DE1620147C - Process for the production of berbin derivatives - Google Patents

Description

wherein X is a bromine atom, hydrogenated with zinc in an alkaline medium or catalytically.

The invention relates to a process for the preparation of berbin derivatives of the general formula

wherein R is a hydrogen atom or a lower alkyl group means with methoxychloromethane in the presence of a Lewis acid or with formaldehyde in Reacts the presence of sulfuric acid and that of a lower alkyl ester of the general formula II The reaction product obtained is treated with alkali on the obtained 5-bromoisochromanone, if necessary Allowing zinc to act in an alkaline medium, the resulting compound of the general formula

30th

35

wherein R ₁ and R _{2 are} identical or different and represent hydrogen atoms, methoxy or ethoxy groups or together represent a methylenedioxy group or one of the radicals R ₁ and R _{2 represents} a benzyloxy group, the radicals R _{3 are} identical and represent hydrogen atoms or methyl groups and R ₄ and R _{5 are} identical or different and are methoxy or ethoxy groups and R _{6 is} a hydrogen atom or a methyl or methoxymethyl group.

The derivatives of berbin of the general formula I have valuable physiological properties. In particular they show a tranquilizing and analgesic effect.

The tetrahydropalmitin, a derivative of the berbin of the formula I, is an alkaloid that is found in plants of the Fumaracia family. Tetrahydropalmitin was used in particular by Späth and co-workers (cf. Ber., 56 [1923], p. 875) isolated from roots of Corydalis cava. It got out too Dicentra formosa extracted.

A number of syntheses for the preparation of tetrahydropalmatine can be found in the literature. Man can, for example, mention the conversion of tetrahydroberberine into tetrahydropalmitine or else the process involved in the condensation of demethylated tetrahydropapaveroline with formaldehyde and the subsequent methylation of the condensation product obtained (cf. Henry, The plant alcaloids, pp. 292 and 343).

However, the methods known up to now give only low yields and the product obtained is often with other compounds, such as where X is a hydrogen or bromine atom, with a / 3-phenylethylamine of the general formula

HIa

to an N - (^ - phenylethyl) phenylacetamide of the general formula

J
R ₆

condensed, this heated with phosphorus oxychloride,

on the resulting dihydroisoquinoline of the general formula

R, R

IVa

an alkali metal borohydride is allowed to act and a compound of the general formula obtained

R, R

R,

wherein X is a bromine atom, hydrogenated with zinc in an alkaline medium or catalytically.

The one used in the reaction of the compound of general formula II with methoxychloromethane Lewis acid is preferably tin chloride or zinc chloride.

When the compound of the general formula II is reacted with formaldehyde, dilute sulfuric acid and a temperature of about 100 to 110 ^° C. are preferably used.

In the cyclization of the compound of general formula IV with phosphorus oxychloride, which of a Is accompanied by chlorination, one works in the heat in an organic solvent such as a benzene hydrocarbon.

When treating the isoquinoline derivative of the general formula IVa with an alkali metal borohydride sodium or potassium borohydride is preferably used.

The catalytic hydrogenation of a compound of the general formula V in which X is a bromine atom means, is carried out, for example, with palladium-carbon in ethanol.

The process according to the invention allows starting by direct synthesis under mild conditions from well-known products with an increased overall yield, to the general berbin derivatives Formula 1 and delivers these products in great purity.

The following examples illustrate the invention.

Example 1 d, l-Tetrahydropalmatine

Level a
3- Oxo-S-bromo-y ^ -dimethoxy-isochroman

1. Dissolve 40 g of 2-bromo-4,5-dimethoxyphenylacetic acid, which according to the in Journ. Chem. Soc, 1925, p. 1451, described procedure

ίο can, in 560 ecm of methylene chloride, distilled about 60 ecm of the solvent to remove traces of water, cools to 0 ° C and then gives 35 ecm Tin tetrachloride and 240 ecm methoxychloromethane.

The reaction mixture is left to stand for 2 hours at room temperature and then poured into ice-cold water Water.

It is then extracted with methylene chloride, washed with water and then with sodium bicarbonate and evaporated to dryness and obtain a neutral amorphous product.

The 3 - oxo - 5 - bromo - 7,8 - dimethoxyisochromane obtained after recrystallization from ether and methanol melts at 188 ° C; Yield: 5% The product is colorless, insoluble in water, in Ether very sparingly soluble, sparingly soluble in alcohol and methanol, and soluble in acetone and chloroform.

Analysis: C ₁₁ H ₁₁ O ₄ Br = 287.12.

Calculated ... C 46.01, H 3.86, Br 27.84%; . Found ... C 46.1, H 4.0, Br 26.8%.

The compound has not yet been described in the literature.

2. Dissolve 1 g of 2-bromo-4,5-dimethoxyphenylacetic acid in 40 ecm of methylene chloride, about 10 ecm of the solution is distilled off and then 1 g of zinc chloride is added and 1 ecm of methoxychloromethane.

The reaction mixture is agitated for 16 hours at room temperature and then poured into water.

It is then extracted with methylene chloride, washed with sodium bicarbonate and with water 'then recrystallized from ether and 3-oxo-5-bromo-7,8-dimethoxy-isochroman, mp 188 ^° C., which is identical to the lactone described above, is obtained ; Yield: 11%.

3. 1.8 ecm of concentrated sulfuric acid is added to 3.6 ecm of water, a mixture of 1.78 g of 2-bromo-4,5-dimethoxyphenylacetic acid and 1.2 ecm of 40% formaldehyde are added and the reaction mixture 18 is then heated Hours at a temperature of 110 ⁰ C.

It is cooled, poured into methylene chloride, washed with water, then with sodium bicarbonate and with water, and after the methylene chloride has been distilled off, 793 mg of neutral resin are obtained. Dissolve in methylene chloride, chromatographed on aluminum oxide, eluted with methylene chloride, crystallized from ether and contains 3 - oxo - 5 bromo - 7,8 - dimethoxy - isochroman, M.p. 188 ° C, which is identical to the lactone described above; Yield: 10%.

Level B.

N- [yS- (3,4-dimethoxyphenyl) ethyl] - (2'-bromo-4 ', 5'-dimethoxy-6'-hydroxymethyl) phenylacetamide

2.155 g of 3-oxo-5-bromo-7,8-dimethoxy-isochroman are dissolved and 1.925 g of homoveratrylamine in 160 ecm of ethanol and then heated under reflux for 16 hours.

One cools down and takes in water and methylene

chiorid on, decanted the water, evaporated to the

Dry and receives 4.76 g of residue, which is dissolved in a mixture of methylene chloride and ether (1: 3). It is cooled, filtered off with suction, dried and 3.02 g of N - [/ S- (3,4-dimethoxyphenyl) ethyl] - (2'-bromo-4 ', 5' - dimethoxy- 6'- hydroxymethyl) phenylacetamide, mp 137 ^° C., after recrystallization from methylene chloride and ether. .

