JPS61251665A - Production of 1,2,3,4-tetrahydroquinoline compound - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., in high selectivity, without generating unreacted material, by-products, and perhydro compound, by adding a sulfur- containing compound to a reaction system in the hydrogenation reaction of a quinoline compound in the presence of hydrogen and a hydrogenation catalyst. CONSTITUTION:The objective compound can be produced by the catalytic hydrogenation of a quinoline compound (e.g. N-methylquinoline, isoquinoline, etc.) in the presence of hydrogen, a hydrogenation catalyst (preferably a nickel-based catalyst containing metallic nickel, such as Raney nickel) and a small amount of a sulfur-containing compound. Any compound containing sulfur atom in the molecule can be used as the sulfur-containing compound for the above reaction. Examples of the sulfur-containing compound are molecular sulfur, sulfur dioxide, mercaptan, thiophene, etc. The amount of the sulfur-containing compound to be added to the system is 10-10,000ppm, preferably 500-5,000ppm in terms of sulfur based on the raw material in the case of adding to the reaction system containing the raw material and hydrogen, etc., or to the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing 1,2,3,4-tetrahydroquinolines useful as intermediates in the fields of medicines, agricultural chemicals, etc.

[Conventional technology]

Generally, 1,2,3,4-tetrahydroquinolines are produced by catalytically hydrogenating the corresponding quinolines in the presence of a suitable hydrogenation catalyst.

[Problem that the invention seeks to solve]

However, in the corresponding catalytic hydrogenation reaction of quinolines, various factors such as the type and amount of the hydrogenation catalyst used, the type and purity of the raw material quinolines, the reaction temperature during the hydrogenation reaction, the hydrogen pressure, Depending on reaction conditions such as reaction time, unreacted quinolines, 5,6,7.8-
Unreacted products such as tetrahydroquinolines and decahydroquinolines, side-reactants, or perhydro forms are produced, and 1,
It has been difficult to selectively produce 2,3,4-tetrahydroquinolines.

The present invention was devised in view of this point of view, and provides a method for selectively producing 1,2,3,4-tetrahydroquinolines by catalytic hydrogenation reaction of quinolines.

[Means for solving problems]

That is, in the present invention, when hydrogenating raw material quinolines in the presence of hydrogen and a hydrogenation catalyst, a 1,2,3.4-
This is a method for producing tetrahydroquinolines.

The raw material quinolines to which the method of the present invention is applied include quinoline, toalkylquinoline such as tomethylquinoline, 2-
Examples include quinolines such as alkyl-substituted quinolines such as methylquinoline, isoquinolines such as isoquinoline, toalkylisoquinolines such as N-methylisoquinoline, and alkyl-substituted isoquinolines such as 2-methylisoquinoline. These raw material quinolines may be synthetic quinolines produced by an appropriate synthesis method, or they may be synthetic quinolines produced by distilling the tar base component extracted with acid from coal tar oil or coal liquefied oil, etc. The resulting tar-based quinolines may also be used.

In addition, the sulfur-containing compound added to the reaction system when catalytically hydrogenating the raw material quinolines mentioned above may be any compound containing a sulfur atom in its molecule, such as molecular sulfur, hydrogen sulfide, sulfur dioxide, disulfide, etc. Sulfur-containing inorganic compounds such as carbon, thiols such as mercaptan and thiophenol, alkyl sulfides such as dimethyl sulfide, thiophenes such as thiophene and benzothiophene, cheno-(3,2-b)pyridines, etc. Examples include sulfur-containing organic compounds.

These sulfur-containing compounds can be used alone or in a mixture of two or more, and if they are easily separated after the catalytic hydrogenation reaction, this sulfur-containing compound can be used. Other compounds may be present as impurities therein.

The sulfur-containing compound may be added in any form as long as it can be present in the reaction system, and there are methods of adding it to the raw material quinolines, hydrogen, hydrogenation catalyst, or a solvent used as necessary.

Regarding the amount of the above-mentioned sulfur-containing compound added during the catalytic hydrogenation reaction of raw material quinolines, when adding it to the reaction system or solvent of raw material quinolines, hydrogen, etc., the sulfur-containing compound is added to the raw material quinoline, The total sulfur content converted to sulfur atoms is in the range of 10 to 10.0001)l, preferably in the range of 5oO to 5,000 ppm, and 10
111) When less than I, the raw material quinoline is 1.2, 3.
Selectivity in reducing to 4-tetrahydro form is reduced, and io, o.

If it is more than 0IIEI, the raw material quinoline will be 1.2,
The conversion rate to 3.4-tetrahydro form decreases.

In addition, if a sulfur-containing compound is present in the raw material quinoline or in the hydrogen to be recycled, it is preferable to use it as is in the catalytic hydrogenation reaction, preferably with the content m of the sulfur-containing compound adjusted within the above range. good.

When added to a hydrogenation catalyst, a catalyst treated with a sulfur-containing compound or a catalyst used in a reaction system to which a sulfur-containing compound is added can be used. When using such a hydrogenation catalyst, it is not necessary to add a sulfur-containing compound to the reaction system, but adding a sulfur-containing compound within the above range provides better selectivity.

