CH618971A5 - Process for the synthesis of (+)-glaziovine - Google Patents

Abstract

The process for the synthesis of (+/-)-glaziovine of the formula 4 starts from a compound of the formula 3: <IMAGE> In the formula 3, X is halogen, <IMAGE> The compound of the formula 3 is irradiated in alkaline solution with ultraviolet light through suitable solid filters such as, for example, Corex, or through liquids such as, for example, solutions of lead salts, transparent to radiation of a wavelength greater than 280 mu m and opaque to radiation of wavelengths less than 280 mu m. The process can be applied to compounds of the formula 3 with X other than halogen, which are obtained in a process by means of selective electrophilic attack on the 8-position of the isoquinoline system.

Description

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CLAIMS 1. Procedure for the synthesis of (+) - glaziovine having formula 4, characterized in that a compound of formula 3

where, in formula 3, X is halogen,

COCHq

■ NsN, -N =

-N = N-N =

NO

cho

cho

-N = N-N-C6H5 H

or -N = N-C (C6H5) 3,

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it is irradiated in alkaline solution with ultraviolet radiation, through suitable solid or liquid filters transparent to radiation having a wavelength greater than 280 (im and opaque to radiation having a wavelength less than 280 p.m.

2. Process according to claim 1, characterized in that the solid filter is glass or quartz and the liquid filter consists of a solution of lead salts.

3. Process according to claim 1, characterized in that the transformation of the compound 3 into the (, ±) -glaziovine of formula 4 takes place by irradiation in an alkaline solution with radiation contained in the visible to ultraviolet range of the spectrum.

4. Process according to claims 1 and 3, characterized in that the (±) -glaziovin is obtained from the compound of formula 3 by heating in irradiated alkaline solution.

5. Application of the process according to claim 1 on compounds of formula 3 with non-halogen X, obtained in a process for selective electrophilic attack of position 8 of the isokinolimic system, that is characterized by the operations of a) subjecting to nitration or nitrosation with nitrous acid or nitric or a derivative thereof a 4'-0-ether or ester of lp-hydroxybenzyl-2-methyl-6-methoxy-7-hydroxy-1, 2,3,4-tetrahydro-isochinoline of formula 1 to selectively obtain a 8-ni-troso- or 8-nitro-derivative of formula:

40

b) transforming said compound of formula 6 into the corresponding 8-amino-4'-hydroxy compound of formula 9

50

55

CH.

65 by reducing the nitrous or nitric group to the missing group and removing the ether or ester group and c) reacting the compound of formula 9 with nitrous acid to obtain the compound of formula 3

3

i j 618 971

N-CH.

Application according to claim 5, characterized in that, when R— ^ -CHZ-, the transformation (b)

occurs in a single step by means of catalytic hydrogenation which produces the reduction of the 8-nitrous or 8-nitro group to the amino group and the simultaneous hydrogenolysis of the 4'-benzyloxy group.

Application according to claims 5 and 8, characterized in that l-p-benzyloxybenzyl-2-methyl-6-methoxy-7 - hydroxy-1, 2,3,4-tetrahydroisoquinoline of formula 10.

wherein X has the meanings indicated in claim 1.

Application according to claim 5, characterized in that the transformation (b) from compound of formula 6 to compound of formula 9 takes place by means of a first reduction stage in which the compound of formula 6 is transformed 20 into the compound having formula

30

10

it is transformed (stage a) into the 8-nitrous derivative of formula

OR

40

and a subsequent removal stage of the ether or ester group present in position 4 '.

Application according to claim 5, characterized in that the transformation (b) takes place by means of a first stage of removal of the ether or ester group present in position 4 ', with the formation of compound 8 of formula

11

and subsequent reduction of the nitrous or nitro group present in position 8 with amino group.

O-CH,

55 by reaction with nitrous acid or an ester thereof, in particular butyl nitrite, or nitrosyl chloride and the 8-nitrous derivative 11 is subjected to catalytic hydrogenation in the presence of a catalyst, in particular a metal of the platinum family in its state pure or supported, or a nickel or cobalt catalyst, obtaining the compound of formula 9.

10. Application according to claim 9, characterized in that the nitrosation of the compound 10 is carried out in glacial acetic acid with an alkaline nitrite, in particular

65 pouring sodium nitrite.

