JPS5817465B2 - Method for producing tetrahydroisoquinoline derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new process for the preparation of 5,7-cyhydroxy-1-(3,4°5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline.

5,7-hydroxyl-1- which is the object compound of the present invention
1 (g, 4, 5-)rimethoxybenzyl)-1,
2,3,4-Tetrahytroinquinoline (L) is known to be a useful medicinal compound with excellent bronchodilatory effect and strong blood flow increasing effect (Japanese Patent Application Laid-Open No. 1986-7
No. 0770).

However, since this compound CI) does not have an electron-donating substituent at the 6-position of the isoquinoline skeleton, its production requires a circuitous route consisting of many steps, making it a simpler industrial method. Manufacturing is desired.

As a result of repeated research and search for a simple synthesis method for compound CI), the present inventors found that by using the Barbier reaction, the number of steps can be shortened and compound CI) can be produced with high yield. I found Shiroko.

According to the present invention, the target compound CI) can be easily produced by the method shown in the following reaction formula.

(However, R1 and R2 are benzyl groups, R3 is 3°4.5
-)rimethoxybenzyl group; The = heavy bond tr between the 3- and 4-positions of the 1,2-dihydroisoquinoline derivative (EV) is reduced to a single bond with sodium monoacetoxyborohydride to produce the 1,2,3,4-tetrahydroisoquinoline derivative [
(2)] and then subjecting this compound to a catalytic reduction reaction to obtain the desired compound CI).

The method of the present invention will be explained in detail below.

The first step, the parvinyl reaction, involves adding 3,4,5-4rimethoxy7benzyl halide to a mixture of inquinolinium salt (II) and magnesium pieces in a suitable solvent;
This can be carried out by immediately reacting the 3,4,5-trimethoxy7benzylmagnesium halide (III) formed in the mixed solution with the inquinolinium salt (I[).

As the raw material ink quinolinium salt (n), for example, symbol X
Compounds in which the group represented by is chlorine, bromine, etc. can be advantageously used.

In addition, if the reaction is difficult to occur, for example, 1,2-
The reaction can also be initiated using small amounts of initiators such as dibromoethane.

In general, the reaction proceeds smoothly when heated, with a high yield of 1,
A 2-dihydroisoquinoline derivative (IV) can be obtained.

Since the compound (IV) obtained here is unstable, it is convenient to use it as a raw material for the next step without isolation.

The reduction reaction in the second step is carried out using sodium monoacetoquine borohydride as a reducing reagent.The reagent itself may be added to the reaction solution, or sodium borohydride may be added to the reaction solution. It is also possible to utilize the reagent generated in the case of reaction by adding acetic acid separately.

The reaction can be carried out, for example, by reacting the 1,2-dihydroisoquinoline derivative (IV) with a reducing reagent in a suitable solvent.
The reduction reaction progresses suitably when heated, and the tetrahydroisoquinoline derivative [■] can be obtained in good yield.

The catalytic reduction reaction in the third step can be carried out by bringing the compound (V) into contact with hydrogen gas in a suitable solvent in the presence of a catalytic reduction catalyst according to a conventional method.

As the catalyst, for example, platinum oxide, palladium/carbon, etc. can be used.

The reaction proceeds smoothly even under normal temperature and normal pressure to heat and pressure, and the target compound [■] can be obtained in high yield.

As explained in detail above, the method of the present invention is applicable to the target compound [I
] The number of steps is reduced by 3 compared to the production method (method using the Lysselt reaction), and
(based on Vl).

Furthermore, the yield was about 37% higher (same standard as above), making it an excellent method for producing the target compound CI).

The starting compound (II) of the present invention can be prepared, for example, from 5°7-disubstituted inquinoline (Vl) by the method shown in the following reaction formula.

(However, R1, R2, and X have the same meanings as above.) Example (1) 5 g of magnesium pieces were suspended in 150 ml of tetrahydrofuran (hereinafter referred to as THF), and 0.5 g of 1,2-dibromoethane was added under a nitrogen stream. Add 9 ml and stir at room temperature for 15 minutes.

To this was added 15.0 g of 2-benzyl-5,7-dibenzyloxyisoquinolinium bromide, and then 34.
5-trimethoxybenzyl chloride 10g THF80
ml solution was added dropwise over 10 minutes, and after stirring at room temperature for 15 minutes,
Reflux for 45 minutes.

From now on, filter off the cine solution from the reaction solution, and remove the 2-benzyl-5
,7-dipenzyloxy-1-(3,4,5-trimethoxybenzyl)-1,2-dihydroisoquinoline (7)
Obtain a THF solution.

(2) Add 11:1 of sodium borohydride to the THF solution obtained in (1), and then add 18 g of acetic acid dropwise while cooling with water.

The reaction solution was stirred at room temperature for 30 minutes and then refluxed for 3.5 hours.

The reaction solution was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with chloroform.

After washing the extracted layer with water and drying, the solvent is distilled off. The remaining yellow oil is dissolved in a methanol/ether mixture, ether containing hydrogen chloride is added thereto, and the mixture is left overnight.

If the precipitated crystals are filtered, 2-benzyl-5,7-dipenzyloxy-1-(3,4゜5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride can be obtained as colorless prism crystals. As 16. :l get.

mp, 127-130°C (decomposition), yield 92% The main idea is that if recrystallized from a methanol/ether mixture, 1 m
p, 132-136°C (decomposed).

(3) Main substance 132.3g, 10% palladium/carbon 25g, 10% hydrochloric acid 150TrLl, methanol 125g
Catalytic reduction is performed by cooling a mixture of 0 ml and 100 ml of water at room temperature in a hydrogen stream (3 to 4 atm) (requires about 5 hours).

After the reaction is complete, the catalyst is filtered off, the solvent is distilled off from the filtrate, and the residue is crystallized from a methanol/ether mixture and collected by filtration to give 5,7-hydroxy-1-(3,45-trimethoxybenzyl )-1,2,3,4-tetrahydroisoquinoline hydrochloride is obtained as colorless crystals of 66, L9.

Yield 87.5%. The main idea is that if recrystallized from a mixture of ethanol and isopropyl ether, it will become colorless needle crystals with m92
40-243°C (decomposition).

Claims (1)

[Claims] 1 General formula (wherein R1 and R2 represent a benzyl group, and X is...
3.4.5-trimethoxybenzyl halide is added to a mixture of an inquinolinium salt represented by the formula (representing a halogen atom) and magnesium, and the mixture is reacted with the general formula (where R1 and R2 have the same meanings as above). ) is obtained, and the double bond between the 3rd and 4th positions of this compound is reduced to a single bond with sodium monoacetoxyborohydride. 5,7-hydroxy-1-(3,4,5- Method for producing (trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline.