JPS6154876B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing cyclic amines. The compound produced by the method of the present invention has the general formula (In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Y is

[Formula] However, R ² and R ³ are hydrogen atoms, hydroxy groups, methoxy groups, or ethoxy groups, and R ^{4 is}

When bonded to [Formula], it is -CH ₂ CH ₂ - or -CH=CH-, and when R ⁴ is bonded to -CH=, it is NH,
O or S. Or Y is

[Formula] However, R ² and R ³ are the same as above, and R ⁴ is

It is bonded to [Formula] and is -CH ₂ CH ₂ - or -CH=CH-. Moreover, R ⁵ is an alkyl group having 1 to 6 carbon atoms or

[Formula] However, R ⁹ and R ⁷ are a hydrogen atom, a hydroxy group, a methoxy group, or an ethoxy group. and X is C, Br or I, or R ⁸ SO ₃
group, provided that R ⁸ is a fluorine atom, a methyl group, a methyl trifluoride group, a phenyl group, a p-tolyl group, or a naphthyl group. ) or general formula (In the formula, Y has the same meaning as above, and R ¹⁰ has 3 to 3 carbon atoms.
8 alkylene group and has a substituent X on the third, fourth or fifth carbon, where X is C, Br, I or R ¹¹ SO ₃ . Here, R ¹¹ is a fluorine atom, a methyl group, a methyl trifluoride group,
It is a phenyl group, p-tolyl group or naphthyl group. Or ^R10 is