In addition, as a hydrogenation catalyst used for catalytic hydrogenation reaction,
Examples include platinum metal catalysts containing platinum metals or compounds such as ruthenium and platinum; non-white metal catalysts containing non-white metal metals or compounds such as nickel, molybdenum, and cobalt; Preferred are nickel catalysts containing metallic nickel such as Raney nickel and stabilized nickel. Any of these hydrogenation catalysts may be used alone, or two or more thereof may be mixed and used simultaneously or in stages after a predetermined period of time. The amount of hydrogenation catalyst to be used is suitably 0.5 to 10% by weight based on the raw material quinoline.

The reaction conditions for this catalytic hydrogenation reaction can be selected as appropriate depending on the type of raw material quinolines and the type of hydrogenation catalyst. For example, when catalytically hydrogenating isoquinoline using a nickel catalyst, the reaction temperature is 50 to 250°C, preferably 100 to 200°C, and the hydrogen pressure is 1 (1g
/i-G or more, preferably 20-150*y/ci・G
It is. As for the reaction time, in principle it is the time until the raw material quinoline is integrated with 1°2.3.4 and the absorption of hydrogen is completed, and is usually 1 to 40 hours.

After the catalytic hydrogenation reaction is completed, the hydrogenation catalyst is separated and removed from the reaction mixture by means such as decantation or filtration, and 1,2,3,4-tetrahydroquinolines are obtained by means such as distillation. Further, the used hydrogenation catalyst, for example, a ruthenium catalyst containing metal ruthenium, is reused if necessary.

[Effect]

In the method of the present invention, when quinolines are catalytically hydrogenated, a 1,2,3,4-tetrahydro form is preferentially produced, and this 1,2,3,4-tetrahydro form is further reacted or hydrogenated. This produces by-products such as 5,6,7,8-tetrahydro and perhydro forms, but at this time, sulfur-containing compounds inhibit the isomerization reaction or hydrogenation of 1,2,3,4-tetrahydro. However, it seems that the 1,2,3,4-tetrahydro compound is selectively produced. (Example) The method of the present invention will be specifically explained below based on Examples and Comparative Examples.

Example 1 Cheno-(3,2-b)pyridine with total sulfur content of 2.
300 g of isoquinoline (purity 96% by weight) adjusted to 900 pl)m was charged into an autoclave, Raney nickel catalyst 259 was added thereto, and catalytic hydrogen was heated for 4 hours at a reaction temperature of 150°C and a hydrogen pressure of 10 (1/d-G). The catalyst was separated and removed from the reaction mixture to obtain 290 g of a product.The composition of this product was investigated by gas chromatography, and it was found that 1.2°3.4-tetrahydroisoquinoline
3.8% by weight, 0.9% by weight of 5.6,7.8-tetrahydroisoquinoline and 1.0% by weight of isoquinoline.

Example 2 Addition of benzothiophene to reduce total sulfur content to 500Elf)
Isoquinoline (purity 99% by weight) adjusted to 1 kg
was charged into an autoclave, 20 g of 5% RLJ/C catalyst was added thereto, and the reaction temperature was 150°C and the hydrogen pressure was 10.
Catalytic hydrogenation was carried out for 14 hours under the conditions of 0 KSF/ci.G, and the catalyst was separated and removed from the reaction mixture to obtain 980 g of a product. The composition of this product was examined by gas chromatography, and it was found that 1,2,3,4-tetrahydroisoquinoline was 97%.
6% by weight, 0.63% by weight of 5.6.7.8-tetrahydroisoquinoline and 0.3% by weight of isoquinoline.

Example 3 Isoquinoline (purity 96% by weight) whose total sulfur content was adjusted to 5001) pl was charged into an autoclave, and stabilized nickel catalyst (trade name: N manufactured by JGC Chemical ■) was charged into an autoclave.
N-113) 60 was added and catalytic hydrogenation was carried out for 21 hours at a reaction temperature of 180° C. and a hydrogen pressure of 127 m/iG. The number of moles of hydrogen absorbed was 17.1 moles, the hydrogen absorption rate (molar ratio to the raw material) was 1°84, and gas chromatographic analysis revealed a total sulfur content of about 201) I) l.

Next, the reaction mixture was filtered, and the filtrate 1. Place OKy and 50 g of the above stabilized nickel in an autoclave,
The reaction was carried out for 14 hours at a reaction temperature of 180° C. and a hydrogen pressure of 123 Ny/aI-G, and the catalyst was separated and removed from the reaction mixture to obtain 980 g of a product. 1.2 in this product,
The 3.4-tetrahydroisoquinoline concentration was 92%.

Example 4 1.2 and 9 of the isoquinoline used in Example 3 above were charged into an autoclave, 120 g of the above stabilized nickel catalyst was added, and the reaction temperature was 180°C and the hydrogen pressure was 14.
Catalytic hydrogenation was carried out for 37 hours under the conditions of 0 Kg/cIi·G.