Application according to claims 9 and 10, characterized in that the catalytic hydrogenation is carried out in glacial acetic acid in the presence of 10% palladium on

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coal at a temperature between 15 and 40 ° C and at a hydrogen pressure between 1 and 10 atmospheres.

12. Application according to claims 10 and 11, characterized in that the catalytic hydrogenation is carried out in the solution in acetic acid of the nitrous compound 11, as obtained from the nitrosation stage.

13. Application according to claim 5, characterized in that the transformation of compound 9 into compound 3 is carried out by reaction with nitrous acid or a derivative thereof, possibly accompanied by a reaction; accessory with an amine or anhydride. t

14. Application according to claims 5 and 13, characterized in that the amino compound of formula 9 is treated in an acid solution at 0-5 ° C with an equivalent amount of an alkaline nitrite, with a formation of the corresponding to diazonium salt of formula 3 wherein X = -N sN-,

Application according to claim 5, characterized in that the lp-hydroxybenzyl-2-methyl-6-methoxy-7-hydroxy-8-amino-1, 2,3,4-tetrahydroisoquinoline of formula 10 is transformed into lp -hydroxybenzyl-2-methyl-6-methoxy-7-5 -hydroxy-8-amino-1,2,3,4-tetrahydroisoquinoline of formula 9 by reaction with nitrous acid or with a derivative thereof such as butyl nitrite or nitrosyl chloride, with the formation of an 8-nitrosocompound of formula 11, followed by a catalytic hydrogenation in the presence of a metal of the I group of platinum in its pure state or on a suitable support, such as for example 10% palladium on coal ; from the fact that this hydrogenation simultaneously reduces the nitrous group to animate and the cleavage of the benzyloxy group, and from the fact that P8-amino compound of formulas 15 is transformed into the corresponding diazonium salt of formula 13 by reaction with nitrous acid at 0- 5 ° C in acid solution, the process being represented by the scheme 1 but following the compound of formula 13 being a special of formula 3.

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In the Swiss patent No. 575 930, filed on 22.12.1972, a process of synthesis of (+) - glazio-. Vina based on the following scheme has been described:

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in which the formula 4 represents the (+) -glaziovine, X represents a halogen atom and RO represents a suitably chosen ether or ester group; main features of the procedure are:

1) the possibility of a selective electrophilic substitution of the position 8 of the isokinolinic system of the compounds of formula 1 by means of a halogenating agent, thanks to the presence of the protective group R,

2) the removal of the protective group R to regenerate the phenolic hydroxyl on the 4 'position of the compounds of formula 3,

3) irradiation of the compounds of formula 3 under controlled conditions 50 to obtain (+) - glaziovine in yields suitable for its industrial production.

It has now been found that the ultraviolet radiation obtainable from the light sources normally used in the photochemical technique has different effects on the transformation reaction of a compound having formula 3 in (+) - glaziovine; in fact, radiations having a wavelength greater than 280 | xm promote the formation of glaziovine with increasing speed as their wavelength decreases, but in any case with considerably greater speed than that with which the radiations themselves produce the decomposition of the (+ ^ glaziovina, while the radiation having the wavelength of 254 jim causes the decomposition of (+) - glaziovina with a high speed and not much lower than that of formation of the (+) - glaziovina itself.

In accordance with this observation it has been found that by using suitable filtering materials, transparent at wavelengths greater than 280 [im, but not transparent at wavelength less than this limit, the best efficiency of the can be obtained. energy emitted by the radiation source, including useful radiation and excluding those which significantly increase the decomposition of (_ +) - glaziovine.

Another further characterization of the process object of the present invention is given by the observation made by the applicant that can be usefully transformed into (+) -glaziovine, in addition to the compounds of formula 3, where X represents a chlorine, bromine and iodine atom, also other compounds, of formula 3, containing diazoic groups, such as those represented in the following scheme:

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6

CH.

COCHg CH3

-X = -NaN, -N <, -N = N-N <"

+ NO CH3

-N = N-NH-C6H5, -N = N-C (C6H5) 3.

According to the invention, the process for the synthesis of (+) -glaziovin, having formula 4, is characterized in that a compound of formula 3

20

where, in formula 3, X is halogen;

COCH3 CH3

-N = N, -N <, -N = N-N <© NO CH3

-N = N-N-C6H5 or -N = N-C (C6H5) 3,

H

it is irradiated in alkaline solution with ultraviolet radiation, through suitable solid or liquid filters transparent to radiation having a wavelength greater than 280jnn and opaque to radiation having a wavelength less than 280 | xm.

