BE613443A - - Google Patents

Description

       

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  "HYDRAZINE DERIVATIVES, INTERMEDIATE COMPOUNDS
FOR THESE DERIVATIVES AND THEIR PREPARATION "

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The present invention relates to hydrazine derivatives and to intermediate compounds for such derivatives.



  It also relates to processes for the preparation of such hydrazine derivatives and such intermediates.
 EMI2.1
 



  The drifts ci 'üydra'zinew sùi Vl2t 1-a wirrr' =. Serta- i: -: - eation.¯¯¯ ¯ correspond to the following general formula:
 EMI2.2
 and their addition salts with acids; in formula I X represents a halogen atom; n represents 0, 1, 2 or 3, R represents a lower alkyl radical (including cycloalkyl radicals), preferably a radical containing 1 to 4 carbon atoms and R ′ represents a hydrogen atom or an alkyl radical.



   These compounds are potent inhibitors of the enzymes responsible for the decarboxylation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (SHTP) both in vitro and in vivo. Likewise, these compounds are inhibitors of dopamine hydroxylase, the enzyme responsible for the oxidation of P- (3,4-dihydroxyphenyl) ethylamine (dopamine) to norepinephrine. When administered to mammals, including humans, they exert an effect on the central nervous system and may be used for the treatment of mental illnesses, especially illnesses associated with abnormal catecholamine and / or 5-hydroxytryptamine values ( 5HT).



   As will be seen, these compounds can be represented by the following general formula:

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 EMI3.1
 in which X, n and R have the meanings indicated above, or by the general formula:
 EMI3.2
 'in which X, n and R have the meanings indicated above and R "represents an acyl radical.



   In the formulas given above, the lower alkyl radical represented by R can be, for example, a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl or cyclobutyl radical, while the halogen atom represented by
X may, if present, consist, for example, of chlorine or bromine. If R 'represents an acyl group, this acyl group may be a carboxylic acyl group or an acyl sulfonic group, such as a benzenesulfo or p-toluenesulfo group.
Substituted hydrazines can be obtained in the form of their addition salts with acids. They can be used for the treatment of disabilities or infirmities, in particular of mental illnesses, as such or in the form of their addition salts with physiologically acceptable acids.

   Such salts can be formed with oxalic acid, phosphoric acid, mandelic acid or hydrochloric acid, for example. Compositions used for the treatment of ailments can comprise the active ingredient as well as a diluent or vehicle thereof.



   The invention also relates to a process for the preparation of a compound corresponding to the general formula I, this process being characterized in that it consists in reducing a
N-nitrosamine of general formula:

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 EMI4.1
 in which X, n, R and R 'have the meanings indicated above, and, if desired, in separating, by hydrolysis, the acyl radical possibly present.



   This reduction can be carried out using zinc in the presence of acetic acid.



   The nitrosamines of general formula II can be represented by the general formulas:
 EMI4.2
 and
 EMI4.3
 in which X, N and R have the meanings given above and R "represents an acyl group.



   The invention also encompasses the compounds corresponding to the general formula II, as well as a process for preparing these compounds, this process comprising reacting a secondary amine of the general formula:
 EMI4.4
 in which X, n, R and R 'have the meanings given above, with nitrous acid or lower alkyl nitrite in the presence of an acid.



   The secondary amines of general formula III can be represented by the general formulas:

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 EMI5.1
 in which X, n and R have the meanings indicated above and R "represents an acyl group.



   As examples of secondary amines of general formula III which can be used, the following may be mentioned: 1. N- (3-hydroxybenzyl) methylamine.



  2. N- (3-bromo-6-hydroxybenzyl) methylamine.



  3. N- (2-hydroxybenzyl) methylamine.



  4. N- (3-chloro-6-hydroxybenzyl) methylamine.



  5. N- (3-benzenesulfonyloxy-6-chlorobenzyl) methylamine.



  6. N- (3-benzenesulfonyloxy-6-chlorobenzyl) ethylamine.



  7. N- (3-benzenesulfonyloxy-benzyl) ethylamine.
 EMI5.2
 



  8. N- (3-benzenesulfonyloxy-6-bromobenzyl) methylamine.



   A compound of general formula III can be obtained by hydrogenation of a Schiff base corresponding to the following general formula:
 EMI5.3
 in which X, n, R and R 'have the meanings indicated above and, if desired, by separation of the acyl radical optionally present, by hydrolysis.



   The hydrogenation can advantageously be carried out by means of hydrogen, in the presence of a hydrogenation catalyst, such as platinum.



   A Schiff base of general formula IV can be prepared by condensation of an aldehyde of general formula:

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 EMI6.1
 in which X, n and R 'have the meanings indicated above, with a primary amine of general formula: R NH2 VI in which R has the meaning given above.



   As examples of acyl radicals designated by the symbol R '. mention may be made of the benzene sulfonyl and p-toluenesulfonyl radicals.



   These radicals can be separated by hydrolysis, using an alkali, for example using potassium hydroxide in methanolic solution.



   It is also possible to obtain a compound corresponding to general formula III, by reacting a substituted benzyl bromide of general formula:
 EMI6.2
 in which X, n and R 'have the meanings indicated above, with a primary amine of general formula VI.



   The hydrazine derivative obtained by the process according to the present invention can, according to another feature of the invention, be isolated in the form of a hydrazone formed from a: volatile aldehyde in the presence of water vapor, such as than benzaldehyde or salicylaldehyde, after which it can be regenerated by subjecting the hydrazone to the action of an aqueous acid at an elevated temperature, and removing the aldehyde thus formed by distillation with steam stripping
The above-mentioned reactions can be carried out by the process or the procedure described in the following examples to which the invention is not limited. In these examples, all temperatures are shown in degrees Centigrade.

