JP4466908B2 - N-tert-butoxycarbonyl-5-ethoxycarbonylindole and process for producing the same - Google Patents

Description

The present invention relates to N-tert-butoxycarbonyl-5-ethoxycarbonylindole useful as a raw material for pharmaceuticals, agricultural chemicals and electronic materials, and a method for producing the same.

At present, indoles are widely used as raw materials for various compounds. In particular, N-acylindolecarboxylic acid esters are useful as raw materials for pharmaceuticals such as antihypertensives, antidepressants, anticancer agents, and antiallergic agents, raw materials for agricultural chemicals, and raw materials for electronic materials. Proposed.
Indole compounds generally have higher reactivity at the 2nd and 3rd positions of the indole ring than the 4th to 7th positions. Therefore, synthesis of compounds having substituents at the 4th to 7th positions while the 2nd and 3rd positions remain unsubstituted. It is difficult.
The production method of N-acylindolecarboxylic acid esters similar to the formula (1) which is the object of the present invention includes 2-ethenylacetanilides equivalent to 10 mol% palladium chloride and equimolar cuprous chloride and alcohol. A method for obtaining N-acetylmethoxycarbonylindoles by reacting in an oxygen atmosphere in the presence of is proposed. However, this method requires o-bromoacetanilides having an alkoxycarbonyl group which is more expensive than nitrobenzoic acid esters which are raw materials of the present invention as raw materials for ethenylacetanilides, In addition to the high-pressure reaction using ethylene gas, a large amount of catalyst is required also in the ring closing step, which is problematic as an industrial production means.

In addition, as a method for producing other similar compounds, there is shown a method of obtaining N-acylindoles by reacting vinyl esters and N-hydroxy-N-acylanilides in the presence of a mercury catalyst or a palladium catalyst. . However, this method has a problem as an industrial production means because expensive Li ₂ PdCl ₄ is used in a large amount of 1 to 3 mol% in order to complete the reaction.

As a method for producing indole carboxylic acids having no substitution at the 2nd and 3rd positions, a method of synthesizing cyanoindoles by hydrolysis is known. (Non-Patent Documents 1 and 2)
However, this method is not preferable as an industrial production method because a large amount of copper cyanide is required for introducing a cyano group and a cyanide detoxification treatment is required in the post-treatment. As another production method, 2-bromo-4-methoxycarbonylaniline is reacted with ethylene in the presence of palladium acetate under high-pressure conditions to give 4-methoxycarbonyl-2-vinylaniline, which is equimolar after N-tosylation. The indole carboxylic acid is obtained by ring closure using a palladium catalyst. However, this method has problems as industrial production means such as high-pressure reaction using ethylene gas and use of a large amount of Pd catalyst.

JP-A-3-24056

Japanese Examined Patent Publication No. 3-12058

J.O.C. 20, 1458-1460 (1955)

J. et al. Amer. Chem. Soc. , 71, 761-766 (1949)

J. et al. Chem. Technol. Biotechnol. 36 (12), 562-564, (1986)

The present invention provides a novel N-tert-butoxycarbonyl-5-ethoxycarbonylindole useful as a raw material for pharmaceuticals, agricultural chemicals, and electronic materials, and a method for producing this with high purity and industrially advantageously. It is to provide.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained the following formula (1) as novel N-acylindolecarboxylic acid esters.

で表わされるＮ−ｔｅｒｔ−ブトキシカルボニル−５−エトキシカルボニルインドールを
見出し、かつ、式（２）

N-tert-butoxycarbonyl-5-ethoxycarbonylindole represented by formula (2)

で表わされるｐ−（Ｎ−ｔｅｒｔ−ブトキシカルボニル−Ｎ−ヒドロキシ）アミノ安息香酸エチルエステルを反応溶媒の存在又は不存在下、貴金属触媒として式（３）
Ｍ_１ ^a［Ｍ₂Ｌ_ｍ］^b （３）
［式中、ｂは０〜−２の整数であり、電荷を表す。Ｌはリガンドを示し、ｍは０〜４の整数であり、ｍが２〜４の場合同一であっても異なっていてもよい。 ａ＋ｂ＝０であり、Ｍ_１はｂが−１または−２の時、対イオンを表す。Ｍ₂は白金族元素を表わす。］で示される構造を有する少なくとも１種の化合物を用い、さらに式（４）
Ｍ₃Ｘ_ｎ（４）
[式中、Ｍ₃は金属原子（ＰｄおよびＨｇを除く）を表わし、Ｘはハロゲン原子を表わす。ｎは１又は２を表わす。]で表わされる助触媒の少なくとも１種の存在下において式（５）

P- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoic acid ethyl ester represented by the formula (3) as a noble metal catalyst in the presence or absence of a reaction solvent
M ₁ ^a [M ₂ L _m ] ^b (3)
[In formula, b is an integer of 0-2, and represents an electric charge. L represents a ligand, m is an integer of 0 to 4, and when m is 2 to 4, they may be the same or different. a + b = 0, and M ₁ represents a counter ion when b is −1 or −2. M ₂ represents a platinum group element. And at least one compound having a structure represented by formula (4):
M ₃ X _n (4)
[Wherein, M ₃ represents a metal atom (excluding Pd and Hg), and X represents a halogen atom. n represents 1 or 2. In the presence of at least one promoter represented by formula (5)

［式中、Ｒ_３は炭素数１〜４のアルキル基またはフェニル基を表わす］で示されるビニル

[Wherein R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group]

According to a method for producing N-tert-butoxycarbonyl-5-ethoxycarbonylindole characterized by reacting with an ester (1)

で表わされるＮ−ｔｅｒｔ−ブトキシカルボニル−５−エトキシカルボニルインドールが高純度で、工業的有利に得られることを見出し、本発明を完成した。

The present invention was completed by finding that N-tert-butoxycarbonyl-5-ethoxycarbonylindole represented by the formula:

Hereinafter, the present invention will be described in more detail.
The p- (N-tert-butoxycarbonyl-N-hydroxyamino) benzoic acid ethyl ester in the present invention is, for example, from p-nitrobenzoic acid ethyl ester, U.S. Pat. Indian Chem. Soc. , Vol. 46, no. It can be produced by hydroxylamination and acylation by a known method such as 9,1969.

As the noble metal catalyst in the present invention, the formula (3)
M ₁ ^a [M ₂ L _m ] ^b (3)
[In formula, b is an integer of 0-2, and represents an electric charge. L represents a ligand, m is an integer of 0 to 4, and when m is 2 to 4, they may be the same or different. a + b = 0, and M ₁ represents a counter ion when b is −1 or −2. M ₂ represents a platinum group element. ]
These catalysts can be used alone or in combination, for example, Pd atom or Pt atom which may be supported on a support, Li ₂ PdCl ₄ , Na ₂ PdCl ₄ , (NH ₄ ) ₂ PdCl ₄ , PdCl ₂ , Pd (OCOCH ₃ ) ₂ , Pd (CH ₃ COCHCOCH ₃ ) ₂ , PtCl ₂ , Na ₂ PtCl _{4, and the} like, and in particular, a Pd atom, Li ₂ PdCl ₄ , Na which may be supported on the support ₂ PdCl ₄ , (NH ₄ ) ₂ PdCl ₄ , PdCl ₂ , Pd (OCOCH ₃ ) ₂ are preferred.

The promoter used in the present invention is represented by the formula (4)
M ₃ X _n (4)
[Wherein M ₂ represents a metal atom (excluding Pd and Hg), and X represents a halogen atom. n represents an integer of 1 to 2. ], For example, halides such as Li, Mg, Ca, Fe, Co, Mn, Ni, Cu, Ag, Zn, etc. Among them, halides of Cu and Zn are preferable, It is usually used in an amount of 1 to 200 mol%, preferably 10 to 50 mol%, based on p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoic acid ethyl ester represented by (2).
By using these cocatalysts, the amount of expensive noble metal catalyst used can be reduced to 0.5 mol% or less compared to 1 mol% or more in the case of only the noble metal catalyst, and 0.05 mol% depending on the combination. It can be greatly reduced to the following.

