JPS6168468A - Production of n-methyl compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate raw material for drugs, agricultural chemicals, etc. under mild reaction conditions in high yield, by reacting an N-hydrogenated nitrogen-containing heterocyclic compound with a formaldehyde as raw materials in the presence of a hydrogenating catalyst under pressure of hydrogen. CONSTITUTION:One or more N-hydrogenated nitrogen-containing heterocyclic compound selected from N-hydrogenated quinolines, e.g., perhydroquinoline, N-hydrogenated isoquinolines and N-hydrogenated pyridines are reacted with formaldehyde or paraformaldehyde in the presence of a hydrogenating catalyst such as platinum system, e.g., ruthenium catalyst, nickel based catalyst, etc. under >=5kg/cm<2> H2 pressure at normal temperature -150 deg.C for 0.5-15hr, and methylated to give an N-methyl compound. EFFECT:The titled compound can be produced industrially advantageously without causing problems of corrosion of devices, etc., and forming by-products which are not separated with ease.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a method for producing N-methyl compounds, and in particular to hydrogenated N-methyl compounds useful as intermediate raw material compounds for pharmaceuticals, agricultural chemicals, etc.
- A method for producing methylquinolines, hydrogenated N-methylisoquinolines or hydrogenated N-methylpyridines.

[Conventional technology]

Conventionally, methods for synthesizing N-methyl compounds such as N-methylperhydroquinolines, N-methylperhydroisoquinolines, or N-methylpiperidines include, for example,
Using perhydroisoquinoline hydrochloride as a raw material,
Method using formic acid and formaldehyde as methylating agents (J, Amer, Chem, Soc, 194
8. Vol. 70.2617-2619), and a direct synthesis method by hydrogenating isoquinoline in methanol in the presence of a Raney nickel catalyst (JCbem,
Soc, 1954.3798-3802) is known.

[Problem that the invention seeks to solve]

However, these methods have problems such as severe reaction conditions and corrosion of equipment, as well as production of by-products that are difficult to separate, resulting in poor yields.

[Means for solving problems]

The present invention was devised in view of this point of view, and is
Hydrogenated quinolines, N-hydrogenated isoquinolines and N-
An N-methyl compound obtained by reacting one or more N-hydrogenated nitrogen-containing heterocyclic compounds selected from the group consisting of hydrogenated pyridines with formaldehyde or paraformaldehyde using a hydrogenation catalyst under hydrogen pressure. This is a manufacturing method.

In the present invention, the N-hydrogenated nitrogen-containing heterocyclic compound used as a raw material has a structure in which at least the nitrogen atom of the nitrogen-containing heterocyclic compound is hydrogenated to become a secondary nitrogen, and the N-hydrogenated quinoline N-hydrogenated isoquinolines or N-hydrogenated pyridines, specifically Bircht O quinolines, 1,2.3.4-tetrahydroquinolines, perhydroisoquinolines, octahydroisoquinolines, 1 .2.3.4-Tetrahydroisoquinolines, piperidines, etc. These N-hydrogenated nitrogen-containing heterocyclic compounds include those having a substituent such as a methyl group, and may be produced by any method. It may also be a mixture of two or more types.

These N-hydrogenated nitrogen-containing heterocyclic compounds are usually produced by hydrogenating or partially hydrogenating quinolines, isoquinolines, or pyridines in the presence of a hydrogenation catalyst.

A preferred method for producing the N-hydrogenated nitrogen-containing heterocyclic compound of this raw material is a method in which hydrogenation is performed using the same hydrogenation catalyst as that used in N-methylation according to the present invention. In particular, this is a method that uses a platinum metal-based or nickel-based catalyst as a hydrogenation catalyst, thereby reducing the nitrogen content of the raw material.
-Hydrogenated quinolines, N-hydrogenated isoquinolines or N
- After producing hydrogenated pyridines, the reaction of the present invention can be carried out continuously without particularly separating and refining this raw material, and the desired N-methyl compound can be produced from quinolines, isoquinolines, or pyridines as raw materials. can be produced industrially advantageously.

Examples of the N-methyl compound for the above purpose include N-methylperhydroquinoline, N-methyl-1,2
, 3,4-tetrahydroquinoline, N-methylperhydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline, N-methyloctahydroisoquinoline, N-methylpiperidine, or a methyl group etc. in the nucleus of these. There are alkyl derivatives in which an alkyl group is substituted.