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 EMI7.1
 



  Example 1 N- (3-hydroxybenzyl) -11lethylnitro ::; nmine (i) 'i- (3-hydroxyl) enzyl) -m (thylairiine (6.85 g, 0.05 mol) was dissolved in ethanol (100 ml) containing HCl (1.825 g, 0.05 mole) and amyl nitrite (6.97 g, 0.055 mole) was added. The solution was heated under reflux for 2 hours, after which the solvent was distilled off under reduced pressure The brown oily residue was partitioned between an ethyl acetate phase and an aqueous phase and the aqueous phase was separated and discarded.

   After washing with water and drying over sodium sulfate, the ethyl acetate extract was concentrated under reduced pressure and the residue was crystallized from di-n-butyl ether, 2,6 g (31%), mp 77-73.



   Pure nitrosamine crystallized from din-butyl ether as colorless platelets, m.p. 77-78.



     (ii) N- (3-Hydroxybenzyl) -methylamine (2.74 g, 0.02 mole) was suspended in water (20 µl) and the equivalent of 4N HCl was added. Acetic acid (1.2ml, 0.02mol) was added to the solution which was then cooled to 0. Sodium nitrite (1.38 g, 0.02 mol) was then added in fractions over 15 minutes, the temperature of the reaction mixture being kept at 0-5.



   The mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate, then evaporated to dryness under reduced pressure. Residual oil crystallized from di-n-butyl ether gave the product 1.0 g (30%), m.p. 76-77.
 EMI7.2
 



  Example 2 A. N- (3-hydroxybenzvl) -N-methylhvdrazine
Zinc powder (analytical grade) (10.45 g, 0.16 atom g) was added in small portions over 45 minutes to a vigorously stirred solution of N- (3-hydroxybenzyl) methylnitrosamine (6.64 g , 0.04 mol) in acetic acid 75% aqueous solution (45 mL). Stirring was continued for 15 minutes, after which the reaction mixture was filtered.

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  The filter cake was washed with a little hot water, after which the combined filtrate and washings were evaporated to dryness in a film evaporator at a temperature of 50 to 60 C and under reduced pressure. . The residue was dissolved in water (50ml) and zinc ions were separated from the solution by treating it with an alcoholic oxine solution (16g in 64ml of solution).



    Zinc oxinate was filtered off and the filtrate was extracted with chloroform (3 x 10 mL). On evaporation of the aqueous solution under reduced pressure, a yellow oil (9.25 g) was obtained.
 EMI8.1
 



  13. N ..,. 3, .hrdroxDrbsaara.l6xhyl-hydaaaeeesalcTlsLléhrd
The yellow oil obtained in A in this example was dissolved in 25% aqueous ethanol (20 ml) and the solution was treated with salicylaldehyde (4.88 g, 0.04 mole).



  After heating the mixture, while stirring, in a steam bath for 5 minutes, this mixture was cooled and N- (3-hydroxybenzyl) -N-methylhydrazone of salicylaldehyde, 6.89 g (67%) mp 110 -114 was separated by f iltration. The compound recrystallized from 50% aqueous ethanol is in the form of colorless prisms, m.p. 113-114.
 EMI8.2
 



  C. Di-rN- (3-hydroxybenzyl) -N-methyl-hydrazinium (1+)] oxalate
Salicyl-aldehyde N- (3-hydroxybenzyl) -N-methyl-hydrazone (4 g, 0.0156 mole) was suspended in a solution of oxalic acid (1.4 g, 0.0156 mole) in water (40 ml) and the mixture was steam distilled until no more salicylaldehyde could be detected in the distillate. The clear aqueous solution was evaporated under reduced pressure, until an oil was obtained which was crystallized.
 EMI8.3
 Ytallized in hot / SFOpanol. 3.13 g, m.p. 125-130.

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   A single recrystallization from a mixture of isopropanol (20 ml) and water (4 ml) raised the melting point to 175-177 * dec., 1.22 g (yield: 39% based on hydrazone).



   The pure compound separates from the aqueous isopropanol as colorless platelets, m.p. 179-180 Dec. This compound was found, on analysis, to be di- (N- (3-hydroxybenzyl) -N-methyl-hydrazinium (1+)) oxalate.
 EMI9.1
 



  D: -'PRôsphà tê --- di: hydrogenated "'Ù15 -' N" - (-.!;. Ny-dt'OxyhenzyX) - .; N-uréthyJ ..-.,. -., hydrazinium (1+),
Salicylaldehyde N- (3-hydroxybenzyl) -N-methylhydrazine (12.25 g, 0.0478 mole) was suspended in water (120 ml) containing 90% ortho-phosphoric acid. % (5.33 g, 0.0478 mole) and the mixture was subjected to steam distillation, until the distillate no longer gave a precipitate with a solution of 2,4-dinitrophenyl- hydrazine.

   The solution was cooled and extracted with ether, so as to remove any water insoluble material present and the aqueous solution was evaporated to dryness under reduced pressure. The oily residue was solidified and recrystallized. in methanol. N- (3-hydroxybenzyl) -N-methyl-hydrazinium (1+) dihydrogen phosphate crystallized as colorless crystals, mp 146-147.



  9.5 g (79%).



  Example 3. N- (2-hydroxybenzyl) -methylnitrosamine
Sodium nitrite (1.54 g, 0.022 mole) was added to a solution of N- (2-hydroxybenzyl) -methylammonium chloride (3.45 g, 0.02 mole) in water (10 ml). ). The solution was heated on a steam bath for 30 minutes, cooled and extracted with ethyl acetate. The ethyl acetate was dried over sodium sulfate, filtered through an alumina column and evaporated. There was thus obtained 1.88 g of nitrosmine m.p. 107-108.5 C. The product crystallized from di-n- ether.

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 butyl prism pale brown, 1.5 g, (45%) M.P.



    109-110.



    Example 4. A. N- (2-hydroxybenzyl) -N-methylhydrazine
Analytical grade zinc powder (33.5 g, 0.515 g atom.) Was added in small portions over 30 minutes to a water-cooled and vigorously stirred suspension of N- (2hydroxybenzyl) -methylnitrosamine (19.5 g, 0.12 mol) in 75% aqueous acetic steel. (148 ml). The temperature was
 EMI10.1
 maintained at 33-45 ° C throughout the addition. Stirring was continued for 30 minutes and the reaction mixture was filtered. The filter cake was washed with a little hot water and the filtrate and the combined washings were evaporated to dryness in a film evaporator under reduced pressure.

   The residue was dissolved in water (200 ml) and the zinc ions were removed from the solution by treating it with an alcoholic solution of oxine (46 g in 180 ml of ethanol). Zinc oxinate was filtered off and the filtrate was extracted with chloroform (3 x 100 mL). By evaporation of the aqueous solution under reduced pressure, a yellow oil is obtained.



    B. N- (2-hydroxybenzyl) -N-methyl-hydrazine desalicylaldehyde.



   The yellow oil obtained in A in this example was dissolved in 25% aqueous ethanol (66 ml) and the solution was treated with salicylaldehyde (14.4 g, 0.12 mole).



  After heating the mixture in a steam bath for 5 minutes,
 EMI10.2
 it was cooled and the crude salicylaldehyde N- (2-hydroctybenzyl) -N-methyl-hydrazone was separated by filtration * By recrystallization from 100-120 petroleum ether, 22.9 g were obtained (yield 75 %), PF 95-96. Recrystallization again from 100-120 petroleum ether gave pale yellow prisms. P.F. 96-97 C.

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 EMI11.1
 



  C. Hydrogenated oxalate of N- (2-h) rdroxybenzyl) -N-methyl-hydrazinium (1+) N- (2-hydroxybenzyl) -N-methylhydrazone salicylaldehyde (2.6 g, 0, 01 mole) was suspended in a solution of oxalic acid (0.9 g, 0.01 mole) in water (80 ml) and the mixture was subjected to distillation in the presence of steam. water until no more salicylaldehyde can be detected in the distillate. The aqueous solution was extracted with ether (50ml) and evaporated under reduced pressure. The residue was washed with ether to give N- (2-hydroxybenzyl) -N-methyl-hydrazinium (1+) hyerogenated oxalate, 2.1 g (87%), PF 140-141.

   Crystallization from ethanol gave needles 0.93 g, m.p. 142.5-143 ".



  Example 5. N- (3-chloro-6-hydroxybenzyl) methylnitrosamine.



   Sodium nitrite (13.8 g, 0.2 mole) was added to a solution of N- (3-chloro-6-hydroxybenzyl) methylammonium chloride (26.9 g, 0.18 mole) in 1 water (100 ml). After 2 hours, the N- (3-Chloro-6-hydroxybenzyl) -methylnitrosamine was filtered off 25.0 g, (95%). M.p. 117-117.5 *. Two dense crystallizations of di-n-butyl ether gave pale brown prisms. M.p. 120-120.5.
 EMI11.2
 



  Example 6 A. N- (3-ehloro-6-hydroxybenzyl) -methylhydraztne
This compound was obtained starting from N- (3-chloro-6-hydroxybenzyl) -methylnitrosamine by the procedure of example 4, part A.



    B. N- (3-Chloro-6-hydroxybenzyl) -N-methylhydrazone of salicylaldehyde.



   This compound was obtained from the product obtained in A in the present example, by operating as described in part B of example 4. This product crystallized from petroleum ether 100-120, in the form of. of pale yellow platelets with a yield of 48%, mp 100-101.



  C. N- (3-Chloro-6-hydroxybenzyl) -N-methylhydrazinium (1+) oxalate.

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   This compound was obtained starting from the product of part B of the present example, operating in the manner described in part C of example 4.
 EMI12.1
 



  Example 7 N- (3-bromo-Ó-hydroxybenzyl) -mebhylnitrosamine
This compound was obtained from N- (3bromo-6-hydroxybenzyl) -methylammonium chloride by operating according to the method of Example 5, except that the reaction mixture was left to stand overnight. at room temperature.



  The compound was obtained in 71.5% yield as pale yellow needles, m.p. 118-119, after recrystallization from 50% aqueous ethanol.
 EMI12.2
 



  Example 8 A. N- (3-bromo-6-hydroxybenzyl) -methylhydrazi.ne
This product was obtained from N- (3-bromo-6-hydroxybenzyl) methylnitrosamine by the procedure of Example 4, part A.



   B. N- (3-Bromo-6-hydroxybenzyl) -N-methyl hydrazone of salicylaldehyde.



   This compound was obtained starting from the product of part A of the present example, by operating as described in part B of example 4. This product crystallized from petroleum ether 100-120, with a yield. 70%, PF 107-108 *.



   C. N- (3-Bromo-6-hydroxybenzyl) -N-ethylhydrazinium (1+) oxalate
This compound was obtained from the product of part B of the present example by the procedure of example 4, part C.
 EMI12.3
 



  Example 9 H- (3-benzenesulronyloxy-Ó-cIùorobenzyl) ltnétylnitrosamine N- (3-benzenesulfanyl.oxy- 6-chlorobenzyl) -methyl-ammonium chloride (17.4 g, 0.05 mol) was dissolved in hot water (270 ml) and the cloudy solution (some hydrolysis occurs) was quickly cooled to 40 C. A solution of sodium nitrite (3.45 g, 0.05 mole) in water (30ml)

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 was added with vigorous stirring and the reaction mixture was stirred for 30 minutes at room temperature, followed by a further 30 minutes on the steam bath.

   The product was extracted with ethyl acetate and the extract was washed successively with water, with 2N hydrochloric acid, with water, with 0.5N hydroxide solution. sodium and again with water. (A small amount of sodium chloride was added to the washings to aid separation). The ethyl acetate solution was dried over sodium sulfate and evaporated to dryness under reduced pressure.



