JP2005139120A - Method for producing dibenzothiepin derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing zaltoprofen as an anti-inflammatory/analgesic agent. <P>SOLUTION: The method comprises the following process: Zinc iodide, sodium cyanide or potassium cyanide, and trimethylsilyl chloride are added to a compound of formula(I) followed by mixing them together to carry out a reaction to form a compound of formula(II). Sodium cyanide or potassium cyanide, trimethylsilyl chloride, acetonitrile and water are added to the compound of formula(II) followed by mixing them together to carry out a reaction to form a compound of formula(III). Polyphosphoric acid is made to act on the compound of formula(III) to effect cyclization, followed by addition of water to form a compound of formula(IV), which is then hydrolyzed to obtain the objective compound(zaltoprofen) of formula(V). In the above formulas, R is a lower alkyl. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a method for producing a dibenzothiepine derivative (generic name: zaltoprofen) represented by the following formula (V), which is useful as a propionic acid-based anti-inflammatory analgesic.

（式中、Ｘはハロゲン原子を表す。）
すなわち上記方法は、式（Ｉ）の化合物を還元して式（VI）の化合物とし、これをハロゲン化反応に付して式（VII）の化合物に変え、次いでシアン化反応に付して式（III）の化合物とし、さらに２段階の加水分解反応に付して目的の式（Ｖ）の化合物とする方法である。
しかし、この方法も工程数が多く、工業的に有利な方法とは言い難い。 Various methods for producing the compound of formula (V) have been proposed, but each method requires many reaction steps from the starting material to the target compound. An example of a promising method among them is as follows.

(In the formula, X represents a halogen atom.)
That is, in the above method, a compound of formula (I) is reduced to a compound of formula (VI), which is subjected to a halogenation reaction to give a compound of formula (VII), and then subjected to a cyanation reaction. In this method, the compound of (III) is further subjected to a two-stage hydrolysis reaction to obtain the desired compound of formula (V).
However, this method also has a large number of steps, and is not an industrially advantageous method.

JP-A-61-050961 JP-A-57-171961 Japanese Patent Laid-Open No. 55-532822

An object of the present invention is to provide an industrially advantageous method for producing a compound of formula (V), that is, zaltoprofen, by reducing the number of reaction steps.

  As a result of intensive studies to solve the above problems, the present inventor prefers that the compound of formula (III) is converted into the compound of formula (III) through three steps from the compound of formula (I) in two steps. A method for obtaining the yield was found, and further studies were made, and the present invention was completed.

（式中、Ｒは低級アルキル基を示す。）の化合物に、ヨウ化亜鉛、シアン化ナトリウム又はシアン化カリウム、及びトリメチルシリルクロライドを加え、混合、反応させて下記式（II）

（式中、Ｒは低級アルキル基を表す。）の化合物とし、式（II）の化合物に、ヨウ化ナトリウム又はヨウ化カリウム、トリメチルシリルクロライド、アセトニトリル及び水を加え、混合、反応させて下記式（III）

（式中、Ｒは低級アルキル基を示す。）の化合物を得、式（III）の化合物にポリリン酸を作用させて閉環させた後、水を加えて下記式（IV）

の化合物とし、さらに加水分解して下記式（Ｖ）の化合物を得る方法、

（２）Ｒがメチル基又はエチル基である前記（１）に記載の方法
を提供することができる。 That is, according to the present invention,
(1) The following formula (I)

To the compound (wherein R represents a lower alkyl group), zinc iodide, sodium cyanide or potassium cyanide, and trimethylsilyl chloride are added, mixed and reacted to form the following formula (II):

(Wherein R represents a lower alkyl group), sodium iodide or potassium iodide, trimethylsilyl chloride, acetonitrile and water are added to the compound of formula (II), mixed and reacted to form the following formula ( III)

(Wherein R represents a lower alkyl group), a compound of formula (III) was allowed to react with polyphosphoric acid to cyclize, and then water was added thereto to add the following formula (IV)

A compound obtained by further hydrolysis to obtain a compound of the following formula (V):

(2) The method according to (1) above, wherein R is a methyl group or an ethyl group.

  According to the present invention, in producing the anti-inflammatory analgesic agent zaltoprofen, the number of reaction steps is shortened by one step compared with the conventional method, and there is an advantage not only in yield improvement but also in work efficiency.