The product is sparingly soluble in ether and soluble in chloroform.

Analysis: C ₂₁ H ₂₆ O ₆ NBr = 468.35.

Calculated ... C 53.85, H 5.6, N 2.99, Br 17.06%; found .... C 54.0, H 5.5, N 3.2, Br 17.1%.

The compound has not yet been described in the literature.

Level C
12-bromo-tetrahydropalmatine

There are 4 g of N - [> (3,4-Dimethoxyphenyl) ethyl] - (2'-bromo-4 ', 5'-dimethoxy-6'-hydroxymethyl) -phenyl- acetamide in 160 ecm benzene, adds 16 ecm phosphorus oxychloride and the reaction mixture is refluxed for IV2 hours.

It is then evaporated to dryness in vacuo and the residue is taken up in a mixture of ice, water and methylene chloride. The resulting solution is washed copiously with water, decanted, evaporated to dryness in vacuo and the residue obtained, which consists essentially of l - [(6'-bromo-3 ', 4'-dimethoxy-2 ^/ -chloromethylphenyl) -methyl ] - 6,7 - dimethoxy - 3,4 - dihydroisoquinoline, in 160 ecm of methanol.

7.2 g of sodium borohydride are added in small portions at room temperature and left with agitation Stand for 2 hours. It is poured into methylene chloride, washed with water until neutral Wash water and evaporates to dryness.

3.94 g of crude product are obtained which are dissolved in methylene chloride and chromatographed on aluminum oxide and eluted with methylene chloride containing 2% methanol.

• After evaporation and recrystallization from ether, 2.421 g of 12-bromo-tetrahydropalmatine are obtained, 162 ° C.

The product is soluble in dilute aqueous acids and in chloroform and not very soluble in ether.

Analysis: C ₂₁ H ₂₄ O ₄ NBr = 434.33.

Calculated ... C 58.07, H 5.57, N 3.23, Br 18.40%; found .... C 58.0, H 5.6, N 3.2, Br 18.1%.

The compound has not yet been described in the literature.

Level D

d, l-tetrahydropalmatine

55

2.06 g of 12-bromo-tetrahydropalmatin are dissolved in 100 ecm of ethanol by heating under reflux Add 10 ecm of sodium hydroxide solution, slowly introduce 16.6 g of zinc dust and keep stirring for 1 hour Reflux.

It is then cooled, filtered off with suction, washed with ethanol and then with methylene chloride and the filtrates are poured in water.

It is extracted with methylene chloride, washed with water until the washing barrels are neutral and evaporated to dryness.

The residue obtained is recrystallized from ether and from a mixture of methylene chloride and ether and 1.368 gd, l-tetrahydropalmatine, mp 151 ^° C. is obtained.

The product is sparingly soluble in ether and soluble in chloroform and dilute aqueous acids.

Analysis: C ₂₁ H ₂₅ O ₄ = 355.42.

Calculated ... C 70.96, H 7.09, N 3.94%; found .... C 70.7, H 7.1, N 3.9%. .

Example 2

d, l-tetrahydropalmatine

Level A
3-oxo-7,8-dimethoxy-isochroman

7.2 g of 3-oxo-5-bromo-7,8-dimethoxy-isochroman are added, which has been obtained according to Example 1, level A, in 220 ecm of ethanol, gives 36 ecm of sodium hydroxide solution and 57.6 g of zinc powder and heated under reflux for 1 hour.

It is cooled, filtered, the zinc is washed with ethanol " and concentrate the filtrate to a small volume under vacuum.

It is diluted with water, brought to pH 1 by adding hydrochloric acid, and stirred for 3 hours Room temperature and extracted with methylene chloride.

The extracts are washed with water, with a solution of sodium bicarbonate and then with pure Water, dry and distilled to dryness.

The residue crystallizes from isopropyl ether, and 4.3 g of 3-oxo-7,8-dimethoxy-isochroman, melting point 99 to 100 ^° C., are obtained.

Analysis: C ₁₁ H ₁₂ O ₄ = 208.21.
Calculated ... C 63.45, H 5.8%; found C 63.3, H 6%.

The compound has not yet been described in the literature.

Level B.

N - [/? - (3,4-Dimethoxyphenyl) ethyl] -6'-hydroxymethyl-4 ', 5'-dimethoxyphenyl acetamide

0.4 g of 3-oxo-7,8-dimethoxy-isochroman and 0.36 g of homoveratrylamine in 15 ecm of ethanol, heated 16 hours under reflux and finally distilled to dryness in vacuo.

The residue is dissolved in methylene chloride, washed with n / 10 hydrochloric acid and then with water, dries, distilled to dryness in vacuo and receives 0.72 g of N - [/ S- (3,4-dimethoxyphenyl) ethyl] -6'-hydroxymethyl-4 ', 5'-dimethoxyphenylacetamide, which is used as it is for further synthesis.

The compound has not yet been described in the literature.

Level C

d, l-tetrahydropalmatine

0.72 g of N - [(8- (3,4-Dimethoxyphenyl) ethyl] -6'-hydroxymethyl-4 ', 5'-dimethoxyphenylacetamide are added to a mixture of benzene and phosphorus oxychloride ( . 10: 1) and heated under reflux for hours is then distilled in vacuo to dryness, the residue is dissolved in aqueous ethanol and then under slight cooling in the course of 30 minutes potassium borohydride is added and stirred for 2 hours at a temperature of 30 ⁰ C.

209 651/183

It is diluted with water, extracted with methylene chloride, the extracts are washed with water, dried and distilled to dryness in vacuo.

The residue is dissolved in methylene chloride and chromatographed on aluminum oxide. One elutes with methylene chloride, the eluate is concentrated, poured into ether and then the crystallized product is filtered off with suction. It consists of 0.4 g of d, l-tetrahydropalmatine; 148 ° C.

Example 3

2,9,10-trimethoxyberbine

(I with R ₁ , R ₄ , R5 = OCH3, R ₂ , Rg = H ₅ R ₃ = H)

15 Level A

N - [/ S- (4-methoxyphenyl) ethyl] - (2'-bromo-4 ', 5'-dimethoxy-6'-hydroxymethyl) phenylacetamide

20th

2.5 g of p-methoxyphenylethylamine are dissolved in 60 ecm of ethanol at room temperature and then added to the resulting solution 4.2 g of 3-oxo-5-bromo-7,8-dimethoxy-isochroman, obtained according to Example 1, stage A and refluxed for 19 hours.