  An oil (12.85 g, 75%) was obtained which could not be solidified.
 EMI13.1
 



  Example 10. A. N- (3-benzenesulfonyloxy-6-ehlorobenzyl) -N-methylhydrazine
Crude N- (3-benzynesulfonyloxy-6-chlorobenzyl) -methylnitrosamine (12.6 g, 0.04 mole) was dissolved in a mixture of acetic acid (60 ml) and water ( 20 ml) and powdered analytical grade zinc (10.45 g, 0.16 g atom) was added in small fractions, while stirring, the temperature of the reaction mixture: rising to 40 -45 C and being maintained at this value. The addition took about 45 minutes and stirring was continued for 15 minutes. Undissolved zinc was filtered off and the filter cake was washed with a little water. The combined filtrate and washings were evaporated to dryness under reduced pressure and the residue was dissolved in water (100ml).

   A sufficient amount of an ION / sodium hydroxide solution was added to redissolve the initial precipitate of zinc hydroxide and the product was extracted with ether (200 mL). The ethereal solution was dried over sodium sulfate.
 EMI13.2
 



  B. rN- (3-Benzenesulfonyloy-6-chlorobzylj- oxalate
N-methyl-hydrazinium (1+) 7
The ethereal solution obtained in A in the present example was treated with a solution of oxalic acid (3.60 g,

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0.04 mole) in hot ethyl acetate (25 mL). The product (11.4 g, m.p. 140-150) was collected and recrystallized from was 50% aqueous isopropanol (80 mL). The product / obtained in the form of colorless crystals (m.p. 167-169 * dec. -8.23 g, 54.6%).



  Example 11 A. N- (2-chloro-5-hydroxybenzyl) -N-methyl-hydrazine
Di- (N- (3-Benzenesulfonylo- xy-6-chlorobenzyl) -N-methyl hydrazinium (1+) oxalate (5.53 g, 0.0149 mole) was added to an 85% solution. of potassium hydroxide (4.94 g, 0.075 mole) in methanol (40 ml) and the reaction mixture was heated under reflux for 30 minutes. Water (30 ml) containing water was then added. acetic acid (4.2 mL, 0.07 mole) and most of the methanol was removed by distillation.



   B. Salicylaldehyde N- (2-Chloro-5-hydroxybenzyl) -N-methylhydrazone.



   Salicylaldehyde (1.83 g, 0.0149 mol) was added to the product obtained in A in this example and the mixture was heated on a steam bath, while stirring, for 5 minutes.



  After cooling the mixture to room temperature, the product was extracted with ether.



   Salicylaldehyde N- (2-Chloro-5-hydroxybenzyl) -N-methylhydrazone was isolated from the ether extract as an oil which solidified. The solid material obtained melted at 117-121 C, 2.63 g, (61%). The hydrazone can be purified by repeated extraction with boiling petroleum ether (100-120) or by recrystallization from toluene (3 parts vol / wt). Hydrazone forms colorless crystals, M.F.



  123-124.5 C.



   This hydrazone can be used for the preparation of other salts of N- (2-chllro-5-hydroxybenzyl) -N-methylhydrazine.



  This hydrazone can however be prepared more advantageously, for this purpose, from the isolated free base obtained in part A of Example 10, by hydrolysis of this base with 3

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 moles of potassium hydroxide dissolved in methanol, as described in part A of example 11, then proceeding as described in part B of example 11.



  This process gave N- (2-Chloro-5-hydroxybenzyl) -N-methyl-hydrazone of salicylaldehyde in an overall yield of 56% from nitrosamine.



   C. N- (2-Chloro-5-hydroxybenzyl) -N-methyl-hydrazinium dihydrogen phosphate.



   Salicylaldehyde N- (2-Chloro-5-hydroxybenzyl) -N-methylhydrazone (1.45 g, 0.005 mole) was suspended in water (30 mL) containing ortho-phosphoric acid. (0.543 g, 0.0055 mol) and the suspension was subjected to steam distillation, until substantially all of the salicylaldehyde had been removed. After cooling, the contents of the still were extracted with ether, so as to remove some oily matter, after which the aqueous solution was evaporated to dryness under reduced pressure.



  The oily residue crystallized on stirring with hot isopropanol (10 ml) and the solid was collected; 940 mg, m.p. 133-136.



   By recrystallization of the solid material from (17 ml), the cauldron ethanol obtained N- (2-chloro-5-hydroxybenzyl) -N-methylhydrazinium dihydrogen phosphate in the form of colorless platelets, mp 135-135 , 5 C. (680 mg, 47.8%).



  Example 12 N- (3-benzenesulfonyloxy-6-chlorobenzyl) -ethylnitrosa- mine
This compound was obtained in the form of a light brown mobile oil (yield: 94.5%) by the process of Example 9, from N- (3-benzenesulfonyloxy-6-chlorobenzyl) - ethylammonium chloride.



  Example 13 A. Salicylaldehyde N- (2-Chloro-5-hydroxybenzyl) -N-ethylhydrazone.



   By working in the manner described in part B of Example 11, this compound was obtained starting from the product of Example 12 with an overall yield of 38%, m.p. 109-110

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 after crystallization canopy of petroleum ether 100-120.
 EMI16.1
 B. 1-N- (2-Chlorc- -hydroxybonzyl) -N-ethyl-hydrazinium (1+)] oxalate
This compound was obtained by working in the manner described in part B of Example 10, with a yield of 69%, in the form of colorless crystals melting at 161-162 C, after recrystallization from ethanol.



  Example 14 N- (3-benzenesulfonyloxy -benzyl) -ethylnitrosamine
This compound was obtained as a pale yellow oil (89%) as described in Example 9, from N- (3-benzenesulfonyloxybenzyl) -ethylammonium chloride.
 EMI16.2
 



  Example 15 A. N- (3-benzenosulfonyloxy-benzyl) -N-ethyl-hydrazine
This compound was obtained by the process of part A of Example 10 from the product of Example 14.



   B. N- (3-benzenesulfonyloxy-benzyl) hydrogen oxalate
N-ethylhydrazinium (1+)
This compound was obtained by a procedure similar to that described in part B of Example 10, starting from the product obtained in A in the present example. This compound was obtained as colorless crystals by recrystallization from 10 parts volume / weight of a 5: 1 mixture of isopropanol and water, m.p. 145-145-5 dec. (50%).