As suitable filter materials, siliceous materials containing suitable additives, such as for example Corex or quartz type M 84, or solutions of organic or inorganic compounds having suitable transmission characteristics, such as lead salts, can be used. Thus, for example, by operating the photochemical transformation of the compounds of formula 3 into a quartz apparatus in which a 2 cm thick cavity containing my 0.5% lead chloride solution is interposed between a mercury vapor lamp with high pressure and the solution to be irradiated, it is possible to obtain (±) -glaziovine, with the technique and times higher than that observable in an apparatus built in Pyrex glass; it is therefore possible in these

45 conditions achieve a significant economic result by reducing the energy consumption and the decay of mercury vapor lamps to about one eighth of the values achievable with Pyrex glass, without prejudice to the yields and quality of the product formed.

It has been found that said compounds can be conveniently synthesized from the same intermediates having formula 1 used in the synthesis of the compounds having formula 3, using a selective electrophilic attack of position 8 of the isokinolinic system, similar to that mentioned for the preparation of the compounds of formula 3.

The synthesis of the compounds of formula 3 can in fact be carried out according to the following scheme:

65

7

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45

where -or has the meaning already specified, and precisely represents- 35 presents an ether group or an ester group which may ex- benzyl (R

easily split, such as the following ether groups:

ch3och2o-, ì n ch2o-, (c6h5) 3c0-0

or similar groups or the following foreign groups:

hcoo-, ch3coo-, ch3s03-, c2h5ocoo- or similar groups, Y has the above meaning and furthermore the group present in position 8 of formulas 6 and 8 can have only one oxygen atom (-NO) thus representing a group nitrous or two oxygen atoms (-N02) thus representing a nitro group.

The above synthesis scheme of the compounds of formula 3 to 50 starting from the compounds of formula 1 is defined by the following characteristics:

1) it has been found that, in accordance with what has been previously observed for the halogenation of the compounds of formula 1,

the nitrosation and nitration reactions of the compounds 55 themselves lead, with a selective replacement with a nitrous group or with a nitro group in position 8,

to the compounds of formula 6;

2) it has also been found that an 8-nitro compound or an 8-nitrous compound of formula 6, can be transformed into the 8-amy 60 no-4'-hydroxy compound (formula 9) by means of a two-stage process, comprising the reduction of the nitro group or the nitrous group to the amine group and the removal of the ether or ester group, making either of the two stages precede as desired and therefore proceeding through an intermediate of formula 7 or through an intermediate of formula 8;

3) it has also been found that, in particular, the use of the group

H2-) l allows to obtain in a single step the transformation of a nitro or nitrous compound in formula 6 into the 8-amino-4'-hydroxy compound of formula 9, by means of a catalytic hydrogenation which produces the reduction of the nitro group or of the amine group nitrous group and the simultaneous hydro-genolysis of the benzyloxy group. In accordance with the above, one of the preferred ways of preparing the compound of formula 9 is represented in the following scheme:

618971

CH.

0-CH "

CH,

0-CH "

.10

11

wherein lp-benzyloxybenzyl-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (fonnula 10) is transformed 20 into the 8-nitroso derivative (formula 11) by reaction with nitrous acid , or with an ester thereof, such as butyl nitrite or also with nitrosyl chloride. Subsequently the compound 11 is subjected to catalytic hydrogenation in the presence of a suitable catalyst, such as for example a metal of the platinum family in its pure state or on a suitable support or a nickel or cobalt catalyst. The nitrosation reaction can be carried out in particular by treating a solution of the compound 10 in glacial acetic acid with an alkaline nitrite, such as for example sodium nitrite. The glacial acetic acid is also a suitable solvent for the subsequent catalytic hydrogenation of compound 11, which can be carried out in this solvent in the presence of 10% palladium on coal at a temperature between 15 ° C and 40 ° C and at hydrogen pressures between 1 and 10 atmospheres. It is also possible, by carrying out a further simplification of the process, to perform the catalytic hydrogenation of the nitrous compound 11 at the end of the preparation of the same compound in acetic solution, without proceeding with its isolation;

4) it has been found that an amino compound formula 9 can be converted into a compound of formula 5 with the usual techniques and in particular with diazotation reactions. One of the preferred ways of carrying out the invention

is the treatment of the amino compound of fonnula 9 in acid solution at 0-5 ° C with an equivalent quantity of alkaline nitrite, for example sodium nitrite, which leads to the formation of the corresponding diazonium salt, having formula 3 with X = - N = N;

+

5) it has been found that the compounds of formula 3 in alkaline solution under the action of ultraviolet radiation and also of visible radiation transform into (±) -glaziovin in a similar way to what has been previously observed for the compounds of formula 3; so in particular, according to one of the preferred ways for the realization of the invention,

with the diazonium salt of formula 3 with X = -N = N, im-

■ +

immediately after its preparation in acid solution, as described above, the solution can be alkalinized and irradiated directly, thus obtaining (+) - glaziovine according to the following scheme through the corresponding diazooxide of formula 12:

The (i) -glaziovin thus obtained can be extracted from the reaction solutions and purified for pharmaceutical use with the techniques previously described, and in particular by direct crystallization operations, by crystallization of its salts or by the use of chromatography on silica gel, on partially deactivated alumina or on ion exchange resins.

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618971

The following examples are intended to describe in detail the process object of the present invention, without however limiting it.

Example 1

To a solution of 40 g of lp-benzyloxybenzyl-2-methyl - 6-methoxy-7-hydroxy-1, 2,3,4-tetrahydroisoquinoline in 600 ml of glacial acetic acid are added at 15 ° C, 17,3 g of sodium nitrite in 25 ml of water; at the end it is stirred for 30 minutes; subsequently most of the acetic acid is evaporated under reduced pressure, the residue is diluted with water, the pH is brought to 8.5 with ammonium hydrate and extracted with chloroform. The chloroform extracts are evaporated and the residue is recrystallized from ethyl acetate. 1-p - benzyloxybenzyl-2-methyl-6-methoxy-7-hydroxy-8-nitroso-1, 2,3,4 - tetrahydroisoquinoline with p is thus obtained. f. 190-192 ° C.

Example 2

A solution of 24 g of lp-benzyloxybenzyl-2-methyl-6-methoxy-7-hydroxy-8-nitroso-1, 2,3,4-tetrahydroisoquinoline in 700 ml of glacial acetic acid is added with 4,8 g of 10% palladium on carbon and hydrogenated at 20-25 ° C with a pressure of 4-5 atmospheres; when the absorption of the calculated quantity of hydrogen is finished, the catalyst is filtered and most of the acetic acid is evaporated under reduced pressure; the residue is taken up with water, the pH is brought to 8.5 with ammonium hydrate and the crystalline precipitate is filtered.

The l-p-hydroxybenzyl-2-methyl-6-methoxy-7-hydroxy-8-amino-1, 2,3,4-tetrahydroisoquinoline is thus obtained, which has p. f. 215-216 ° C.

Example 3

A solution of 31.4 g of l-p-hydroxybenzyl-2-methyl-6 - methoxy-7-hydroxy-8-amino-1,2,3,4-tetrahydroisoquinoline in

1 liter of normal sulfuric acid is cooled to 0-5 ° C and 5 treated in 30 minutes by stirring with a solution of 6.92 g of sodium nitrite in 15 ml of water. A solution of 1-n-hydroxybenzyl-2-methyl-6-methoxy-7-hydroxy-1, 2,3,4-tetrahydro-8-isochinolindiazonium is thus obtained; this solution is alkalinized with the addition of 1500 ml of 8% caustic soda and is heated for 30 minutes at 70 ° C. At the end it is cooled, the pH is brought to 12 with hydrochloric acid and extracted with chloroform. The chloroform extracts are evaporated under reduced pressure and the residue is chromatographed on a column containing 700 g of neutral alumina (activity IV of 15 Brockmann). The column is eluted with chloroform containing 1% methanol, the eluted fractions are checked by thin-layer chromatography of silica gel using as a solvent a mixture of methylene chloride, methanol and water in the ratios 89: 10: 1, the fractions containing (+) - 20 glaziovine. By evaporating these fractions and recrystallizing the residue from ethyl acetate, pure (+) - glaziovine is obtained with p. f. 220-222 ° C.

Example 4

The (+) -glaziovine can be obtained by operating as in example 3, but by subjecting the alkalized solution of the diazonium salt to the radiation of a 2000 W mercury vapor lamp for 2 hours at 15 ° and subsequently proceeding with the purification of the product as described in Example 3. In the absence of light, in a sample of the above solution no formation of (+) -glaziovin is observed after

2 hours at 15 ° C.

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