NO126483B - - Google Patents

Description

Method for the production of

tetrahydroisoquinoline compounds.

The present invention relates to a new process for the production of 1-substituted-6,7-dihydroxy-1,2,3,3-tetrahydroisoquinoline with the formula:

where ring A means a phenyl, methoxyphenyl, dimethoxyphenyl or trimethoxyphenyl group.

Relatively recently, it has been found that the tetrahydroisoquinoline compounds (I) produced according to the invention are useful as bronchodilators or cardiotonic agents (see Japanese Journal of Pharmacology Vol. 17, No. 2, June 1967, pages 143-164).. As stated

in this article shows 1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1>2,3,4-tetrahydroisoquinoline, 1-(3,4-dimethoxybenzyl)-6,7-dihydroxy-1, 2,3,4-tetrahydroisoquinoline and 1-(3,5-dimethoxybenzyl)-6,4-dihydroxy-1,4,3,4-tetrahydroisoquinoline have excellent protective and depressant effects for asthma paroxysm, and the cardiotonic effects of these compounds are characterized by very long duration. Two synthesis routes for tetrahydroisoquinoline compounds (I) were also indicated in the above-mentioned article (see e.g. tetrahedron, Suppl. 8, part 1, pages 129 - 134), one of which consists in reacting 3j4-dihydroxyphenethylamine with glycidine compounds represented by the formula:

where R<1> means an alkyl radical or an alkali metal atom, while ring A has the same meaning as stated above, while the other means that 3,4-dihydroxyphenethylamines are reacted with the aldehyde with the formula:

where ring A has the same meaning as stated above.

Known methods which can generally be used for the preparation of compounds of the isoquinoline type can be divided into three groups. The first and second methods comprise a condensation reaction of a phenethylamine compound with glycidine ester compounds or aldehyde compounds. The other method by which aldehyde compounds are used as one of the starting materials is known as the Pictet-Spengler synthesis and it has been used for the production of various tetrahydroisoquinoline compounds (cf. Organic Reactions vol.. 6, pages 151-190). The third method is the Bishler-Napieralski reaction for phenethyl acetamide compounds followed by a hydrogenation reaction. However, this method is not practical for the preparation of 6,7-di-hydroxytetrahydroisoquinoline compounds due to the difficulty in obtaining the necessary mono-N-acylated phenethylamine starting compounds because an amiho group and two hydroxy groups in the molecule can be acylated at the same time.

The above-mentioned known methods can be illustrated through the following reaction core if they are used for the production of the compounds mentioned in the present invention:

where R' means an alkyl radical and ring A has the meaning given above. The present method differs from these known methods in particular with regard to the output connections used.

In Organic Reactions vol. 6, pages 191-206, it is stated that acid-catalyzed cyclization of benzalaminoacetal results in the formation of isoquinoline compounds. However, this represents an intramolecular cyclization reaction which is termed the Pomeranz-Fritsch method and which is completely different from the intermolecular cyclization effected in the present method. From table II on page 204 of the above-mentioned reference, it is also clear that compounds of the 1-benzylisoquinoline type cannot be prepared by means of the Pomeranz-Fritsch method and this cannot therefore be used as an alternative to the present method.

As a result of further investigations, however, a new method for the production of the above-mentioned tetrahydroisoquinoline compounds (I) has been found.

According to the present invention, tetrahydroisoquinoline compounds (I) are prepared by heating 3>4-dihydroxyphenethylamine with a compound represented by the following formulas (II) or (III), where R<1> means a hydrogen atom, a lower alkyl or a lower aliphatic acyl group, R 2 means a lower alkyl group, R means a hydrogen atom or an alkyl group, while ring A has the same meaning as indicated above, under acidic conditions and in an inert solvent.

The pH of the reaction mixture can be adjusted using a common acid such as hydrochloric acid, acetic acid, etc. As a reaction solvent, water, water-miscible organic solvents such as ethanol, methanol, propanol or mixtures of these can be used. One can consequently obtain 1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 1-(4-methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline , 1-(3-,4-dimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 1-(3,5-dimethoxybenzyl)-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline, 1_(3 j ^ >5-1rimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and their acid addition salts, e.g., the hydrochloride

The starting compounds (II) and (III), which are mostly also new compounds, can respectively be prepared using the following reaction core:

where R 3 means an alkyl group, R 4 means a lower aliphatic acyl group.

2

rings A and R have the same meaning as stated above.