  Example 16 N- (3-benzenesulfonyloxy-6-bromobenzyl) -methyl-nitrosamine
This compound was obtained in the form of a pale yellow oil (93%) by the procedure of Example 9 from
 EMI16.3
 N- (3-benzenesulfonyloxy-6-bromobenzyl) -methylammenium chloride. However, in this case the nitrosation was carried out at room temperature, in solution in aqueous acetic acid (7 parts of glacial acetic acid to 3 parts of water), finally heating to 60 for 30 minutes. Nitrosamine was obtained as a yellow oil (93%).



  Example 17 A. N- (3-benzenesulfonyloxy-6-bromobenzyl) -N-methyl-hydrazine
This compound was obtained by the procedure of part A of Example 10 from the product of Example 16.

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 B. N- (3-benzenesulfonyloxy-6-bromobenzyl) hydrogen oxalate -
 EMI17.1
 N-methylhydrazinium (1+)
This compound was obtained by a procedure similar to that of Part B of Example 10, from the product of Part A of this Example. It was obtained as colorless crystals from 10 parts volume / weight of a 10: 1 mixture of isopropanol and water, m.p. 169-171 * dec. (49%).



  Example 18 A. N- (3-hydroxybenzyl) -N-ethylhydrazine
N- (3-Benzenesulfonyloxy-benzyl) -N-ethylhydrazine, obtained by the method described in part A of Example 10, from product of Example 14 (10 g, 0.032 mole) was dissolved. in methanol (20 mL). A methanolic solution of potassium hydroxide (40 mL, 0.05 mole) was added.



  The solution was heated under reflux for 20 minutes, cooled and acidified with hydrochloric acid in ethanolic solution. The precipitate was filtered, then the filtrate was evaporated to dryness and the residue was treated with excess anhydrous potassium carbonate. After extraction with chloroform (200 ml), the solid material was filtered off and the chloroform was evaporated.



   B. N- (3-hydroxybenzyl) -N-ethylhydrazinium (1+) hydrogen oxalate
The product of part A of this example was dissolved in isopropanol (15 ml) and treated with a solution of oxalic acid (3 g) in isopropanol (10 ml). The solid which precipitated on leaving the mixture to stand at -10 ° C was recrystallized from a 10: 1 mixture of isopropanol and water. There was thus obtained N- (3-hydroxybenzyl) -N-ethylhydrazinium (1+) hydrogen oxalate as colorless crystals, m.p. 133-4 (4.5 g, 54%).
 EMI17.2
 



  Example 19 A. N- (3-hydroxy-6-bromobezyl) -N-methylhydrazine
Crude N- (3-benzenesulfonyloxy-6-bromobenzyl) -N-methyl-hydrazine, obtained in part A of Example 17, (22.9 g, 0.06 mole) was dissolved in methanol ( 34 ml) and a 17% methanolic solution of potassium hydroxide (66ml,

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 0.18 mol) was added. The solution was heated under reflux for 20 minutes, then cooled, after which was added glacial acetic acid (10 ml). The precipitate was filtered off and the filtrate was evaporated to dryness.



   B. Salicylaldehyde N- (3-hydroxy-6-bromobenzyl) -N-methylhydrazone.



   The product of Part A of this example was dissolved in ethanol (50ml) and water (100ml) and salicylaldehyde (6.7ml, 0.06 mol) was added. was heated in a steam bath for 30 minutes, then cooled and extracted with ether. The ethereal solution was washed with 2N hydrochloric acid, with water, with dilute sodium carbonate solution and again with water, after which it was dried over sodium sulfate. . Distillation of the ether gave a residue (10.35 g) of solicyl hydrazone, which did not solidify.



   Hydrogenated Oxalate
 EMI18.1
 C. N- (3 -hydroxy-6-bromobenzyl) -N-methylhydrazinium (1+)
The product of part B of this example was treated with water (150 ml) and oxalic acid (2.78 g) and the mixture was steam distilled, until the distillate gives a negative result in the test for the determination of salicylaldehyde (6 hours). The residual aqueous solution was extracted with ether and evaporated to dryness, which gave a pasty residue. By recrystallization from a mixture of isopropanol and water (10: 1), colorless crystals of hydrogen oxalate of N- (3-hydroxy-6-bromobenzyl) -N-methylhydrazinium (1+) were obtained, PF 163-4 '(dec). (5.1 g, 26%).



  Example 20 N- (2-toluenesulfonyloxy-benzyl) -methylnitrosamine
N- (2-p-Toluenesulfonyloxy-benzyl) -methylammonium chloride (10 g, 0.031 mole) was dissolved in a mixture of glacial acetic acid (50 ml) and water (50 ml) at 35 "and Sodium nitrite (2.11 g, 0.031 mol) was added. The solution was stirred until the nitrite dissolved, after which

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 she was left at. rest at room temperature for 3 hours. The resulting precipitate was filtered off, washed with water and dried. There was thus obtained 8.3 g of a colorless solid melting at 83.5-84.5 C. By diluting the mother liquors with water (200 ml) a new crop was obtained, m.p.



  82-82.5 * (0.72 g) was obtained. Total yield 9 g (92%).



  Example 21 A. N- (2-hydroxybenzyl) -N-methylhydrazone of salicylaldehyde
N- (2-p-toluenesulfonykoxybenzyl) - was dissolved
 EMI19.1
 ¯¯.-t ;, irWtxa-xi - {9-g; OtQ25 -aole # in # du-aé4> hanol (40 ml) .. 3. hot, and a solution of potassium hydroxide (6 g, 0.09 mole) in methanol (40 ml) was added, the mixture being kept constantly under nitrogen. The mixture was warmed to 50 C for 10 minutes, then allowed to stand at room temperature for 2 hours. After addition of glacial acetic acid (6 ml), the precipitated potassium p-toluenesulfonate was filtered off and washed (with a little methanol.