It is a cyclic amine represented by the formula: where R ¹² , R ¹³ and R ¹⁴ are a hydrogen atom, a hydroxy group, a methoxy group or an ethoxy group, and X is the same as above. The cyclic amines 1 and 2 of the present invention are useful as medicines, particularly as antihypertensive agents, analgesics, antitumor agents, bactericidal agents, and the like. The cyclic amines of the present invention are also useful as intermediates for isoquinoline alkaloid drugs having the same uses as mentioned above. Conventional methods for producing the above-mentioned cyclic amines require complicated and long steps, or use very expensive or dangerous chemicals, resulting in many problems in terms of environmental protection. The target compound obtained by the method of the present invention has the following general formula which can be easily produced as a starting material. (In the formula, Y and R ¹ are the same as above, and Z represents an anion.) A compound represented by the general formula R ⁵ X (in the formula, R ⁵
and X are the same as above) by electrode reduction in the presence of an electrophilic reagent. In addition, the target compound obtained by the method of the present invention has the general formula (In the formula, Y and Z are the same as above, R ⁹ is represented by R ¹⁰ X, and R ¹⁰ is the same as above) by electrode reduction. To explain the above reaction of the present invention in more detail, the general reaction formula is The reductive alkylation reaction of immonium salts such as those represented by R', R'' and R are arbitrary substituents can be carried out within a certain limited range using a reagent such as a Grignard reagent or an alkyl lithium. However, even in such cases, the yield is not good and the reaction is not easy.Furthermore, a major drawback of this method is that special reagents such as Grignard reagents or alkyl lithiums cannot be used for very limited compounds. Moreover, the reaction conditions are very special, and it cannot be used to produce cyclic amines with delicate structures such as those aimed at by the method of the present invention. On the other hand, the production method of the present invention is an original new production method that can be applied to an extremely wide range of R', R'' and R in the above reaction formula, and has no other targets for comparison. This is an innovative method that has many advantages not found in conventional manufacturing methods. (b) The raw materials are easily available (b) The target product can be obtained with very simple and safe operations (c) The process is very short with good selectivity and yield ( d) There is no by-product of isomers that are difficult to separate.(e) There is no use of any special or environmentally friendly chemicals.The starting materials of the present invention are as shown in the reaction formula below.
It can be obtained very easily by reacting both compounds, preferably in a solvent. (However, Y, Z, R ¹ and R ⁹ are the same as above.) In the above formula, Z represents any anion, and particularly preferred examples include C,
Examples include Br, I, an alkylsulfonate group, and an arylsulfonate group. The reaction of the present invention is necessarily a simple reaction in which the above compound 3 is electrolytically reduced in the presence of an electrophilic reagent represented by R ⁵ X, or the above compound 4 is electrolytically reduced. The above reaction is usually carried out in a suitable solvent by passing a direct current through it. Examples of solvents include water, alcohols such as methanol and ethanol, dimethylformamide,
Aprotic polar solvents such as dimethyl sulfoxide and hexamethylphosphoramide, and nitriles such as acetonitrile can be used. One of the characteristics of this reaction is that it proceeds at room temperature, but of course it can also be carried out at a low temperature below room temperature or under heating, for example in a wide range of -10°C to 100°C. However, it is most advantageous to carry out the reaction at temperatures between 0°C and room temperature. Typically, it is necessary to add a suitable or supporting electrolyte to pass a direct current through the solvent system in carrying out electrode reduction.
In the case of the method of the present invention, since the starting material solution already has conductivity, there is no need to add an electrolyte. In some cases, the reaction may proceed more favorably by coexisting a quaternary ammonium salt or a quaternary ammonium salt. All commonly used materials can be used as the electrode material, but platinum, mercury, lead, carbon, etc. are particularly effective. It is also optional to use a diaphragm, but when a diaphragm is used, it is a matter of course that the reaction is carried out in the cathode chamber. The optimum values of the current and terminal voltage vary depending on the equipment used and the scale of the reaction, and the equipment or scale of the reaction used when carrying out the method of the present invention is completely arbitrary. It is. Therefore, the current value and the voltage value between the terminals can also be appropriately determined. However, controlling the electrode potential of the cathode often provides advantageous results. In this case, the cathode potential is suitably determined by measuring the reduction potential of the immonium salt as the starting material, and setting the potential to be around that range. In the method of the present invention, the target product can be obtained from the starting materials without producing complex isomers as by-products, so purification after the reaction is very easy. can be obtained with extremely high purity and high yield. Furthermore, if necessary, the target product can be easily purified by column chromatography. Examples of the present invention are shown below. Example 1 A lead cathode and a platinum anode were used, and a clay cylinder was used as a diaphragm. A solution of dimethylformamide and p-toluenesulfonic acid tetraethylammonium salt was added as a supporting electrolyte was used as the anolyte, and electrode reduction was performed at room temperature while adjusting the cathode potential to 1.8 volts vs. SCE. After evaporation, extract with ether three times. After washing the ether extract with saturated brine, the ether was distilled off under reduced pressure to obtain 1-benzyl-2-methyl-1,2 dihydroisoquinoline with a yield of 90%. A portion of this was then dissolved in a mixture of 50 ml of water and 50 ml of ethanol, 1 g of caustic soda, 1 g of NaBH ₄ 1
After reducing the mixture by heating and refluxing for 5 hours, ethanol and water were distilled off, and the mixture was further extracted with ether. Next, the ether was distilled off, the residue was purified by column chromatography, and 1-benzyl-2-
Methyl-1,2,3,4-tetrahydroisoquinoline is obtained with a yield of 90%. The NMR spectra of this product are δ2.40 (3H), δ3.80 (1H), δ6.70 ~
It showed a unique absorption at 7.25 (9H), which completely matched that of the standard compound. Example 2 8.13 g (0.03 mol) of isoquinoline methiodide and 12.06 g (0.06 mol) of p-methoxybenzyl bromide were reacted in the same manner as in Example 1, and 1-
(p-methoxybenzyl)-2-methyl-1,2
-Dihydroisoquinoline was obtained in a yield of 95%. This compound was reduced with NaBH ₄ in the same manner as in Example 1 to obtain 1-(p-methoxybenzyl)-2-methyl-
1,2,3,4-tetrahydroisoquinoline is obtained with a yield of 95%. The NMR of this product is δ2.40
(3H), δ3.68 (3H), and δ6.25 to 7.05 (8H), which completely matched those of the standard compound. Example 3 1-(3,4- dimethoxybenzyl)-2-
Yield of methyl-1,2-dihydroisoquinoline 70
Obtained in %. This compound is reduced in the same manner as in Example 1 to obtain 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline in a yield of 93%. The NMR of this product is δ
2.40 (3H), δ3.58 (3H), δ3.70 (3H), δ2.20
(1H) and δ6.50 to 6.95 (7H), which were consistent with the standard compound. Example 4 1 g (0.003 mol) of compound (A) and 2.13g (0.015mol) of methyl iodide in 70ml
A solution dissolved in dimethylformamide was reduced with the electrode in the same manner as in Example 1 to obtain the formula The target product represented by was obtained in a yield of 65%. b・
The p value was 170°C/1 mmHg, which agreed with the fractional value. Example 5 A solution of 1 g (0.003 mol) of compound (A) and 1.2 g (0.006 mol) of p-methoxybenzyl bromide dissolved in 70 ml of dimethylformamide was reduced with the electrode in the same manner as in Example 1 to obtain the formula The desired product represented by was obtained in a yield of 90%. This one has NMR δ2.35 (3H), δ3.46 (3H), δ5.90 ~
6.95 (6H), which was consistent with the standard. Example 6 1 g (0.003 mol) of compound (A) and 1.4 g (0.006 mol) of 3,4-dimethoxybenzyl bromide in 70 ml
A solution of 1-(3,4-dimethoxybenzyl)-2-methyl-6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline ( Rhodanosine) was obtained in 90% yield. Melting point: 89℃. Example 7 0.765g (0.003mol) of compound (B) A solution prepared by dissolving 1.4 g (0.006 mol) of 3,4-dimethoxybenzyl bromide in 70 ml of dimethylformamide was subjected to electrode reduction using mercury as the cathode and using the other conditions as in Example 1. ,1-(3,
4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (tetrahydropapaverine) was obtained in a yield of 80%. Elemental analysis values are C, 69.90%; H, 7.37%; N,
It was 4.13%, which was in good agreement with the theoretical value. Example 8 Immonium salt (C) produced from isoquinoline and o-xylylene dibromide 1.18g (0.003mol) of dimethylformamide
The solution dissolved in 70 ml was reduced with the electrode in the same manner as in Example 1, and the formula The compound represented by was obtained in a yield of 80%. This compound was reduced in the same manner as in Example 1 to give the formula We obtained Belbin expressed as . The melting point of this compound was 83°C, which was consistent with the standard. Example 9 Immonium salt (D) obtained from isoquinoline and 1,3-trimethylene dibromide 1g (0.003 mol) of dimethylformamide 70
ml of the solution was subjected to electrode reduction in the same manner as in Example 1 to obtain 1,2-propylene-1,2-dihydroisoquinoline in a yield of 60%. This compound was reduced in the same manner as in Example 1 to give the formula 1,2-propylene-1,2,3, represented by
4-Tetrahydroisoquinoline was obtained with a yield of 97%. The elemental analysis value of this compound is C, 83.02%;
H, 8.76%; N, 8.22%, which agreed with the theoretical values. Example 10 1.37g (0.003mol) of compound (E) was dissolved in 70 ml of dimethylformamide and reduced by electrode in the same manner as in Example 1 to obtain The target product represented by was obtained in a yield of 70%. The NMR spectrum of this compound is δ3.60 (3H), δ3.72
(3H), δ6.28 (1H), δ6.40 (1H), δ6.95−
7.05 (4H), which matched the structure. Example 11 1.5 g (0.003 mol) of compound (F) Dissolved in 70 ml of dimethylformamide, reduce the solution with an electrode using mercury as a cathode to obtain the formula Yield of the target product (zylopinin) expressed as 70
Obtained in %. The melting point of this compound was 1147-148℃, which completely matched that of the standard product. Example 12 1.38g (0.003mol) of compound (G) was dissolved in 70 ml of dimethylformamide and reduced with the electrode in the same manner as in Example 1 using mercury as the cathode to obtain the formula The target product represented by was obtained in a yield of 80%. The NMR spectrum of this compound is δ3.80 (3H), δ3.75
(3H) and δ5.9−7.0 (6H), which matched the structural formula. Example 13 14.8 g (0.003 mol) of compound (H) was dissolved in 70 ml of dimethylformamide and reduced with the electrode in the same manner as in Example 1 using mercury as the cathode to obtain the formula The target product represented by was obtained in a yield of 70%. The elemental analysis values of this compound are C, 75.45%; H, 6.68%;
N, 8.35%, which was in good agreement with the theoretical value.

Claims (1)

[Claims] 1. General formula (In the formula, ^{R 1} is ^a hydrogen atom or an alkyl group having 1 ^{to 6} carbon atoms, Y is When bonded to [Formula], it is -CH ₂ CH ₂ - or -CH=CH-, and when R ⁴ is bonded to -CH=, it is NH,
O or S. Alternatively, Y is [Formula], where R ² and R ³ are the same as above, and R ⁴ is bonded to [Formula] and is -CH ₂ CH ₂ - or -CH=CH-. Moreover, Z represents an anion. ) is a ^{compound represented} by ^the general formula R ⁵ and X is C, Br or I, or R ⁸ SO ₃
group, provided that R ⁸ is a fluorine atom, a methyl group, a methyl trifluoride group, a phenyl group, a p-tolyl group, or a naphthyl group. ) A general formula characterized by electrode reduction in the presence of an electrophilic reagent A method for producing cyclic amines represented by the formula (wherein R ¹ , Y and R ⁵ are the same as above). 2 General formula (In the formula, Y has the same meaning as Y described in claim 1, ^R9 is represented by ^R10X , ^R10 is an alkylene group having 3 to 8 carbon atoms, and Has a substituent X on the third, fourth or fifth carbon, where X is C, Br, I or R ¹¹ SO ₃ , where R ¹¹ is a fluorine atom, a methyl group, a trifluoride A methyl group ^, a phenyl group, ^a p-tolyl ^group , or a naphthyl group. Alternatively, R ¹⁰ , X is the same as above, and Z represents an anion.) A general formula characterized by electrode reduction of a compound represented by A method for producing cyclic amines represented by the formula (wherein Y and R ¹⁰ are the same as above).