(1) The alkyl-oi-formyl-phenylacetate compound (V) can namely

is prepared by subjecting the alkyl-phenylacetate compound (IV) to formylation. The pormylation reaction can be efficiently carried out by

treating the compound (IV) with formic acid or alkyl formate (eg methyl formate, ethyl formate, etc.) in the presence of an alkali metal hydride or an alkali metal alkoxide, preferably at room temperature. A common solvent, such as e.g. ether can be used as reaction solvent.

(2) The alkyl-α-lower aliphatic acyloxymethylene-phenylacetate compound (VI) can be prepared by subjecting compound (V) to acylation. The acylation reaction can be carried out by treating the compound (V) with a common acylating agent (eg a lower aliphatic acyl anhydride or a lower aliphatic acyl halide). When a lower aliphatic acyl anhydride is used as the acylating agent, the reaction should

preferably carried out at room temperature or under ice cooling, in the presence of a small amount of sulfuric acid as a catalyst. When a lower aliphatic acyl halide is used as an acylating agent, the reaction can preferably be carried out in the presence of an acid acceptor such as e.g. pyridine or sodium carbonate.

(3) The alkyl-α-(dialkoxymethyl)-phenylacetate compound (VII) can

is prepared by subjecting the compound (V) to acetalization. This acetalization reaction can be carried out by treating the compound (V) with a lower alkanol (e.g. methanol, ethanol, propanol, etc.) in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.) under heating .

(4) the α-(dialkoxymethyl)-phenylacetic acid compound (VIII) can

is prepared by subjecting the compound (VII) to hydrolysis. The hydrolysis can preferably be carried out by allowing the compound (VII) to stand at room temperature in the presence of an alkali metal hydroxide (e.g. sodium hydroxide). (5) the cl-(dialkyloxymethyl)-phenylacetic acid compound (VIII) can,

if necessary, is treated with a thionyl halide to thereby convert it to an ot-alkyl-methylene-phenylacetic acid compound (IX). The reaction should preferably be carried out at room temperature.

The above-mentioned compounds (V) - (IX) can be individually used as one of the starting compounds according to the present invention.

Production of used output connections:

Example 1

0.58 g of sodium hydride was added to 25 ml of absolute ether, and

a solution containing 5.08 g of ethyl-3,4,5-trimethoxyphenylacetate and 1.63 g of ethyl formate at 25°-30°C was added to the mixture under vigorous stirring. After stirring for a further 2 hours at the same temperature, the mixture was extracted with water while cooling with ice water. The aqueous layer was acidified with 10% hydrochloric acid under cooling and then extracted with ether. The ether extract was washed with a saturated aqueous solution of sodium bicarbonate, then with water and then dried. The solution was then evaporated to remove the ether. Almost colorless crystals were obtained and these were recrystallized from a mixture of benzene and petroleum ether, whereby 3.3 g of ethyl-α-formyl-3,4,5-trimethoxyphenylacetate was obtained. A new recrystallization from the same solvent gives colorless needles which melted at 92.4° 94°C.

Analysis calculated for C^H-^Og; C 59.56, H 6.43

found: C 59.58, H 6.33.

Example 2

11.2 g of ethyl-α-formyl-3,4,5-trimethoxyphenylacetate was dissolved in 56 ml of a 5# hydrochloric acid solution in ethanol. The solution was heated under reflux for 3 hours. After cooling to 0°C, the solution was made alkaline with a 30% aqueous solution of potassium hydroxide, and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure keeping the temperature below 40°C, and then extracted with ether. The ether layer was washed with water and then dried. The solution was then evaporated to remove the ether. The residue thus obtained was distilled under reduced pressure and gave 10.8 g of ethyl-α-(diethoxymethyl)-3,4,5-trimethoxyphenylacetate which boiled at 145° - 150°C/0.1 mm Hg. Colorless oil. n^5.5 = 1.5012.

Example 3-4

The following compounds were prepared in the same manner as described in Example 2.