The solution is then cooled and precipitated by. is poured into water. It is extracted with methylene chloride, the organic phase is washed with 2N hydrochloric acid and then with water and dried. It is filtered, concentrated to a small volume and, after the addition of ether, the solvent is driven off by distillation. The mixture is concentrated to a small volume and cooled for half an hour, filtered off ,, washed with ether, dried in a drying oven at 8O ⁰ C and receives 5,69g N-0 (4-methoxyphenyl) ethyl] - (2 ' bromo-4 ', 5' - dimethoxy - 6 '- hydroxymethyl) - phenylacetamide (IV); F. 145 ° C.

The product arises in the form of colorless needles that are sparingly soluble in alcohol and in acetone and chloroform are soluble.

Analysis: C ₂₀ H ₂₄ O ₅ NBr = 438.32. Calculated ... C 54.81, H 5.51, N 3.19, Br 18.24%; found .... C 54.9, H 5.8, N 3.5, Br 18.30%.

The compound has not yet been described in the literature.

Level B.

l - [(2'-Chloromethyl-3 ', 4'-dimethoxy-6'-bromophenyl) methyl] -7-methoxy-3,4-dihydro-isoquinoline

4.64 g of N- [j3- (4-methoxyphenyl) - ethyl] - (2 '- bromo- 4', 5 '- dimethoxy - 6' - hydroxymethyl) phenylacetamide in 18 ecm anhydrous phosphorus oxychloride and heated under for 2 hours Reflux.

The solution is then cooled and poured into a mixture of ice and water, the temperature between 0 and 10 ^° C. being maintained. The smear formed is extracted with methylene chloride, the organic phase is washed with water, dried, filtered, and distilled to dryness, whereby a vacuum is applied at the end, and the l - ^ '- chloromethyl-S' ^ '- dimethoxy-6'- bromophenyl) methyl] -7-methoxy-3,4-dihydro-isoquinoline, which is used as it is for further synthesis.

The compound has not yet been described in the literature.

45

Level C

2,9,10-trimethoxyT12-bromoberbin

The l-ß ^ '- chloromethyl-S' ^ '- dimethoxy-o'-bromophenyl) -methyl] -7-methoxy-3,4-dihydro-isoquinoline is dissolved while stirring, obtained in the previous step in 50 ecm of ethanol containing 15% water. Then you give 7 g of potassium borohydride are added in the course of 15 minutes, and the solution is stirred for 2 hours at room temperature and pour in water.

It is extracted with methylene chloride, washed with water, dried, filtered and distilled to dryness, whereby a vacuum is applied at the end and a gummy residue is obtained.

This residue is dissolved in acetone, perchloric acid is added up to pH 1 and the Crystallization by scratching started.

The mixture is cooled for half an hour and then filtered off with suction, washed with acetone and 2.1 g of one is obtained crystallized product, which is dissolved in methylene chloride. After washing with alkali, then with water, it is dried, filtered and distilled to dryness, a vacuum being applied at the end.

Recrystallization of the residue obtained gives 1.45 g of 2,9,10-trimethoxy-12-bromoberbin; F. 140 ⁰ C.

The product arises in the form of prisms, which are sparingly soluble in alcohol and in acetone and chloroform are soluble.

Analysis: C ₂₀ H ₂₂ O ₃ NBr = 404.3.

Calculated ... C 59.39, H 5.48, N 3.46, Br 19.76%; found .... C 59.5, H 5.5, N 3.3, Br 19.7%.

The compound has not yet been described in the literature.

Level D
2,9,10-trimethoxy-berbin

1.54 g of 2,9,10-trimethoxy-12-bromoberbin are dissolved in 75 ecm of ethanol while heating under reflux, then cools down to room temperature and adds 7.5 ecm of sodium hydroxide solution while stirring.

6 g of zinc dust are then added over the course of 10 minutes and the reaction mixture is heated 1 hour on an oil bath under reflux.

It is cooled, the zinc dust is removed by filtration, washed with ethanol and with methylene chloride, then pour the filtrate into water and extract with methylene chloride.

The organic phase is washed with water, dried, filtered and distilled to dryness, whereby a vacuum is applied at the end. The gummy residue obtained is dissolved in ether and passed the solution over adsorption earth, concentrated to a small volume, added isopropyl ether and cooled.

It is filtered off with suction, washed with isopropyl ether, dried and obtained 1.04 g (yield: 85%) of 2,9,10-trimethoxyberbine, 129 ° C.

The product arises in the form of leaflets, which are very little soluble in ether and in alcohol, acetone and chloroform are soluble.

Analysis: C ₂₀ H ₂₃ O ₃ N = 325.39.

Calculated ... C73.82, H7.12, N4.3%;
found ... C73.6, H7.3, N4.3%.

Example 4
2,3,9,10-tetramethoxy-11-methyl-berbin

(I, with R ₁ , R ₂ , R ₄ , R ₅ = -OCH ₃ ,
R ₃ = H and R ₆ = CH ₃ )

Level a

isochromanic

IO

8.50 g of the methyl ester of 2-bromo-3-methyl-4,5-dimethoxyphenylacetic acid are added in 200 ecm methylene chloride, distilled 40 ecm of the solvent and then add 9.5 g of melted comminuted zinc chloride and 9 ecm of methoxychloromethane and stirs 138 hours.

It is then poured into a mixture of water and methylene chloride, the methylene chloride solution is washed alternately with water and with sodium hydroxide solution until neutral, then 80 ecm isopropanol and 50 ecm 1 η-sodium hydroxide solution are added, the mixture is refluxed for 1 ¹ I for ₂ hours and half is removed of the isopropanol by distillation.

It is cooled, mixed with 20 ecm of concentrated hydrochloric acid and left to stand for 2 hours.

The residue formed is then taken in Methylene chloride, washed with sodium bicarbonate and water, dried and distilled to dryness.

The product obtained is crystallized from ether and 3.04 g of 3-oxo-5-bromo-6-methyl-7,8-dimethoxy-isochromane are obtained; F. 135 ^° C. This compound is colorless, sparingly soluble in ether and soluble in acetone and chloroform.

Analysis: C ₁₂ H ₁₃ O ₄ Br = 301.14.

Calculated ... C 47.86, H 4.35, Br 26.54%; found ... C 47.7, H 4.5, Br 26.7%.

The compound has not yet been described in the literature.

Level B.

N-0 (3,4-dimethoxyphenyl) ethyl] -

(2-bromo-3-methyl-4 ', 5-dimethoxy-6-hydroxy-

methyl) phenylacetamide

10.42 g of S-oxo-S-bromo-o-methyl- ^ S-dimethoxy-isochroman are dissolved and 6.57 g /? - (3,4-Dimethoxyphenyl) ethylamine in 100 ecm of ethanol and heated the resulting solution under reflux for 20 hours.

At the end of the refluxing, 60 ecm of the solvent is distilled off over the course of one hour and 40 minutes and the concentrated solution is then refluxed for 3 ¹ I for _{2 hours.}

After cooling, a spongy mass is obtained, which is dissolved in ethanol on a water bath and diluted with Water, starts crystallization by scratching, cools, sucks off and washes with water.

