarbonyl-lower alkyl and phenyl lower alkyl.

Particularly, the material prepared by the first method of the above method can obtain the same compound as the object of the present invention. However, the conventional production method is difficult to perform the reaction process and requires repeated washing and recrystallization due to the generation of by-products during the reaction. Pure objectives can be attained, resulting in high loss of raw materials and low yields of around 30%, making them unsuitable for process or industrial production on a large scale.

In addition, each reaction used expensive 4-methyl-2-pentanone as an organic solvent as a condensation reaction, and since the reaction rate is slow, expensive potassium iodide (K1), which is a promoter, is used to promote this reaction. Even if a small amount was used, high prices of raw materials could not be excluded during mass production.

The present invention improves these drawbacks in the prior art to prevent the formation of reaction by-products and to produce the target product by a simple reduction reaction without the use of expensive organic solvents or promoters, the reaction is not only simple but also large quantities It is suitable for producing a high yield of the target object and the significance of the improved method than the conventional one.

That is, 1-chloro-3-bromo-furophane which can be provided inexpensively to the known compound 4- (5-chloro-2-oxo-1- benz imidazolidyl) -1-piperidine hydrochloride (2) 2-one (3) is condensed to produce the compound of formula (4), and condensation of the compound of formula (5), which is a known compound, in the presence of sodium amide, to produce the compound of formula (6) (6) It is a method of obtaining the target object (1) in a relatively simple and high yield by reducing the compound.

When the present invention is represented by the reaction diagram as follows.

Hereinafter, the present invention will be described in detail with reference to the following examples, and all parts in the examples refer to parts by weight.

Example 1

Preparation of 1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3-chloro furophan-2-one.

4.2 parts of 4- (5-chloro-2-oxo-1-benzimidazolidil) -1-piperidine hydrochloride were dissolved in 140 parts of tetrahydrofuran while heating, and then methane was added to 5 parts of 3-chloro- A solution of 1-Buromo-furopan-2-one is added dropwise and 4 parts of triethyl amine are added continuously. The whole was evaporated and the remaining solid residue was washed successively with water and hydrochloric acid solution and crystallized to give 8.2 parts of 1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3- Obtain white crystals of chlorofuropan-2-one. (Yield 84.5%)

Melting Point: 123-126 ℃ C MW342.03

C ₁₅ H ₁₇ N ₃ Cl ₂ O ₂

Theoretic value: C 49.45; H 4.67; N 15.38; C1 22.71; O 8.79

Found: C 49.51; H 4.65; N 15.33; C1 22.68; O 8.83

Example 2

1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3- (2-oxo-1-benzimidazolidyl) -furopan-2-one Manufacturing.

5.6 parts of 1-4- (5-chloro-2-oxo-1-benzimidazolidil) -1-piperidyl-3-chloro furophan-2-one with 1.05 parts of sodium amide and 4- (2- 4.6 parts of oxo-1-benzimidazolyl) -5-piperidine hydrochloride are stirred dropwise into a mixed solution of 132 parts of benzene and 14 parts of methanol while heating to 70 ° C. and stirred and refluxed at 58 ° C. for 2 hours.

The suspension was vigorously shaken at room temperature and held for 18 hours. The suspension was then suspended by addition of 30 parts of water and the precipitated product was filtered and washed with acetone to give 6.15 parts of 1-4- (5-chloro-2-oxo-1-benzami Obtained crystals of dazolidil) -1-piperidyl-3- (2-oxo-1-benzimidazoliyl) -furopan-2-one (yield 92.5%).

Melting Point: 173-176 ℃ MW 439.5

C ₂₂ H ₂₂ Cl N ₅ O ₃

Theoretic value: C 60.06; H 5.03; C1 8.07; N 15.92; O 10.92

Found: C 59.84; H 5.15; C1 8.11; N 15.87; O 11.03

Example 3

Preparation of 1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3- (2-oxo-1-benz imidazolidyl) furophan and hydrochloride 70 5.1 parts 1-4- (5-chloro-2-oxo-1-benz imidazolidyl) -1-piperidyl in 58 parts tetrahydrofuran in a stirred mixture of parts tetrahydrofuran and 1.5 parts lithium aluminum hydride A small amount of -3- (2-oxo-1-benzimidazoliyl) furanpan-2-one was added in small portions, and the whole was stirred at room temperature for 1.5 hours and at reflux for 2 hours. The reaction mixture was cooled to 10 ° C. and decomposed by successively adding 1.1 parts of 0.8 parts of 17% sodium hydroxide solution, and 3.7 parts of water. The entire reaction mixture was filtered, washed with ether, evaporated and dried to give 4.6 parts of 1-4- (5-chloro-2-oxo-1-benz imidazolidyl) -1-piperidyl-3- (2- Obtain oxo-1-benzimidazoliyl) furopane. (Yield 96.4%)

Melting Point: 252-245 ℃ MW 425.65

C ₂₂ H ₂₄ N ₅ O ₂ Cl

Theoretic value: C 62.02; H 5.68; N 16.45; 0 7.52; Cl 8.33

Found: C 59.95; H 5.63; N 16.48; L 7.56; Cl 8.38

The crystalline material is then treated with hydrogen chloride gas in methanol and ether to obtain hydrochloride.

Claims (1)

3-Chloro-1-part which is a compound of formula (3) using 4- (5-chloro-2-oxo-1-benzimidazoliyl) -1-piperidine hydrochloride as a known compound (2) as a starting material Condensation of lomo-furopan-2-one to prepare the compound of formula (4), and then condensation of the compound of formula (5) in the presence of sodium amide to produce an intermediate of the formula (6) (6) A method of reducing the compound to produce a benzimidazolinone derivative of the formula (1) and salts thereof.