  After addition of glacial acetic acid (32 ml) and water (16 ml) the methanol was distilled off under a slight vacuum.



  The residue was heated to 50 ° C with stirring and analytical grade powdered zinc (8g, 0.123 atom g) added in fractions over 30 minutes to maintain the temperature at 50-55. C. Stirring was continued for 1 hour after addition was complete, then unreacted zinc was filtered off and the filtrate was diluted to a volume of 200 mL with water. After addition of salicylaldehyde (3.2 ml, 0.0285 mol), the mixture was heated on a steam bath for 5 minutes, then cooled. The oil which solidified by scraping was filtered off, washed with water and dried.



   Salicylhydrazine yield, m.p. 91-3. 5.8 g. (Overall yield 75%).



   B. N- (2-hydroxybenzyl) N-methylhydrazine
The product of part A of this example was suspended in a solution of sulfuric acid (2.4 g, 0.0245 mole) in water (50 ml) and the mixture was subjected to a

 <Desc / Clms Page number 20>

 steam distillation. After 1 hour, the distillate no longer contained salicylaldehyde. The residue was extracted with ether (50 ml) and the aqueous phase was treated with one equivalent of a saturated solution of barium hydroxide. The precipitate was treated with CO 2 for a short time and centrifuged, to remove sulfate and barium carbonate.



  The solution was found to contain 3.1 g (90%) of the free hydrazine.
 EMI20.1
 



  C. N- (2-hydrobenzyl) -N-methylhYdrazinium (1+) Iandelate
An aqueous solution of the free hydrazine (50ml, containing 1g) was treated with racemic mandelic acid (1.0g). The solution was evaporated to dryness under reduced pressure and the residue was washed with ether, so that N- (2-hydroxybenzyl) -N-methylhydra- a zinium (1 +) mandelate was obtained, PF 120-121 *, 1.8 g. This compound crystallized in the form of prisms in isopropanol, m.p. 123-4 *.
 EMI20.2
 



  Example 22 N- (2-benzenesulfonyloxY-3-bromobenzyl) -methyl nitrosamine
This compound was prepared from N- (2-benzenesulfonyloxy-3-bromobenzyl) -methyl ammonium chloride by the procedure of Example 16. The compound was obtained as a pale yellow oil.



  Example 23 N- (3-benzenesulfonyloXY-4-bromobenzyl) methyl-nitrosamine
This compound was prepared from N- (3-benzenesulfonyloxy-4-bromobenzyl) -methyl ammonium chloride by the procedure of Example 16. The compound was obtained as a pale yellow oil. we could not crystallize.
 EMI20.3
 



  Example 24 N- (3 -benzene tallow onyloxy-benzyl) -isopropylnitrosamine
This compound was prepared from N- (3-benzenesulfonyloxy-benzyl) -isopropyl ammonium chloride by the procedure of Example 16. The compound was obtained in a yield of 81% as a colorless solid. , Mp 64.5-65.

 <Desc / Clms Page number 21>

 



   Example 25. N- (2-toluenesulfonyloxy-benzyl) -isopropylnitrosamine
This compound was prepared from N- chloride
2-p-Toluenesulfonyloxybenzyl) -isopropyl ammonium by the process of Example 16, but in this case a 90% solution of acetic acid was used. The product obtained was isolated by evaporating the reaction mixture to about half of its initial volume, then slowly pouring this mixture, while stirring, into water. Nitrosamine was obtained in 59% yield, m.p. 92-93.5 *, after recrystallization from ethanol, (2 parts v / w). The pure compound crystallizes from ethanol as long, pale cream needles, m.p. 93.5-94.5 *.



   Example 26 A. N- (2-hydroxybenzyl) -isopropyl nitrosqmine
N- (2-p-toluenesulfonyloxy-benzyl) - was added. isopropyl nitrosamine (74.3 g, 0.213 mole) suspended in methanol (150 ml) and the suspension was stirred under nitrogen, while: 'a solution of potassium hydroxide (42.1 g, 0.64 mole) ) in methanol-280 ml) was added slowly. The mixture was stirred for 1 hour at room temperature, then acidified to pH 6 with acetic acid, after which it was evaporated in a rotary film evaporator. After addition of water. at the residue, the product was extracted with ether. The ethereal extract was dried over sodium sulfate and evaporated to an oil (47.5g) which was dissolved *, in di-n-butyl ether (60ml).



   On cooling of the solution, the product crystallized out as pale yellow prisms. M.p. 79-81 *. A second crop of crystals was obtained, concentrating the mother liquor to a total volume of 30 ml. There was thus obtained a total yield of 35.02 g (84.7%).



   N- (2-Hydroxybenzyl) -isopropyl nitrosamine crystallizes from di-n-butyl ether (5 parts vol./weight) as (very pale cream 79-80.

 <Desc / Clms Page number 22>

 



     B. N- (3-bromo-2-hydroxybenzyl) -methyl nitrosamine
This compound was obtained as described in A in this example with an overall yield of 97% starting from N- (2-benzenesulfonyloxy-3-bromobenzyl) -methyl ammonium chloride, but in this case the crude product crystallized, by pouring it into water, so that extraction with ether has proved unnecessary. The crude product melted at 85-90. Pure N- (2-Hydroxy-3-bromobenzyl) -methyl nitrosamine crystallizes from di-ni-butyl ether (10 parts vol./weight) as colorless prisms, m.p. 108-109.
 EMI22.1
 vs.

   N- (4-bromo-3-hydroxybenzy1) -methyl nitrosamine
This compound was obtained as described in A in the present example with an overall yield of 92%, m.p. 132-134.5, from N- (4-bromo-3-hydroxybenzenesulfonyloxybenzyl) -methyl nitrosamine. The pure compound crystallized as small rods from di-n-butyl ether (20 parts vol./weight) m.p. 134.5 - 135.5.
 EMI22.2
 



  D. N¯ (3-hydroxybenzyl) -cyclopropyl nitrosamine
This compound was obtained as described in A in the example from N- (3-hydroxybenzenesulfonyloxybenzyl) -cyclopropyl nitrosamine. The crude product was isolated as an oil with an overall yield of 85%. The nitrosamine obtained could not be crystallized.