Dissolve the product formed in ethanol which is heated to 6O ⁰ C, diluted with water, cooled, filtered off, washed with water, and dried to give 15 g (yield: 90%) of N- |> (3,4-dimethoxyphenyl ) -äthyl] - (2 '- bromo - 3' - methyl - 4 ', 5' - dimethoxy - 6 '- hydroxymethyl) phenylacetamide, mp 119 ° C. This product is colorless and insoluble in water and in alcohol and Soluble in chloroform.

The compound has not yet been described in the literature.

Level C

2,3,9,10-tetramethoxy-1, 1-methyl-12-bromide, 1-berbin

7 g of N - [> (3,4-dimethoxyphenyl) ethyl] - (2 ' - bromo - 3 '- methyl - 4', 5 '- dimethoxy - 6' - hydroxymethyl) phenylacetamide in 28 ecm phosphorus oxychloride, heated under reflux for 2 hours and distilled to dryness in the course of a few minutes.

The residue formed is poured onto a mixture of ice and water and then extracted with methylene chloride, the organic phase is washed with water and distilled to dryness. The residue is taken in 120 cc of ethanol and 20 cc of water, added at about 15 ⁰ C in the course of half an hour to 14 g of potassium borohydride and then the reaction mixture stirred IV2 hours.

It is then extracted with methylene chloride, the organic phase is washed with water and distilled to Dry, dissolve the residue in methylene chloride and chromatograph on aluminum oxide and elute with methylene chloride according to the following work plan:

Analysis: C ₂₂ H ₂₈ Nr NO ₆ = 482.37.

65 parliamentary group

Amount of solvent

250 ecm
260 ecm
170 ecm
270 ecm
400 ecm
480 ecm
500 ecm
750 ecm
660 ecm
500 ecm

Methylene chloride methylene chloride methylene chloride methylene chloride methylene chloride Methylene chloride methylene chloride methylene chloride methylene chloride methylene chloride

Product received

425 mg

800 mg

1337 mg

1028 mg

610 mg

370 mg

334 mg

180 mg

80 mg

Calculated ... C 54.78, H 5.85, Br 16.57, N 2.9%; Found ... C 54.9, H 5.8, Br 16.8, N 2.6%.

Fractions 4 to 10 are distilled to dryness and the residue is crystallized from ether.

After recrystallization from ether, 2,3,9,10-tetramethoxy-11-methyl-12-bromo-d, l-berbine is obtained in a yield of 60%; M.p. about 122 ° C;

Analysis: C ₂₂ H ₂₆ BrNO ₄ = 448.36.

Calculated ... C 58.93, H 5.85, N 3.13, Br 17.82%; Found ... C 59.0, H 5.8, N 3.0, Br 17.7%.

The compound has not yet been described in the literature.

Level D
2,3,9,10-tetramethoxy-11-methyl-berbin

4.6 g of 2,3,9,10-tetramethoxy-II-methyl-12-bromoberbin are dissolved in 250 ecm of ethanol, 25 ecm of sodium hydroxide solution are added, the mixture is heated under reflux, during which process introduces 40 g of zinc dust over the course of one hour and then continues to heat after the addition has ended 1 hour.

It is cooled, filtered off with suction, extracted with methylene chloride, and the organic extracts are washed with water and distilled to dryness. The residue is dissolved in methylene chloride, chromatographed on aluminum oxide, eluted with methylene chloride and then with

1 b'ZÜ 14 /

Methylene chloride, which contains 1% methanol, and crystallizes that obtained by evaporation of the eluate Fractions of ether.

After recrystallization from ether, 3.09 g of 2,3,9,10-tetramethoxy-11-methyl-berbin are obtained; F, 141 ° C.

This product is sparingly soluble in ether and soluble in chloroform and methylene chloride.

Analysis: C ₂₂ H ₂₇ NO ₄ = 369.45.

Calculated ... C 71.52, H 7.37, N 3.79%;
found ... C 71.7, H 7.5, N 3.8%.

The compound has not yet been described in the literature.

The required starting material of the general formula II was prepared as follows:

a) Methyl ester of 2-bromo-4,5-dimethoxyphenylacetic acid

50 g of 2-bromo-4,5-dimethoxyphenylacetic acid are added to 100 ecm of methanol, and 1 ecm of concentrated Hydrochloric acid is added and the mixture is heated under reflux for 15 minutes.

It is then poured onto ice, diluted with water and brought onto the by adding sodium bicarbonate pH 10 and extracted with methylene chloride.

The organic phase is washed with water, dried, distilled to dryness and one wins oily residue.

Petroleum ether is added to the oily residue, crystallization is started by scratching, sucks off and receives 49.5 g of the methyl ester of 2-bromo-4,5-dimethoxyphenylacetic acid; 66 ° C.

A further 1.3 g are obtained from the mother liquors from the crystallization, which have been evaporated to dryness of the product. The product is colorless and insoluble in dilute aqueous alkalis and in the Most common organic solvents are soluble.

The compound has not yet been described in the literature.

b) methyl ester of 2-bromo-3-chloromethyl-4,5-dimethoxyphenylacetic acid

50.1 g of the methyl ester of 2-bromo-4,5-dimethoxyphenylacetic acid are dissolved in 800 ecm of methylene chloride, the solution is concentrated by distilling off 100 ecm and then cooled to room temperature. Then 50 g of freshly powdered zinc chloride and 50 ecm of methoxychloromethane are added. The mixture is stirred for 66 hours at a temperature of 20 ^° C. The reaction mixture is then poured onto an ice-water mixture. The precipitate which has occurred is absorbed by a mixture of water and methylene chloride until it is completely dissolved, the aqueous solution is extracted four times with methylene chloride, the methylene chloride phases are combined, dried over magnesium sulfate and this solution is then run over a column charged with aluminum oxide.

The column is then eluted with methylene chloride, the first 600 ecm of methylene chloride do not deliver a solid residue. Further elution with methylene chloride provides after evaporation 31.2 g of crude product. A third elution with methylene chloride still delivers 20.4 g of product. Further elutions only deliver small amounts of other products.

The dry residue from the second elution taken up by a minimal amount of methanol provides 13 g of 2-bromo-3-chloromethyl-4,5-dimethoxyphenylacetic acid methyl ester; Mp 65 ° C. The residue from the third elution yields 5.06 g of the same ester; F. 65 ° C. A total of 18.06 g of pure ester is obtained.

The product is colorless, sparingly soluble in methanol and in alcohol, ether, acetone, benzene and chloroform soluble.

The compound has not yet been described in the literature.

c) methyl ester of 2-bromo-3-methyl-4,5-dimethoxyphenylacetic acid

With stirring 11g Dissolve the Methylesters of 2-bromo-3-chloromethyl-4,5-dimethoxy-phenyl-acetic acid in 200 cc of acetic acid, heated ⁰ C to about-8O, then in the course of 40 minutes 35 g of zinc dust and the reaction mixture is heated for a further hour. .