The formaldehyde used in the method of the present invention usually has a
It is used as a 50% formalin aqueous solution, and
Paraformaldehyde usually contains 60% by weight or more as formaldehyde. The amount of formaldehyde or paraformaldehyde to be used varies depending on whether formaldehyde or paraformaldehyde is used, but when formaldehyde is used, it is 1 times the amount per 1 mole of the raw material N-hydrogenated nitrogen-containing heterocyclic compound. A molar amount or more, preferably 2 to 3 times the molar amount, and when using paraformaldehyde, 1 times the molar amount or more in terms of formaldehyde per 1 mole of the raw material N-hydrogenated nitrogen-containing heterocyclic compound, Preferably 1.1
~2 times the molar amount. Paraformaldehyde is advantageous in terms of yield and separation and purification.

Further, as the hydrogenation catalyst used in the method of the present invention, conventionally known hydrogenation catalysts can be used, but platinum metal-based or nickel-based catalysts are preferable, and platinum metal-based catalysts are more preferably ruthenium-based catalysts. The nickel-based catalyst is a Raney nickel catalyst or a hydrogenated stabilized nickel catalyst. The amount of these hydrogenation catalysts used is usually o, oi% by weight, preferably 1 to 10% by weight, based on the N-hydrogenated nitrogen-containing heterocyclic compound as the raw material.

The reaction conditions for N-methylation according to the method of the present invention are such that the hydrogen pressure is 589/cm or more, preferably 10'
/ cm or more, and the reaction temperature is room temperature to 150°C,
When using formalin aqueous solution, preferably 50 to 1
When paraformaldehyde is used, the temperature is preferably room temperature to 100°C. When paraformaldehyde is used, the temperature is preferably raised to 100 to 150°C after the reaction is completed to remove unreacted To decompose paraformaldehyde into a water-soluble substance such as methanol so that separation and purification can be easily performed. The reaction time is usually 0.5 to 15 hours, preferably 2 to 5 hours.
This is carried out until the absorption of hydrogen is completed.

〔Example〕

Hereinafter, the method of the present invention will be specifically explained based on Examples.

Example 1 Perhydroisoquinoline (90% degree) 50 g and 37
% formalin aqueous solution in an autoclave, and 5% ruthenium carbon catalyst (water content) 2
．． 5 g, the reaction temperature was 75°C and the hydrogen pressure was 25°C.
Kg/cm for 5 hours, and the catalyst and aqueous phase were removed from the reaction mixture to obtain N-methylperhydroisoquinoline 5C1 with a purity of 80%. The yield was 81 mol%.

Example 2 Perhydroisoquinoline (purity 92%) 15Kg and 37
9 and 22% formalin aqueous solution were placed in an autoclave, 750 g of Raney nickel catalyst was added thereto, and the mixture was reacted for 9 hours at a reaction temperature of 70°C and a hydrogen pressure of 30 kg/cd, and the catalyst and aqueous phase were removed from the reaction mixture. N-methylperhydroisoquinoline 15 with a purity of 78%
I got Ky. The yield was 77 mol%.

Example 3 100 g of perhydroisoquinoline (purity 98%) and 32.5 g of paraformaldehyde (purity 80%) were placed in an autoclave, 2 g of Raney nickel catalyst was added thereto, the reaction temperature was 150°C and the hydrogen pressure was 25 Kl/
The reaction was carried out under ci conditions for 3 hours, and the catalyst and aqueous phase were removed from the reaction mixture to obtain 108 g of N-methylbarchtroin quinoline with a purity of 90.3%. The yield was 90 mol%.

Example 4 Perhydroisoquinoline (purity 98%) 1009 and paraformaldehyde (purity 80%) 29.7g were charged in an autoclave, 2g of Raney nickel catalyst was added thereto, and the reaction temperature was 70°C and the hydrogen pressure was 25%. The reaction was carried out under CD conditions for 2 hours, and then the temperature was raised to 150°C to decompose most of the unreacted paraformaldehyde into methanol, etc., and the reaction mixture was cooled to remove the catalyst and aqueous phase to obtain a product with a purity of 95%. 108 g of N-methylperhydroisoquinoline was obtained. The yield was 95 mol%.

Example 5 1.2.3.4-tetrahydroisoquinoline (purity 94
% > 30 (l and paraformaldehyde (80% purity) 9
0 g was placed in an autoclave, 10 g of Raney nickel catalyst was added thereto, and the mixture was reacted for 2 hours at a reaction temperature of 70°C and a hydrogen pressure of 25 Ag/ci, and then the temperature was raised to 150°C to remove the amount of unreacted paraformaldehyde. A portion was decomposed into methanol etc., cooled and the catalyst and aqueous phase removed from the reaction mixture to obtain 330 g of N-methylperhydroisoquinoline with a purity of 90%. Yield is 95 mol%
Met.