In the present invention, when zinc iodide, sodium cyanide or potassium cyanide, and trimethylsilyl chloride are added to the compound of formula (I) and mixed and reacted, the reaction is usually carried out in a solvent. Examples of the solvent include acetonitrile, tetrahydrofuran, dioxane, methylene chloride, chloroform, N, N-dimethylformamide, dimethyl sulfoxide, and the like, and acetonitrile is preferred. The amount of the reagent used in this reaction is within the range of a catalytic amount of zinc iodide, 1 to 10 times mol of sodium cyanide or potassium cyanide, and 1 to 6 times mol of trimethylsilyl chloride with respect to the compound of formula (I). Can be used.
The reaction is usually carried out under mild conditions. For example, it is preferably performed at 40 to 80 ° C. for 1 to 48 hours.

In the present invention, sodium iodide or potassium iodide, trimethylsilyl chloride, acetonitrile and water are added to the compound of the formula (II), mixed and reacted, usually in a solvent. Examples of the solvent include n-hexane, cyclohexane, acetonitrile, toluene, tetrahydrofuran, dioxane, methylene chloride, chloroform, and the like. Among them, n-hexane or a mixed solvent of n-hexane and acetonitrile is preferable.
The amount of the reagent used in this reaction is 2 to 10 times mol of sodium iodide or potassium iodide, 2 to 10 times mol of trimethylsilyl chloride and 1 to 3 times mol of water with respect to the compound of formula (II). It may be used within the range, and tolyl may be used in an amount of at least 2 times mol, preferably about 5 to 7 times mol in aceto.
The reaction is usually carried out under mild conditions. For example, it is preferably performed at 0 to 40 ° C. for 1 to 36 hours.

In the present invention, polyphosphoric acid is allowed to act on the compound of formula (III) to cyclize it, and when hydrolyzed, polyphosphoric acid is about 5 to 20 times the weight of the compound of formula (III), and water is excessively large. It is preferable to use for.
The ring closure reaction is usually preferably carried out at 70 to 110 ° C. for about 1 to 10 hours, and the hydrolysis reaction at 40 to 80 ° C. for about 0.5 to 5 hours.

  In the present invention, the method of hydrolyzing the compound of formula (IV) to obtain the compound of formula (V) is not particularly difficult, and a general method in the case of hydrolyzing the amide compound to obtain carboxylic acid is followed. That's fine.

(1) Add 120 ml of acetonitrile to 24 g (0.08 mol) of 5-acetyl-2-phenylthiophenylacetic acid methyl ester, and further add 11.76 g (0.24 mol) of sodium cyanide and 1.3 g of zinc iodide. It was. After adding 14 g (0.13 mol) of trimethylsilyl chloride to this mixed solution, it was stirred for 36 hours while heating and gently refluxing. Next, the reaction solution was allowed to cool to room temperature, added to 200 ml of a 10% aqueous sodium hydrogen carbonate solution, and organic substances were extracted with 300 ml of toluene. The aqueous layer was further extracted with 100 ml of toluene, combined with the previous toluene layer, washed with water and dried, and then the solvent was distilled off under reduced pressure to give oily 5- (1-cyano-1-trimethylsilyloxyethyl) -2-phenylthio. 32 g of phenylacetic acid methyl ester (area percentage by high performance liquid chromatography 93%; conversion yield 93%) was obtained.

(2) 16 g of oily 5- (1-cyano-1-trimethylsilyloxyethyl) -2-phenylthiophenylacetic acid methyl ester (converted mole: 0.037 mol) was dissolved in 50 ml of n-hexane, and the mixture was stirred under ice cooling. Then, 36 g (0.24 mol) of sodium iodide, 26 g (0.24 mol) of trimethylsilyl chloride and 10 g (0.24 mol) of acetonitrile were sequentially added. Further, 1.44 g (0.08 mol) of water was added and stirred at room temperature for 18 hours. To this reaction solution, 150 ml of toluene was added and stirred, and then 100 ml of 40% aqueous sodium thiosulfate solution was added and left stirring for a while to separate the toluene layer. The aqueous layer was re-extracted with 50 ml of toluene, washed with water together with the previous toluene layer, dried, and then the solvent was distilled off under reduced pressure. After adding 60 ml of ethyl acetate to the residue and treating with activated carbon, the solvent was distilled off under reduced pressure to give 12 g of oily methyl 5- (1-cyanoethyl) -2-phenylthiophenylacetic acid (area percentage 87% by high performance liquid chromatography). Converted yield 91%).