It is cooled, the zinc is removed by filtration, washed with methylene chloride and the filtrate is diluted with water and then extracted with methylene chloride.

The organic phase is washed successively with water and sodium bicarbonate and then dried and distilled to dryness.

The residue is taken up in petroleum ether, triturated, then filtered off with suction, dried and obtained 85 g of the methyl ester of 2-bromo-3-methyl-4,5-dimethoxyphenylacetic acid; F. 7O ⁰ C.

This product is insoluble in petroleum ether and soluble in alcohol, ether, benzene and chloroform.

Analysis: C ₁₂ H ₁₅ O ₄ Br = 303.16.

Calculated ... C 47.54, H 4.99, Br 26.36%;
Found ... C 47.4, H 5.1, Br 26.2%.

The compound has not yet been described in the literature.

Example5
3,9,10-trimethoxy-berbin

(I, R ₂₅ R ₄₅ R ₅ = -OCH ₃ ,

R ₁ = R ₆ = H, R ₃ = H ₂ )

Level a

N - [/ S- (3-methoxyphenyl) ethyl] -

(2-bromo-4 ', 5-dimethoxy-6-hydroxymethyl) -

phenylacetamide

0.6 ecm of m-methoxyphenylethylamine is added (cf. L. H e 1 f e r, Helvetica, 7, 948 [1924]) in 5 ecm ethanol, adds g3-Oxo-5-bromo-7,8-dimethoxy-isochroman, which has been obtained according to Example 1, Stage A, dissolved in 10 ecm of ethanol, and heated under reflux for 16 hours.

It is cooled, poured into water, stirred, extracted with methylene chloride and washed the organic Phase with 2 η-hydrochloric acid and with water.

It is dried, filtered and concentrated until the beginning of the

Crystallization to a small volume, then mixed with ether and chased away the methylene chloride by distillation. It is then cooled for 1 hour, suction filtered, washed with ether and dried.

After recrystallizations from hot isopropanol and ethyl acetate, 950 mg of N-fj9- (3-methoxy-

phenyI) ethyl] - (2'-bromo-4 ', 5'-dimethoxy-6'-hydroxymethyl) phenylacetamide; 136 ° C.

The product arises in the form of colorless crystals that are sparingly soluble in ether and in acetone are soluble.

Analysis: C ₂₀ H ₂₄ O ₅ NBr = 438.32.

Calculated ... C 54.8, H 5.51, N 3.19, Br 18.25%; found C 54.7, H 5.5, N 3.2, Br 18.2%.

The compound has not yet been described in the literature.

Level B.

3,9,10-trimethoxy-12-bromoberbin

There are 4 ecm of phosphorus oxychloride in 40 ecm anhydrous benzene, heated and then cooled and sets 2 g of N - [> (3-methoxyphenyl) ethyl] - (2'-bromo-4 ', 5'-dimethoxy-6'-hydroxymethyl) phenylacetamide.

The reaction mixture is then heated under reflux for 2 hours, cooled and then pour on ice and stir for 1 hour. j Extraction with methylene chloride is carried out and the organic extracts with water, dried, filtered and evaporated the filtrate to dryness, whereby one finally evacuated.

The residue is added in 40 cc of ethanol containing 15% water, cooled to about 10 ⁰ C, then in small fractions 3 g of potassium borohydride is added and stirred the reaction mixture for 3 hours.

It is poured into water, extracted with methylene chloride, the organic phase is washed with water, dried, filtered and distilled the filtrate to dryness, evacuating at the end. Dissolve the residue in ethyl ether, chromatographed on magnesium silicate and eluted with ether. The eluate is on a narrowed small volume; then the crystallization is started and the mixture is cooled for 1 hour.

It is filtered off with suction, washed with ether, dried and 540 g of 3,9,10-trimethoxy-12-bromoberbin are obtained; 142 ° C.
'The product is soluble in ether and acetone.

Analysis: C ₂₀ H ₂₂ O ₃ NBr = 404.31.

) Calculated ... C 59.39, H 5.48, N 3.48, Br 19.76%;

found ... C59.4, H5.5, N3.4, Br 19.7%.

The compound has not yet been described in the literature.

Level C

3,9,10-trimethoxy-berbin

570 mg of 3,9,10-trimethoxy-12-bromoberbin are dissolved in 28.5 ecm of ethanol by heating under reflux.

After cooling to room temperature, 3 ecm of sodium hydroxide solution and 4.6 g of zinc dust are added and then heated the reaction mixture for 1 hour with stirring and reflux.

It is then cooled to room temperature, the zinc is removed by filtration, washed with ethanol, dilute the filtrate by adding 10 volumes of water and extracting with methylene chloride.

The organic phase is washed with water, dried and distilled to dryness, being used for Finally evacuated.

The residue is dissolved in ethyl ether, chromatographed on magnesium silicate, eluted with ether, concentrates the eluate to a small volume, cools 1 hour, sucks off, washes with ether, dries and receives 360 mg 3,9,10-trimethoxy-berbin; Mp 128 ° C.

The product comes in the form of skewers,

which are soluble in alcohol, ether, acetone and chloroform.

Analysis: C ₂₀ H ₂₃ O ₃ N = 325.39.

Calculated ... C 73.82, H 7.13, N 4.30%;
Found ... C 73.8, H 7.2, N 4.3%.

The compound has not yet been described in the literature.

Example 6
2,3,9,10-tetramethoxy-5,5-dimethyl-berbin

(I, with R ₁ , R ₂ , R ₄ , R ₅ = -OCH ₃ ,

R ₃ = -CH ₃ , R ₆ = H).

Level a

N - [/ S- (3,4-dimethoxyphenyl) - / 3-dimethylethyl] -. (2-bromo-4 ', 5-dimethoxy-6-hydroxymethyl) phenylacetamide

It adds α, α-dimethyl-homoveratrylamine, the by adding 815 mg of α, α-dimethyl-homoveratryl amine perchlorate to 30 ecm 1 η sodium hydroxide solution Stirring, extraction with methylene chloride * washing the organic phase with water, filtering, drying and distilling in vacuo to dryness has been obtained with 500 mg of 3-oxo-5-bromo-7,8-dimethoxy-isochroman, which has been obtained according to Example 1, stage A, in 7.5 ecm ethanol and heated the reaction mixture under reflux for 16 hours. It is distilled to dryness in vacuo, the Residue in methylene chloride and then washed

with phosphoric acid diluted to V100 and with water.
It is filtered, dried and distilled in vacuo

• Dry and receive 900 mg of N - [> (3,4-Dimethoxyphenyl) - ß- dimethylethyl] - (2 '- bromo-4', 5 '- dimethoxy-6'-hydroxymethyl) -phenylacetamide, which are not obtained in crystalline form could.