Example 6 50 g of perhydroisoquinoline (95% purity) and 14.8 g of paraformaldehyde (80% purity) were placed in an autoclave, 1 g of Raney nickel catalyst was added thereto, and the reaction temperature was 70°C and the hydrogen pressure was 25 Kl/ c.
The reaction was allowed to proceed for 2 hours under the conditions of (m), and then the temperature was raised to 150°C to decompose most of the unreacted paraformaldehyde into methanol, etc., and the catalyst and aqueous phase were removed from the reaction mixture by cooling, resulting in a product with a purity of 92%. N-methylperhydroisoquinoline 529 was obtained. The yield was 92 mol%.

Example 7 1.2.3.4-tetrahydroisoquinoline (purity 95
．． 6%) 50g and paraformaldehyde (Iili degree 8
0%) 15゜5!7 etc. were placed in an autoclave, 5g of Raney nickel contact W was added thereto, and the reaction temperature was 70°C.
and reacted at a hydrogen pressure of 25/9/ci for 2 hours,
Thereafter, the temperature was raised to 150°C to decompose most of the unreacted formaldehyde into methanol, etc., and the catalyst and aqueous phase were removed from the reaction mixture by cooling, resulting in 80% pure nitrogen.
-Methyl perhydroisoquinoline 5Cl was obtained. The yield was 76 mol%.

Example 8 50 g of piperidine (purity 95%) and 24.39 g of paraformaldehyde (purity 80%) were placed in an autoclave, 5 g of Raney nickel catalyst was added thereto, and the reaction temperature was 70°C and the hydrogen pressure was 25°C at 9/ci. The reaction was carried out under these conditions for 2 hours, and then the temperature was raised to 150°C to decompose most of the unreacted paraformaldehyde into methanol etc.
Cool and remove the catalyst and aqueous phase from the reaction mixture to a purity of 6.
70 g of 0% N-methylpiperidine were obtained. Yield is 72
It was mol%.

[Effects of the Invention] According to the method of the present invention, the N-methylation reaction of N-hydrogenated quinolines, N-hydrogenated isoquinolines, and N-hydrogenated pyridines can be carried out with good yield, and -The reaction conditions during the methylation reaction are mild, so there are no problems such as corrosion of the equipment, and there are few by-products that are difficult to separate, making it industrially advantageous to produce N-methylated nitrogen-containing heterocyclic compounds. can do.

Patent applicant Nippon Steel Chemical Co., Ltd. Agent
Patent Attorney Masaru Naruse Daido 1
Patent attorney Satoshi Nakamura procedure? Hoshosho (spontaneous) September 20, 1980 2, Name of the invention Process for producing N-methyl compounds 3, Relationship to the case of the person making the amendment Patent applicant address (residence) 5-13, Ginza, Chuo-ku, Tokyo No. 16 Name (664) Nippon Steel Chemical Co., Ltd. 4, Agent 105 Ti No. 03 (4,33) 442
05, date of amendment order 8, detailed statement of contents of amendment, page 10, line 7, line 15, and line 18,
In addition, "isoquinoline" written on page 11, line 7 is corrected to "quinoline."

9. Agents other than those listed in 1.

Claims (4)

[Claims] (1) 1 selected from the group consisting of N-hydrogenated quinolines, N-hydrogenated isoquinolines, and N-hydrogenated pyridines
N- characterized by reacting a species or two or more N-hydrogenated nitrogen-containing heterocyclic compounds with formaldehyde or paraformaldehyde using a hydrogenation catalyst under hydrogen pressure.
Method for producing methyl compounds. (2) The method for producing an N-methyl compound according to claim 1, wherein the hydrogenation catalyst is a platinum metal-based or nickel-based catalyst. (3) The method for producing an N-methyl compound according to claim 2, wherein the platinum metal catalyst is a ruthenium catalyst. (4) The N-hydrogenated nitrogen-containing heterocyclic compound is perhydroquinolines, perhydroisoquinolines, 1,2,3,4-
A method for producing an N-methyl compound according to any one of claims 1 to 3, which is a tetrahydroquinoline, a 1,2,3,4-tetrahydroisoquinoline, or a piperidine.