The number of moles of hydrogen absorbed was 29.0 moles, the hydrogen absorption rate (molar ratio to raw material) was 3.11, and gas chromatographic analysis confirmed 98.4% by weight of 1.2,3.4-tetrahydroisoquinoline.

Example 5 Isoquinoline (purity 99% by weight) 2009 whose total sulfur content was adjusted to 100 Eel) II was charged into an autoclave, 10 g of Raney nickel catalyst was added thereto, and the reaction was carried out at 100° C. and hydrogen pressure of 15 Kg/CIi・G. Catalytic hydrogenation was carried out for 2 hours under the following conditions, and the catalyst was separated and removed from the reaction mixture to obtain 194 g of a product. The composition of this product was investigated by gas chromatography and found to be 92.2% by weight of 1,2,3.4-tetrahydroisoquinoline, s, e, y, a-
Tetrahydroisoquinoline was 4.411% and isoquinoline was 1.1%.

Comparative Example 1 Isoquinoline with no total sulfur content <99.9% by weight) 100
g into an autoclave, add 5 g of Raney nickel catalyst, and set the reaction temperature to 150°C and hydrogen pressure to 100°C.
3rR catalytic hydrogenation was carried out under the conditions of Kg/cd-G, and the catalyst was separated and removed from the reaction mixture to obtain 98 g of a product. As a result of examining the composition of this product using a gas chromatograph, it was found that 1.
2,3.4-tetrahydroisoquinoline is 86.3 times
%, 5,6,7.8-tetrahydroisoquinoline is 1
It was 3.7% by weight.

Example 6 Catalytic hydrogenation was carried out under the same conditions as in Comparative Example 1, except that the hydrogenation catalyst 59 used in Example 1 after completion of the reaction was used, and 98 g of a product was obtained from the reaction mixture. The composition of this product is 1,
95.8% by weight of 2,3.4-tetrahydroisoquinoline and 1% by weight of 5,6,7.8-tetrahydroisoquinoline.
．． 0% by weight and 1.5% by weight of inquinoline.

〔Effect of the invention〕

According to the method of the present invention, 1,
2,3,4-tetrahydroquinolines can be selectively produced.

Patent applicant Nippon Steel Chemical Co., Ltd. Patent applicant
Representative of Osaka Hydrogen Industry Co., Ltd.
Patent attorney Katsuo Naruse (and 2 others) Procedural amendment May 29, 1985 Manabu Shiga, Commissioner of the Patent Office 1, Indication of the case 1985 Patent Application No. 92882 2, Name of the invention 1.2, 3. Method for producing 4-tetrahydroquinolines 3,
Relationship with the case of the person making the amendment Patent applicant address 5-13-16 Ginza, Chuo-ku, Tokyo Name (6
64) Nippon Steel Chemical Co., Ltd. (1 other person) 4. Agent 105 Telephone (433) 4420 Address 3-8-8 Shinbashi, Minato-ku, Tokyo, 5th Floor, Building 5, Voluntary amendment of date of amendment order 7. Column 8 of "Claims" of the amended companion specification, Contents of the amendment As per the appendix, claims (1) When hydrogenating raw material quinolines in the presence of hydrogen and a hydrogenation catalyst, 1, 2, 3.4, characterized in that catalytic hydrogenation is carried out by adding 9 cm of a sulfur-containing compound to the reaction system.
-Production method of tetrahydroquinolines.

(2) 1.2゜3.4-tetrahydroquinolines according to claim 1, wherein 10 to 10,000 ppm of sulfur-containing compounds are added as a total sulfur content converted to sulfur atoms into the raw material quinolines. Manufacturing method.

(3) The method for producing 1,2,3,4-tetrahydroquinolines according to claim 1, wherein a sulfur-containing compound is added to hydrogen in an amount of 10 to 10,000 ppm as a total sulfur content calculated as sulfur atoms.

(4) A method for producing 1,2,3,4-tetrahydroquinolines according to claim 1, wherein a sulfur-containing compound is added to a hydrogenation catalyst.

Claims (4)

[Claims] (1) When hydrogenating raw material quinolines in the presence of hydrogen and a hydrogenation catalyst, catalytic hydrogenation is carried out by adding a small amount of a sulfur-containing compound to the reaction system 1, 2, 3, 4
-Production method of tetrahydroquinolines. (2) Production of 1,2,3,4-tetrahydroquinolines according to claim 1, in which a sulfur-containing compound is added to the raw material quinolines in an amount of 10 to 10,000 ppm as a total sulfur content converted to sulfur atoms. Law. (3) The method for producing 1,2,3,4-tetrahydroquinolines according to claim 1, wherein a sulfur-containing compound is added to hydrogen in an amount of 10 to 10,000 ppm as a total sulfur content calculated as sulfur atoms. (4) Production of 1,2,3,4-tetrahydroquinolines according to claim 1, wherein a sulfur-containing compound is added in a hydrogenation catalyst in an amount of 10 to 10,000 ppm as a total sulfur content calculated as sulfur atoms. Law.