The product is insoluble in water and dilute aqueous acids and alkalis and in alcohol, Ether, acetone, benzene and chloroform soluble.

The compound has not yet been described in the literature.

Level B.

l - [(2'-chloromethyl-3 ', 4-dimethoxy-6-bromophenyl) methyl] -4,4-dimethyl-6,7-dimethoxy-
3,4-dihydro-isoquinoline

3.8 g of N- |> (3,4-dimethoxyphenyl) - £ -dimethylethyl] - (2'-bromo-4 ', 5'-dimethoxy-6'-hydroxymethyl) -phenylacetamide in 75 ecm of anhydrous Benzene, then 7.6 ecm of anhydrous phosphorus oxychloride are added and the reaction mixture is ^{refluxed 1 x} / ₂ hours.

It is concentrated in vacuo to about 10 ecm, poured onto a mixture of ice and water and extracted then with methylene chloride.

The organic phase is recovered, washed with water, dried, filtered, and distilled to dryness receives 3.8 g of 1 - [(2 '- chloromethyl - 3', 4 '- dimethoxy-6'-bromophenyl) methyl] -4,4-dimethyl-6,7-dimethoxy- 3,4-dihydro-isoquinoline, which is used as it is for the following synthesis stage.

The compound has not yet been described in the literature.

209 651/183

17th
Level C

2,3,9,10-tetrams & oxy-5,5-dimethyl-12-bromberbine

3.8 g of l - [(2'-chloromethyl-3 ', 4'-dimethoxy-6'-bromophenyl) methyl] -4,4-dimethyl-6,7-dimethoxy-3,4-dihydro- isoquinoline in 57 ecm of ethanol, which contains 15% water, then adds im at room temperature 5.7 g of potassium borohydride are added over the course of 15 minutes and the mixture is stirred for 2 hours.

The reaction mixture is diluted with water, then extracted with methylene chloride and washed organic phase with water.

It is dried, nitrated and distilled to dryness and the residue is taken up in hot methanol.

It is cooled, filtered off with suction, washed with methanol and with ether, dried and 1.6 g of 2,3,9,10-tetramethoxy-5,5-dimethyl-12-bromoberbin are obtained; Mp 166 ° C after recrystallization from methanol. This product yields in the form of yellow leaflets which are insoluble in water, dilute aqueous alkalis and ether, are sparingly soluble in benzene and soluble in dilute aqueous acids, alcohol, acetone and chloroform.

Analysis: C ₂₃ H ₂₈ O ₄ NBr = 462.38.

Calculated ... C59.74, H6.10, N3.01, Br 17.29%; found ... C60.0, H6.2, -N3.0, Br 17.2%.

The compound has not yet been described in the literature.

Level D
2,3,9,10-tetramethoxy-5,5-dimethyl-berbin

1 g of 2,3Ä10-tetramethoxy-5,5-dimethyl-12-bromoberbinin is dissolved 10 cc of ethanol, add 1 ecm of sodium hydroxide solution, heat to the boil, then slowly add 1.6 g Zinc dust and heated under reflux for 1 hour.

It is then cooled to room temperature, the zinc is removed by filtration and washed with ethanol and then with methylene chloride.

It is concentrated to a small volume, diluted with water and then extracted with methylene chloride and wins the organic phase, which is washed with water. "

It is dried, filtered, distilled to dryness in vacuo, the residue is then crystallized from methanol and 760 mg of 2,3,9,10-tetramethoxy-5,5-dimethylberbin are obtained; F. 6O ⁰ C.

This product takes the form of light yellow prisms that are diluted in water and aqueous Alkalis insoluble and in dilute aqueous acids, alcohol, ether, acetone, benzene and chloroform are soluble.

Analysis: C ₂₃ H ₂₉ O ₄ N = 383.47.

Calculated ... C72.03, H7.62, N3.65%;
found ... C 72.00, H 7.7, N 3.8%.

The compound has not yet been described in the literature. .

The required α, α-dimethyl homoveratrylamine perchlorate was made as follows:

600 mg of lithium aluminum hydride are added to 10 ecm of anhydrous dioxane and one is then added dropwise Solution of 1 g of α, α-dimethyl-homoveratronitrile, which by J. Knabe and coworkers in Arch. Pharm., 296, 591 (1963), is added in 5 ecm of dioxane and the reaction mixture is heated under for 1 hour Reflux.

It is then cooled to about 10 ° C. and carried out dropwise 20 ecm of dioxane containing 50% water, filtered, washed with a warm mixture of dioxane and chloroform and extracted the filtrate with methylene chloride.

The organic phase is washed with water and extracted with 1N hydrochloric acid.

The acidic phase is cooled, neutralized by adding sodium hydroxide solution, and the alkaline phase obtained is saturated Phase with sodium chloride and extracted with methylene chloride.

The organic phase is washed with water, dried, filtered and distilled in vacuo Dry.

The residue is dissolved in methanol, cooled, and concentrated perchloric acid is added Excess.

It is cooled, filtered off with suction, washed with methanol and ether, dried, and 0.8 g of α, α-dimethyl homoveratrylamine perchlorate is obtained; F. 270 ⁰ C.

This product is obtained in the form of colorless ( skewers, which are soluble in chloroform, sparingly soluble in water and dilute aqueous acids, and insoluble in ether, acetone and benzene.

Analysis: C ₁₂ H ₂₀ O ₆ NCl = 309.74.

Calculated ... C 46.52, H 6.51, N 4.52, Cl 11.45%; found ... C46.7, H6.6, N4.6, Cl 11.3%.

The compound has not yet been described in the literature.

Example .7
2,3,9,10-tetramethoxy-II-methoxymethyl-berbin

(I, with R ₁ , R ₂ , R ₄ , R ₅ = -OCH ₃ ,
R ₃ = H, R ₆ ^ -CH ₂ -OCH ₃ ).

Level a

3-oxo-5-bromo-6-methoxymethyl-7,8-dimethoxyisochroman

5 g of the methyl ester of 2-bromo-3-methoxymethyl-4,5-dimethoxyphenylacetic acid are added 100 ecm of anhydrous methylene chloride and then adds 5 g melted and pulverized zinc chloride and 5 ecm methoxychloromethane are added and the reaction mixture is stirred 7 hours at room temperature.

It is diluted with water, extracted with methylene chloride, and the organic phase is washed until neutral with water and distilled to dryness.

The residue obtained is dissolved in methanol, 100 ecm 1 of η-aqueous sodium hydroxide solution is added and the mixture is heated 1 hour under reflux. One cools down, acidifies by adding hydrochloric acid, takes in methylene chloride and wash the mixture with sodium bicarbonate.

The organic phase is washed with water, dried and distilled to dryness in vacuo receives the S-Oxo-S-bromo-o-methoxymethyl ^ S-dimethoxy-isochroman in a yield of 30%. The compound could not get crystalline will.