(3) Ethyl α-(diethoxymethyl)-4-methoxyphenyl acetate:

kp. 155° - 160°C/3 mm Hg.

colorless oil

n£<3> = 1.520

(4) Ethyl α-(diethoxymethyl)-3,4-dimethoxyphenylacetate:

kp. 174° - 178°C/2 mm Hg.

n^5'5 =1.4977

Example 5

8.9 g of ethyl α-(dimethoxymethyl)-3,4,5-trimethoxyphenyl acetate was dissolved in 50 ml of ethanol, and to this solution was added 10 ml of a 30 #'s aqueous solution of sodium hydroxide. The solution was then left for 2 days under stirring. It was then evaporated to remove the solvent. The residue was dissolved in a small amount of water, and the solution was extracted with ether to remove water-insoluble substances. The pH of the aqueous layer was adjusted to 3 with 10% hydrochloric acid while cooling, after which the whole. was extracted with ether. The ether layer was washed with water, dried and evaporated. The obtained crystalline residue was recrystallized from a mixture of benzene and petroleum ether, whereby 5.0 g of a-(diethoxymethyl)-3,4,5-trimethoxyphenylacetic acid was obtained. A new recrystallization from the same solvent gives colorless needles with a melting point of 106° to 107°C. Analysis: calculated for Cl6H24O7: C 58.52; H 7.37

found: C 58.78; H 7.33.

Example 6-7

The following compounds were prepared in the same manner as described in Example 5.

(6) α-(diethoxymethyl)-4-methoxyphenylacetic acid:

melting point 103° - 105°C (recrystallized from a mixture of benzene and petroleum ether).

Colorless, fine needles.

Analysis: Calculated for C-^H^O : C 62.-67; H 7.51

Found: C 62.80; H 7.31.

(7) α-(diethoxymethyl)-3,4-dimethoxyphenylacetic acid:

melting point 85.5° - 87°C (recrystallized from a mixture of benzene and petroleum ether).

Colorless, fine needles.

Analysis, calculated for C15<H>22°6: C 6°'^ >1> H 7.^1

found: C 60.31; H 7.50. Example 8

14.9 g of α-(diethoxymethyl)-3,4,5-trimethoxyphenylacetic acid was dissolved in 75 ml of chloroform, and 5.43 g of thionyl chloride was then added to the solution. This solution was then allowed to stand for 19 hours at room temperature. After the solvent was removed, the residue was dissolved in a small amount of chloroform. The solution was extracted with an aqueous solution of sodium bicarbonate. The water layer was cooled to a lower

temperature than 0°C, and the pH was adjusted to 3 with 10% hydrochloric acid followed by extraction with chloroform. The chloroform extract was washed with water, dried and evaporated to dryness. The obtained residue was crystallized from a mixture of benzene and petroleum ether, and 3.43 g of α-ethoxymethylene-3,4,5-trimethoxyphenylacetic acid was obtained. Colorless prisms of the compound melted at 146°-148°C after a recrystallization from ether.

Analysis: Calculated for C14H18°6: c 59.56; H 6.43

Found: C 59.74; H 6.25.

Example 9-10

The following compounds were prepared in the same manner as described in Example 8.

(9) α-ethoxymethylene-4-methoxyphenylacetic acid:

melting point 111° - 113°C (recrystallized from a mixture of benzene and petroleum ether),

Analysis: Calculated for c12Hi4°4<:> c 64.85; H 6.35

Found: C 64.90; H 6.40.

(10) α-ethoxymethylene-3,4-dimethoxyphenylacetic acid:

melting point 136° - .137°C (recrystallized from a mixture of benzene and petroleum ether),

colorless fine needles,

Analysis: Calculated for C^H^C^: C 61.89; H 6.39

Found: C 62.00; H 6.38.

Example 11

5.0 g of ethyl α-formyl-3,4,5-trimethoxyphenylacetate was suspended in 50 ml of acetic anhydride. The solution was cooled with ice water, after which 0.1 ml of concentrated sulfuric acid was added with stirring. After stirring for 1 hour at 5°-13°C, the solution was poured into ice water to decompose the excess of acetic anhydride, after which the whole was extracted with ether. The extract was washed with water, dried and evaporated to remove the ether. The residue thus obtained was distilled and gave 2.21 g of ethyl-α-acetoxymethylene-3j4,5-trimethoxyphenylacetate which boils at 195°-200°C (bath temperature)/0.05 mm Hg. A pale, yellowish, viscous oil.

The method according to the present invention shall be illustrated with reference to the following examples.

Example 12

7.6 g 3,4-dihydroxyphenethylamine hydrochloride, 12.4 g ethyl-a-

formyl-354,5-trimethoxyphenylacetate, 100 ml of methanol and 100 ml of 10 µM hydrochloric acid were mixed and the mixture was heated to reflux for 25 hours. The mixture was then concentrated under reduced pressure. After adding a small amount of acetone to the residue, the acetone solution was triturated to crystallize 1-(334,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. 2.9 g of the compound decomposed at 224.5° - 226°C after a recrystallization from 2% hydrochloric acid. The compound was obtained in the form of colorless fine prisms.