  In the present invention, the formula (5)

で示されるビニルエステル類において、Ｒ_３は炭素数１〜４のアルキル基またはフェニル基を示し、具体的には、酢酸ビニル、プロピオン酸ビニル、酪酸ビニル、２−メチルプロピオン酸ビニル、安息香酸ビニルが挙げられ、なかでも酢酸ビニルが好ましい。

R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group, specifically vinyl acetate, vinyl propionate, vinyl butyrate, vinyl 2-methylpropionate, vinyl benzoate. Among them, vinyl acetate is preferable.

    Examples of the ring-closing reaction solvent used as necessary in the present invention include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, and fats such as pentane, hexane and heptane. Hydrocarbons, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, aliphatic and cyclic ethers such as diethyl ether, di-n-propyl ether, methyl-tert-butyl ether, tetrahydrofuran and dioxane, methyl formate , Esters such as ethyl formate, methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate, nitriles such as acetonitrile, propionitrile, butyronitrile, benzonitrile, acetone, diethyl ketone, diisopropyl ketone, methyl Examples include ketones such as tilketone and methyl isobutyl ketone, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone. Among them, heptane, toluene, chlorobenzene, vinyl acetate , Ethyl acetate and diisopropyl ether are preferred, and vinyl acetate is more preferred, and the amount used is usually based on p- (N-tert-butoxy N-hydroxyamino) benzoic acid ethyl ester represented by formula (2). 3 to 100 mol%, preferably 5 to 50 mol%.

  In the present invention, the temperature during the ring-closing reaction is usually between 0 to 120 ° C, preferably 20 to 75 ° C, more preferably 50 to 75 ° C. The pressure during the reduction reaction is usually carried out at normal pressure, but can also be carried out under pressure, reduced pressure or dehydration.

The present invention provides N-tert-butoxycarbonyl-5-ethoxycarbonylindole useful as a raw material for pharmaceuticals, agricultural chemicals and electronic materials.
Further, according to the method of the present invention, industrially used and inexpensive Pd / C, PdCl ₂ or the like can be used as a catalyst for the ring closure reaction, and further, by using a metal halide as a cocatalyst, Since the usage-amount of an expensive noble metal catalyst can be reduced significantly, high purity N-tert-butoxycarbonyl-5-ethoxycarbonylindole can be produced industrially advantageously.

Next, although the detail of this invention is shown in the following examples, this invention is not limited to these.

Palladium chloride 5.0 mg (0.028 mmol), zinc chloride 2.3 g (16.88 mmol), p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoic acid ethyl 17.8 g (67 0.2 mmol) and 86.8 g (1008 mmol) of vinyl acetate were charged, and the gas phase portion was replaced with nitrogen, followed by stirring at 55 ° C. for 7 hours.
At this point, the reaction mixture was analyzed by HPLC. As a result, N-tert-butoxycarbonyl-5-ethoxycarbonylindole: 97.0%, p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoic acid ethyl ester It was a detection.
The reaction mixture was cooled and filtered, and the filtrate and washings were washed with water. The organic layer was concentrated to dryness to give N-tert-butoxycarbonyl-5-ethoxycarbonylindole having a purity of 97.5%. 7 g was obtained. (Yield 96.0%) The obtained N-tert-butoxycarbonyl-5-ethoxycarbonylindole was a novel substance, and the physical properties thereof were as follows.
Melting point 67-70 ° C. Mass spectrometry; 289.13 (calculated value 289.33) Elemental analysis result C66.4 (calculated value 66.4); H6.6 (calculated value 6.6); N4.9 (calculated value 4) .9); O22.1 (calculated value 22.1) NMR spectrum (270 MHz, CDCl ₃ ): 1.42 ppm (3H, t); 1.63 ppm (9H, s); 4.39 ppm (2H, q) 6.64 ppm (1H, d); 7.64 ppm (1H, d); 8.02 ppm (1H, dd,); 8.18 ppm (1H, d); 8.30 ppm (1H, d)