The compound has not yet been described in the literature.

i 620

Level B.

N - [> 3,4-Dimethoxyphenyl) ethyl] - (2'-bromo-3-methoxymethyl-4 ', 5'-dimethoxy-

6-hydroxymethyl) phenylacetamide

1 g of S-oxo-S-bromo-o-methoxymethyl-7,8-dimethoxy ^ isochroman is added and 0.7 g / S- (3,4-dimethoxyphenyl) ethylamine in 10 ecm of ethanol, the reaction mixture is heated under reflux for 24 hours and distilled to dryness in vacuo.

The residue is taken up in methylene chloride and the excess amine is removed through Extract with 1 η-hydrochloric acid. The organic phase is washed with water, then the solvent is driven off by distillation and receives 1.2 g of N - [/ S- (3,4-dimethoxyphenyl) ethyl] - (2'-bromo-3'-methoxymethyl-4 ', 5'-dimethoxy - 6 '- hydroxymethyl) - phenylacetamide. The compound could not get crystalline will.

This compound has not yet been described in the literature.

Level C

2,3,9,10-tetramethoxy-II-methoxymethyl-12-bromoberbin

25th

1 g of N - [^ - (3,4-dimethoxyphenyl) ethyl] - (2'-bromo-3'-methoxymethyl-4 ', 5'-dimethoxy-6'-hydroxymethyl) phenylacetamide is added in 5 ecm phosphorus oxychloride, heated under reflux for 2 hours and distilled in a vacuum to dryness without exceeding a temperature of 50 ° C.

The residue obtained is taken up in 25 cc of ethanol and 5 cc of water, and then in 35: the course of half an hour at about 15 ° C 5 g of sodium borohydride in small portions, and stirring is continued for 2 hours at about 30 ⁰ C.

It is diluted with water, extracted with methylene chloride, and the organic phase is washed with water and distilled to dryness.

The residue is dissolved in methylene chloride, chromatographed on aluminum oxide and eluted with methylene chloride.

After evaporation of the methylene chloride, 2,3,9,10-tetramethoxy-11-methoxymethyl-12-bromoberbin is obtained in a yield of 65%. The compound could not be obtained in crystalline form.

The compound has not yet been described in the literature.

Level D

2,3,9,10-tetramethoxy-II-methoxymethyl-berbin

200 mg of 2,3,9,10-tetramethoxy-II-methoxymethyl-12-bromoberbin are dissolved in 10 ecm of ethanol

1 ecm 10N sodium hydroxide solution and heated under reflux.

You then give in the course of half an hour

2 g of zinc powder are added and the mixture is refluxed for a further 1 hour.

It is cooled, the zinc is filtered off, washed with ethanol, the filtrate is diluted with water and extracted with methylene chloride.

The organic phase is washed with water, concentrated to a small volume and chromatographed then on aluminum oxide and eluted with methylene chloride and obtained by evaporation of the eluate 2,3,9,10 - tetramethoxy - 11 - methoxymethyl - berbin in a yield of 72%; F. 239 ° C.

The compound has not yet been described in the literature.

The methyl ester of 2 - bromo - 3 - methoxymethyl - 4,5 - dimethoxyphenylacetic acid required as starting material was made as follows:

a) Methyl ester of 2-bromo-3-chloromethyl-4,5-dimethoxyphenylacetic acid

8.78 g of the methyl ester of 2-bromo-4,5-dimethoxyphenylacetic acid are dissolved in 170 ecm with heating anhydrous methylene chloride, cools and then gives 9 g of powdered zinc chloride and 9 ecm of monochlorodimethyl ether and the reaction mixture is stirred for 3 days at room temperature.

It is diluted with water, extracted with methylene chloride, the organic phase is washed with water, then distilled to dryness and obtained 10.1 g of a mixture of the methyl ester of 2-bromo-3-chloromethyl - 4,5 - dimethoxy - phenylacetic acid and the methyl ester of 2-bromo-6-chloromethyl-4,5-dimethoxy-phenylacetic acid, which one does not need to separate for further implementation.

b) 2-Bromo-3-methoxymethyl-4,5-dimethoxyphenylacetic acid

10.1 g of the mixture of the methyl esters of 2-bromo-3-chloromethyl-4,5-dimethoxyphenylacetic acid are dissolved and 2-bromo-6-chloromethyl-4,5-dimethoxyphenylacetic acid in 200 ecm of methanol then 200 ecm 1 η-aqueous sodium hydroxide solution are added and the reaction mixture is refluxed for 40 minutes.

It is then cooled, the pH is brought to 1 by adding dilute hydrochloric acid and extracted with methylene chloride and wash the organic phase with bicarbonate.

The bicarbonate phase is acidified by adding hydrochloric acid, extracted with methylene chloride and then the solvent is distilled off. It is crystallized from ether and 2-bromo-3-methoxymethyl-4,5-dimethoxyphenylacetic acid is obtained; F. 65 to 68 ⁰ C.

Analysis: C ₁₂ H ₁₅ O ₅ Br = 319.16.

Calculated ... C 45.16, H 4.74, Br 25.04%; .
found ... C 45.2, Ή 5.0, Br 24.8%.

The compound has not yet been described in the literature.

c) methyl ester of 2-bromo-3-methoxymethyl-4,5-dimethoxyphenylacetic acid

5 g of 2-bromo-3-methoxymethyl-4,5-dimethoxyphenylacetic acid are dissolved in methylene chloride, cools to about 0 ° C and then gives a solution of 1% Diazomethane in methylene chloride to a permanent yellow color.

The excess of the reagent is then destroyed by adding acetic acid, the solvent is driven off and the methyl ester of 2-bromo-3-methoxymethyl is obtained - 4,5 - dimethoxy - phenylacetic acid, which is used as it is.

The compound has not yet been described in the literature.

B e i s ρ i e 1 8

2,3-methylenedioxy-9,10-dimethoxy-berbin
(I, with R ₁ + R ₂

-O

-O

CH,

R ₄ , R ₅ = -OCH ₃ , R ₃ = H and R ₆ = H)

Level a

N - [/ 9- (3,4-Methylenedioxy-phenyl) -ethyl] - (2-bromo-4 ', 5-dimethoxy-6-hydroxymethyl) -

phenylacetamide

0.9 g of homopiperonylamine and 1.4 g of 3 - oxo - 5 - bromo - 7,8 - dimethoxy - isochroman, are added according to Example 1, stage A, was obtained in 25 ecm ethanol, heated under reflux for 18 hours and distilled to dryness in vacuo.

The residue formed is taken up in methylene chloride, washed with n / 10 hydrochloric acid and then with water and the organic phase is distilled to dryness. 2.1 g of N-fj? - (3,4-methylenedioxyphenyl) are obtained - ethyl] - (2 '- bromo - 4', 5 '- dimethoxy-6'-hydroxymethyl) -phenylacetamide, which is as it is, is used for the following synthesis stage.