IRν max cm ⁻¹ (film): 2242 (CN), 1737 (C═O)
¹ H-NMR ¹ NMR (CDCl ₃ ) δ (ppm): 1.62 (3H, d, C—CH ₃ ), 3.61 (3H, s, O—CH ₃ ), 3.82 (2H, s, CH ₂ ), 3.85 (1H, m, CH), 7.1-7.4 (8H, m, Ar-H)
¹³ C-NMR 1 NMR (CDCl ₃ ) δ (ppm): 22 (CH ₃ ), 31 (CH), 40 (CH ₂ ), 52 (CH ₃ ), 127 to 135 (Ar)

(3) 120 g of polyphosphoric acid is added to 12 g of oily 5- (1-cyanoethyl) -2-phenylthiophenylacetic acid methyl ester (equivalent mol: 0.034 mol) and heated to maintain the reaction temperature at about 95 ° C. Stir for 5 hours. After allowing to cool, 200 ml of ice water and 50 ml of 2-propanol were added, and this mixture was kept at about 60 ° C. under heating and stirred for 1 hour. After allowing to cool, the precipitated crystals are collected by filtration, washed with a mixed solution of 2-propanol and water, dried, and dried to give pale tan crystals of 2- (10,11-dihydro-10-oxobenzo [b, f]. 9.5 g (thiepin-2-yl) propionamide (area percentage by high performance liquid chromatography 93%; conversion yield 89%) was obtained.

¹ H-NMR ¹ NMR (DMSO-d ₆ ) δ (ppm): 1.29 (3H, d, C—CH ₃ ), 3.60 (1H, q, CH), 4.24 (2H, s, CH ₂ ), 6.9~8.1 (9H, m, Ar-H, CONH 2)
¹³ C-NMR 1 NMR (DMSO-d ₆ ) δ (ppm): 19 (CH ₃ ), 45 (CH), 51 (CH ₂ ), 127 to 146 (Ar), 176 (CONH ₂ ), 192 (CO)

(4) 3- (10,11-dihydro-10-oxobenzo [b, f] thiepin-2-yl) propionamide 3 g (converted mol: 0.009 mol) of pale tan crystals to 6.6 g of potassium hydroxide A solution prepared by dissolving (0.12 mol) in 26 ml of water and 15 ml of methanol were added and heated to dissolve the crystals. Then, the methanol was distilled off at normal pressure, and the mixture was stirred for 8 hours while heating under reflux. The reaction mixture was then cooled in an ice bath, neutralized with 6N aqueous hydrochloric acid with stirring, 50 ml of ethyl acetate was added, and the pH was adjusted to 2 with 6N hydrochloric acid. After stirring this mixture for a while, the ethyl acetate layer was separated, washed with water and dried, and the solvent was distilled off under reduced pressure. To the residue was added 8 ml of ethyl acetate, and the precipitated crystals were collected by filtration, washed with n-heptane, dried, and pale yellowish white crystals of 2- (10,11-dihydro-10-oxobenzo [b, f] thiepine. -2-yl) propionic acid 1.7g (area percentage 99% by high performance liquid chromatography; conversion yield 60%) was obtained.

¹ H-NMR ¹ NMR (CDCl ₃ ) δ (ppm): 1.48 (3H, d, C—CH ₃ ), 3.72 (1H, q, CH), 4.35 (2H, s, CH ₂ ), 7.1-8.2 (7H, m, Ar-H)
¹³ C-NMR 1 NMR (CDCl ₃ ) δ (ppm): 19 (CH ₃ ), 45 (CH), 51 (CH ₂ ), 126 to 142 (Ar), 180 (COOH), 192 (CO)
MASS m / z: 298 (M ⁺ )

  According to the present invention, since the anti-inflammatory analgesic agent zaltoprofen can be produced in a shorter process than before, it can be used as an industrially advantageous production method.

Claims (2)

Formula (I)

To the compound (wherein R represents a lower alkyl group), zinc iodide, sodium cyanide or potassium cyanide, and trimethylsilyl chloride are added, mixed and reacted to form the following formula (II):

(Wherein R represents a lower alkyl group), sodium iodide or potassium iodide, trimethylsilyl chloride, acetonitrile and water are added to the compound of formula (II), mixed and reacted to form the following formula ( III)

(Wherein R represents a lower alkyl group), a compound of formula (III) was allowed to react with polyphosphoric acid to cyclize, and then water was added thereto to add the following formula (IV)

And further hydrolyzing to obtain a compound of the following formula (V).

The method according to claim 1, wherein R is a methyl group or an ethyl group.