  In a reaction vessel, palladium chloride 0.30 mg (0.0017 mmol), zinc chloride 536 mg (3.95 mmol), p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoate 4.46 g (16.8). Mmol) and 21.7 g (251.7 mmol) of vinyl acetate, the gas phase portion was replaced with nitrogen, and the mixture was stirred at 55 ° C. for 24 hours, followed by the same treatment as in Example 1, and a purity of 97.1. % N-tert-butoxycarbonyl-5-ethoxycarbonylindole (4.37 g) was obtained. (Yield 90%)

  In a reaction vessel, 11.1 mg (0.063 mmol) of palladium chloride, 312.6 mg (3.15 mmol) of cuprous chloride, 3.35 g of ethyl p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoate. (12.63 mmol) and 16.32 g (189.6 mmol) of vinyl acetate were added, and the mixture was stirred at reflux temperature (about 72 to 74 ° C.) for 4 hours. 3.45 g of 1% N-tert-butoxycarbonyl-5-ethoxycarbonylindole was obtained. (Yield 94.4%)

In a reaction vessel, 0.90 mg (0.005 mmol) of palladium chloride, 404 mg (2.965 mmol) of zinc chloride, 2.97 g (11.2) of ethyl p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoate (11.2) Mmol), 1.45 g (16.75 mmol) of vinyl acetate and 13.2 g of toluene, the gas phase was replaced with nitrogen, and the mixture was stirred at 55 ° C. for 16 hours, and then the same treatment as in Example 1 was performed. As a result, 3.01 g of N-tert-butoxycarbonyl-5-ethoxycarbonylindole having a purity of 97.2% was obtained. (Yield 93.0%)

In a reaction vessel, platinum chloride 4.13 mg (0.0154 mmol), zinc chloride 0.42 g (3.08 mmol), p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoate 8.17 g (30 .8 mmol) and 51.65 g (600 mmol) of vinyl acetate, and the mixture stirred at 72 ° C. for 2 hours was analyzed. As a result, N-tert-butoxycarbonyl-5-ethoxycarbonylindole 8 having a purity of 91.0% was analyzed. .19 g was obtained. (Yield 92.0%)

In a reaction vessel, 31.6 mg (0.0074 mmol) of 5% Pd / C containing 50.65% of water, 978 mg (7.18 mmol) of zinc chloride, p- (N-tert-butoxycarbonyl-N-hydroxy) aminobenzoic acid 7.59 g (28.6 mmol) of ethyl acid and 73.96 g (860 mmol) of vinyl acetate were charged, and the gas phase portion was replaced with nitrogen, followed by stirring at 55 ° C. for 8 hours. After cooling, ethyl acetate was added to dissolve the organic crystals precipitated by the reaction, and the inorganic solid content was removed by filtration. The filtrate and washings were washed with water, and then the ethyl acetate layer was concentrated to dryness to obtain 8.02 g of N-tert-butoxycarbonyl-5-ethoxycarbonylindole having a purity of 98.6%. (Yield 97.0%)

Claims (2)

Formula (1)

N-tert-butoxycarbonyl-5-ethoxycarbonylindole represented by Formula (1)

In the production of N-tert-butoxycarbonyl-5-ethoxycarbonylindole represented by the formula (2)

P- (N-tert-butoxycarbonyl-N-hydroxyamino) benzoic acid ethyl ester represented by the formula: Pd element as a noble metal catalyst, Pd element supported on a carrier, supported on a carrier in the presence or absence of a reaction solvent At least one compound selected from Pd-containing compounds, Li ₂ PdCl ₄ , Na ₂ PdCl ₄ , (NH ₄ ) ₂ PdCl _4, PdCl ₂ , Pd (OCOCH ₃ ) ₂ , p- (N-tert- Butoxycarbonyl-N-hydroxyamino) benzoic acid ethyl ester is used in an amount of 0.0067 to 0.33 Wt% , and p- (N-tert-butoxycarbonyl-N-hydroxyamino) benzoic acid ethyl ester is 10 to 10 %. 50 mol% CuCl, CuCl ₂ , at least one auxiliary selected from ZnCl ₂ Using a catalyst , the formula (5)

[Wherein R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group], and a method for producing N-tert-butoxycarbonyl-5-ethoxycarbonylindole,