The compound has not yet been described in the literature.

Level B.
2,3-methylenedioxy-9,10-dimethoxy-12-bromoberbin

For ₂ hours, 1 g of N - [> (3,4-methylenedioxyphenyl) - ethyl] - (2 '- bromo - 4', 5 '- dimethoxy-6'-hydroxymethyl) phenylacetamide in 5 ecm of phosphorus oxychloride is heated under reflux distilled to dryness in vacuo.

The residue is taken in 25 cc of ethanol on, diluted with 5 cc water and then in the course of 30 minutes at about 10 ⁰ C 4 g of potassium borohydride in small portions to and stirred for 2 hours at a temperature of 30 ⁰ C.

It is poured into water, extracted with methylene chloride, the organic phase is washed with water, dries, distilled to dryness and receives 0.75 g of 2,3-methylenedioxy-9,10-dimethoxy-12-bromoberbin, which is used as it is for the following synthesis stage.

The compound has not yet been described in the literature.

Level C
2,3-methylenedioxy-9,10-dimethoxy-berbin

0.75 g of 2,3-methylenedioxy-9,10-dimethoxy-12-bromoberbin are added and 3 ecm 10 η sodium hydroxide solution in 30 ecm ethanol, heated under reflux and then added 6.5 g of zinc powder are added over the course of half an hour and the reaction mixture is heated a further Hour under reflux.

It is cooled, the zinc is removed by filtration, washed with ethanol, and the filtrate is taken up in water and extracted with methylene chloride.

The organic phase is washed with water and distilled to dryness, and the residue is dissolved in methylene chloride and then chromatographed on aluminum oxide and eluted with methylene chloride.

The eluate is evaporated to dryness, the residue is dissolved in ether and a stream of gaseous is passed Hydrogen chloride through.

The precipitate formed is treated with aqueous 1 η sodium hydroxide solution and the aqueous phase with Extracted methylene chloride.

The organic phase is washed with water and dried, the solvent is removed by distillation, the residue is crystallized from ether and 2,3-methylenedioxy-9,10-dimethoxy-berbin is obtained; F. 172 ⁰ C, which is also called d, l-canadine and was described by I. S a 11 ay and coworkers in Tetrahedron, 19, p. 1397 (1963), in a yield of 75%.

Example 9 2-Benzyloxy-3,9,10-trimethoxy-berbin

(I, with R ₂ , R ₄ , R ₅ = -OCH ₃₅ R ₁ = -OCH ₂ -C ₆ H ₅ , R ₃ = H and R ₆ = H)

Level a
3-oxo-7,8-dimethoxy-isochroman

Dissolve 2 g of 3-oxo-5-bromo-7,8-dimethoxy-isochroman, which was obtained according to Example 1, stage A, in 60 ecm refluxed ethanol, are 6 ecm 10 η-sodium hydroxide solution and then im Add 6 g of powdered zinc for half an hour and heat for another 30 minutes.

It is then cooled, the zinc is removed by filtration, washed with ethanol and brought to pH by adding hydrochloric acid to 1, diluted with water and extracted with methylene chloride.

The organic phase is washed with water, dried and distilled to dryness and this is obtained 3-oxo-7,8-dimethoxy-isochroman in a yield of 68%; 100 ° C. . ■.

The compound has not yet been described in the literature.

Level B.

N - [/ 3- (4-Benzyloxy-3-methoxyphenyl) ethyl] - (4 ', 5'-dimethoxy-6'-hydroxymethyl) phenylacetamide

0.2 g of 3-oxo-7,8-dimethoxy-isochroman and 0.26 g of? - (3-methoxy-4-benzyloxyphenyl) ethylamine are added, that is described by Shozo Kabayashi, Chem. Zentralblatt, I, p. 1027 (1928), in 5 ecm of ethanol, the reaction mixture is heated under reflux for 20 hours and distilled to dryness in vacuo. Man takes up the residue in methylene chloride and washes with n / 10 hydrochloric acid and with water. Man the organic phase distills to dryness and receives 0.44 g of N - [/? - (4-Benzyloxy-3-methoxyphenyl) -ethyl] - (4, 5 '- dimethoxy - 6' - hydroxymethyl) - phenylacetamide.

The compound has not yet been described in the literature.

Level C.

2-benzyloxy-3,9,10-trimethoxy-berbin

0.44 g of N - [^ - (4-BenzyIoxy-3-methoxyphenyl) - ethyl] - (4 ', 5' - dimethoxy - 6 '- hydroxymethyl) phenylacetamide are added in 10 ecm benzene, the 1 ecm phosphorus oxychloride contains, the reaction mixture is heated

2 hours under reflux and distilled to dryness in vacuo.

The residue is taken in 15 cc of ethanol on, diluted with 2 cc of water and then at about KFC in the course of 30 minutes, 1.5 g of potassium borohydride in small portions to and stirred for 2 hours at a temperature of 30 ⁰ C.

It is diluted with water, extracted with methylene chloride, the organic phase is washed with water, dries, distilled to dryness and receives the 2-benzyloxy-3,9,10-trimethoxy-berbin in one yield of 57%; Mp 221 ° C.

The compound has not yet been described in the literature.

Claims (1)

Claim: Process for the production of Berbinder derivatives of the general formula wherein R ₁ and R _{2 are} identical or different and hydrogen atoms, methoxy or ethoxy groups or together represent a methylenedioxy group or one of the radicals R ₁ and R _{2 represents} a benzyloxy group, the radicals R _{3 are} identical and represent hydrogen atoms or methyl groups and R ₄ and R _{5 are} identical or different and denote methoxy or ethoxy groups and R ₆ denotes a hydrogen atom or a methyl or methoxymethyl group, characterized in that a phenylacetic acid derivative of the general formula COOR II wherein R represents a hydrogen atom or a lower alkyl group, with methoxychloromethane in the presence of a Lewis acid or with formaldehyde in the presence of sulfuric acid and the reaction product obtained from a lower alkyl ester of the general formula II Treated with alkali, the 5-bromoisochromanone obtained, optionally zinc in alkaline Allow the medium to act, the compound of the general formula obtained III NH ₂ 20th 30th 35 40 45 55 jvorin X denotes a hydrogen or bromine atom, with a / S-phenylethylamine of the general formula IHa general formula NH CH, OH IV condensed, this heated with phosphorus oxychloride, on the resulting dihydroisoquinoline the general formula CH ₂ Cl IVa to an N - (^ - phenylethyl) phenylacetamide of XJR ₅ R ₅ an alkali metal borohydride can act and one obtained compound of the general formula norcorydalin, mixed (cf. Henry, The plant alcaloids, p. 343). The process according to the invention is now characterized in that a phenylacetic acid derivative is used the general formula COOR