Analysis: Calculated for C19H2^N.HC1: C 59 .76; H 6.34; N 3.67; Cl 9.23

Found: C 59.72; H 6.33; N 3.96; Cl 9.20. Example 13

2.09 g of 3,4-dihydroxyphenethylamine hydrochloride, 3.4 g of α-ethoxy-methylene-3,4,5-trimethoxyphenylacetic acid, 3.4 g of methanol, 21 ml of water, 20 ml of 10% hydrochloric acid and 3 ml of acetic anhydride were mixed, and the mixture was heated under reflux for 54 hours. The reaction solution was treated in the same manner as described in example 1, whereby 1.23 g of 1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1>2j3>4-tetrahydroisoquinoline hydrochloride was obtained. When the compound was mixed with the crystals prepared in Example 12, and then subjected to a mixed melting point determination, no lowering of the melting point could be observed.

Example 14

1.17 g of 3,4-dihydroxyphenethylamine hydrochloride, 2.21 g of ethyl-α-acetoxymethylene-3,4,5-trimethoxyphenylacetate, 30 ml of methanol and 30 ml of water were mixed. After the pH has been adjusted to 2.2 with 10% hydrochloric acid, the solution was heated under reflux for 71 hours. The reaction mixture was treated in the same way as described in example 12, whereby 0.56 g of 1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was obtained. When the compound was mixed with crystals prepared as described in Example 12, then subjected to a mixed melting point determination, no lowering of the melting point could be observed.

Example 15 - 17

The following compounds were prepared in the same manner as described in Examples 12-14 or Example 19.

(15) 1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, melting point 245° - 256°C (decomposition), (recrystallized

sert from a mixture of methanol and ether).

Colorless fine prisms.

Yield: 56.7% (in accordance with Example 19). Analysis: Calculated for C15H17°2N•HC1: C 65.86; H 6.22; N 4.80; Cl 12.15 Found: C 65.90; H 5.98; N 5.06; Cl 12.17. (16) 1-(4-Methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride: mp 218.5° - 220°C (decomp.) (recrystallized from a mixture of methanol, acetone and ether).

Colorless, fine needles.

Yield: 62.8% (in accordance with Example 13).

Analysis: Calculated for C-^H^O^N.HCl:

C 63.43; H 6.27; N 4.35; Cl 11.02 Found: C 63.54; H 6.24; N 4.38; Cl 11.30. (17) 1-(3,4-dimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride: Melting point 275°C (decomp.) (recrystallized from a 1 ? hydrochloric acid solution).

Colorless, fine prisms.

Yield: 76.1% (in accordance with Example 13). Analysis: Calculated for C gH^O^N.HCl: C 61.55; H 6.31; NO 3.99; Cl 10.09 Found: - C 61.91; H 6.15; N 4.08; Cl 10.22. Example 18

3.84 g of 3,4-dihydroxyphenethylamine hydrochloride, 7.48 g of ethyl α-(diethoxymethyl)-3,4,5-trimethoxyphenyl acetate, 60 ml of methanol and 40 ml of 10% hydrochloric acid were mixed, after which the mixture was heated under reflux for 91 hours. The reaction mixture was treated in the same way as described in example 12, whereby 1.93 g of 1-(3,4,5-trimethoxybenzy 1")-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was obtained. When the compound was mixed with crystals prepared as described in Example 12 and subjected to a mixed melting point determination, no lowering of the melting point could be observed.Example 19

6.3^ g of 3,4-dihydroxyphenethylamine hydrochloride, 12.1 g of α-(di-ethoxymethyl)^,4,5-trimethoxyphenylacetic acid, 80 ml of methanol and 60 ml of 10 55 * s hydrochloric acid were mixed, after which the mixture was heated under

reflux for 70 hours. The reaction solution was treated in the same way as described in example 12, whereby 2.9 g of 1-(3>4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was obtained. When the compound was mixed with crystals prepared as described in Example 12 and subjected to a mixed melting point determination, no lowering of the melting point could be observed.

Claims (1)

Process for the preparation of tetrahydroisoquinoline compounds of the formula: where ring A means a phenyl, methoxyphenyl, dimethoxyphenyl or trimethoxyphenyl group, characterized in that a mixture of 3,4-dihydroxyphenethylamine and a compound with the formula: where R means a hydrogen atom, a lower alkyl or lower aliphatic acyl group, R 2 means a lower alkyl group, R means a hydrogen atom or an alkyl group, and ring A has the above meaning, is heated under acidic conditions in an inert solvent.