  Example 27 A. Salicylaldehyde N '- (2-hydroxybenzyl) -N'-isopropyl hydrazine
N- (2-Hydroxybenzyl) -isopropyl ni-trosamine (33.5g, 0.173mol) was dissolved in acid (150ml) and water (50ml) was added to the solution. . Analytical grade zinc powder (45.05 g, 0.69 atom.g) was added in small portions over 15 minutes to the stirred solution at 50 ° C. The reaction mixture was stirred for 1 hour. additional 50 C, after which it was filtered. The filter cake was suspended in water (50 ml)

 <Desc / Clms Page number 23>

 and refiltered. To the overall filtrate was added salicylaldehyde (20.4 g, 0.167 mol) and after allowing the mixture to stand for 15 minutes, water (about 200 ml) was slowly added thereto.

   The product (41.37 g - 84.3%) m.p. 130-132.5 * was recrystallized from hot toluene (125 mL).



   Hydrazone 39.1 g (79.1%) was obtained, m.p. 132-134
The pure compound crystallizes from di-n-butyl ether (10 parts vol. Weight) as colorless prisms, m.p. 133-134 C.
 EMI23.1
 



  B. Nt- (3-bromo-2-hydroxybenzyl) -Nt-methyl hydrazary of salicylaldehyde
This compound was obtained as described in A in the present example from N- (3-bromo-2-hydroxybenzyl) -methyl nitrosamine with a yield of 62%, mp 124.5 - 126.5 'after recrystallization of the product. crude in ethanol (10 parts vol / weight).



   The pure compound crystallizes from ethanol as prisms, m.p. 129-130.
 EMI23.2
 



  C. Nl- (4-bromo-3-hydroxybenzyl) -N'-methyl hydrazine of salicylaldehyde
This compound was obtained as described in A in the present example from N- (4-bromo-3-hydroxybenzyl) -methyl nitrosamine with a yield of 78%, mp 123.5 -125 after recrystallization of the crude product in de ethanol.
 EMI23.3
 



  D. Salicylaldehyde N '- (3 ** hydroxybenzyl) -N'-cyclopropylhydrazone
This compound was obtained by the process described in A in the present example, from N- (3-hydroxybenzyl) - methyl anitrosamine with a yield of 55.4%, mp 134-138 * after recrystallization of the crude product in di-n-butyl ether (about 8 parts vol / weight).



   Pure hydrazone which crystallizes from the above solvent as very pale yellow prisms, m.p. 139-140.5.



  Example 28 N- (3-benzenesulfonyloxybenzyl) -cyclopropyl- nitrosamine

 <Desc / Clms Page number 24>

 This compoze was prepared from N- (3-benzenesul-
 EMI24.1
 fony1oxybenzyl) -cyclopbopylamine by the procedure of Example 16? This compound was isolated as a pale amber oil and could not be made to solidify.

   
 EMI24.2
 Example 29 Salicylaldehyde Nt- (3-hydroxybenzyl) -NI-isopropyl hydrazone
A methanolic solution of N- (3-hydroxybenzyl) -isopropyl nitrosamine, obtained as described in A in example
 EMI24.3
 26 from N- (3-benzenesulfonyloxybenzyl-¯irar.onx..xi.tro-¯ samine, was acidified with acetic acid, followed by reduction with zinc, by the method described in part A of example 27. The product was obtained with an overall yield of 65% Bar recrystallization from toluene (1.5 part volume / weight) small prisms were obtained, melting at 116-7 *.
 EMI24.4
 



  Example 30 N- {3-Bromo-4-hydroxybenzyl) -methyl nitrosamine
A solution of N- (3-Bromo-4-hydroxybenzyl) methylammonium chloride (2 g, 0.008 mole) in water (25 ml) containing glacial acetic acid (0.5 ml) was treated with sodium citrate (0.55 g, 0.008 mole). After allowing the mixture to stand at room temperature for 30 minutes, the precipitate was filtered off, washed with water and dried.



   By recrystallization from di-n-butyl ether (10 parts vol / weight) yellow prisms were obtained which, m.p. 139.5-140.5, with a yield of 77%.
 EMI24.5
 



  Example 31 N '- (3-brodno-Q-hydroxybenzy7.) - N' '- methylhydrazine of salicylaldehyde.



   This process was obtained as described in Example 27, Part A, from N- (3-bromo-4-hydroxybenzyl) -methyl nitrosamine in 81% yield as prisms, PF 184 , 5-185.5, after recrystallization of the crude product from toluene (10 parts vol / weight).

 <Desc / Clms Page number 25>

 Example 32 (1+) N '- (3-hydroxybenzyl) - dihydrogen phosphate -
 EMI25.1
 N '-âsopropylhydrazinimn
Salicylaldehyde N '- (3-hydroxybenzyl) -N'isopropylhydrazone (5.42 g, 0.019 mole) was suspended in 1N sulfuric acid (28 ml) and the mixture was subjected to distillation. steam until no more solicylaldehyde can be detected in the distillate.



  The solution was treated with o-phosphoric acid at
 EMI25.2
 88% (2.12 g, 0.019 -mole) then. with- # carfoonet-e- d -potassium - '.



  (2.62 g, 0.019 mole), and finally with bos charcoal. The solution was filtered and evaporated to dryness in a rotary film evaporator applying a vacuum using a water pump. To remove traces of water, the residue was treated twice with isopropanol (2 x 50 mL) and evaporated to dryness in the film evaporator. The residue was then extracted with boiling methanol (100ml) and the potassium sulfate was filtered off.



  By evaporating the methanolic solution to dryness, N '- (3-hydroxybenzyl) -N'-isopropylhydrazinium dihydrogen phosphate was obtained as a solid (2.36 g, 44.7%), PF 173-175. It was purified by dissolving in hot 75% aqueous isopropanol (15 ml) by filtering the solution and adding isopropanol (15 ml) to the filtrate, 2.19 g (41.4%), mp 166-178 '.



   Pure salt separates from hot 75% isopropanol as prisms, m.p. 177-178 ° C.



  Example 33 (1+) N '- (2-hydroxybenzyl) - dihydrogen phosphate -
 EMI25.3
 N'-isōprlhydrazinium.



   This compound was prepared as described in Example 32 from N '- (2-hydroxybenzyl) -N'-isopropyl hydrazone of salicylaldehyde. The residue from the methanolic extract did not crystallize until dissolved in a hot mixture of ethanol and isopropanol (about 10 parts vol / wt) 1: 1). salt then crystallized very slowly
 EMI25.4
 with a yield of 40.556, m.p. 145-160 C.

 <Desc / Clms Page number 26>

 



   Hydrazinium phosphate can be purified by dissolving in hot methanol (5 parts vol / weight) and adding isopropanol (5 parts vol / weight) to the filtered solution. Colorless prisms M.P. 164.5-165.5.



  Example 34 (1+) N '- (3-hydroxybenzyl) -N'-cyclopropyl hydrazinium oxalate
This compound was prepared by the method of Example 32 from N '- (3-hydroxybenzyl) -N'-cyclopropyl hydrazone of salicylaldehyde, but the theoretical amount of oxalic acid was substituted with phosphoric acid. Product yield, m.p. 174-175.5 Dec. reached 51%, after recrystallization of the crude salt from 10 parts vol / weight of a 60% aqueous colouration of isopropanol.



   The pure compound crystallizes from methanol (20 parts vol / wt) as colorless rombic crystals, m.p. 174.5-175 dec.



  Example 35 (1+) N '- (3-bromo-2-) dihydrogen phosphate
 EMI26.1
 hydroxybenzyl) -N '-methylhydrazinium This compound was prepared by the process of Example 32 from Nt- (3-bromo-2-hydroxybenzyl) -N'-methylhydrazone of salicylaldehyde, except for the ions sulfate were removed from the solution after steam distillation, adding the theoretical amount of barium hydroxide solution and removing the precipitated barium sulfate in a centrifuge. Phosphric acid was then added to the solution and the hydrazinium phosphate was isolated, by evaporating the solution to dryness, followed by purification, as described in Example 32. Yield 43%, mp 185-186.



   The pure salt crystallizes from aqueous isopropanol as platelets, m.p. 191-192.



  Example 36 (1 +) N '- (4-bromo-3-hydroxybenzyl) -N'-methyl-hydrazinium dihydrogen phosphate

 <Desc / Clms Page number 27>

 This compound was prepared by the method of Example
 EMI27.1
 35, from salicylaldehyde Nt- (4-bromo-3-hydroxybenzyl) Nt-methylhydrazone in 76% yield. It was obtained as colorless platelets, m.p. 176-7 * after recrystallization from methanol.
 EMI27.2
 



  Example 37 (1+) NI- (3-bromo-4-hydroxybenzyl) -Nl-hydrazinium chloride
This compound was prepared by the method described in Example 32, from N '- (3-bromo-4-hydroxybenzyl) -N'-
 EMI27.3
 methylhydrazone of salicylaldehyde, except that the crude sulfate solution from the steam distillation was treated with an excess of sodium carbonate solution, to precipitate the free hydrazine as of a gummy material. This was dissolved in ethanol, after which a slight excess of ethanolic hydrochloric acid was added. The solution was then heated to boiling and treated with a filter aid called "Spercel" and with charcoal.



  By hot filtration, cooling and dilution with ether, a crystallized salt was obtained, which was recrystallized in ethanol (10 parts vol / weight). Colorless prisms, m.p. 182-182.5, were thus obtained with a yield of 35%.



   The following preparations describe how to obtain the starting materials used in some of the examples given above.



  Preparation 1
 EMI27.4
 The N- (3-Bromo-6-hydroxybenzyl) -methylammonium chloride required in Example 7 was prepared as follows: A. 6-bromo-N-methyl-3.4-dihydro-3.2-benzoxine.



   Prepared from p-bromo-phenol, 25-30% aqueous methylamine and 37-41% aqueous formaldehyde by the method described by W.J. Burke & C. Wayne Stephens, J. Am.C.S.



  74, 1518. Yield 36.5%, colorless prisms, m.p. 86-7 C.

 <Desc / Clms Page number 28>

 
 EMI28.1
 



  B. N -, - bromo-6-hydroxybenzyl) -methylammonium chloride
Prepared by refluxing 6-bromo-N-methyl-3,4-dihydro-1,3,2-benzoaazine with concentrated hydrochloric acid in ethanol as in the method described by WJ Burke & C. Weyne Stephens, J.AM. C. S. 74, 1518. Yield 78%; M.p. 174-5 * C. colorless cubes.



  Preparation 2
The N- (3-benzenesulfonyloxy-6-chlorobenzyl) - methylammonium chloride required for Example 9 is prepared as follows: A. 3-Benzenesylfonyloxy-6-chlorobenzyl bromide
DU.1 3-benzenesulfonyloxy-6-chlorotoluene (133 g, 0.471 mol) was dissolved in boiling carbon tetrachloride (650 mL) and the solution was heated under reflux, while bromine (75.5 g, 0.472 mole) was added dropwise at such a rate that a permanent color did not remain in the reaction mixture. The bromination was caalysed by irradiating the solution using an untrimmed 500 watt tungsten filament lamp.



  The solvent was removed under reduced pressure, so that a viscous liquid was obtained which crystallized on standing; @ 175 g (etheoretical yield 175 g). The crude product was used in the next step, but the compound can be recrystallized from ethanol (3 parts vol / weight). The in the form of colorless needles. M.p. 60.5-61.5 *.



  B. N- (3-Benzenesulfonyloxy-6-chlorobenzyl) - methylammonium chloride
3-Benzenesulfonyloxy-6-chlorobenzyl bromide (18.07 g, 0.05 mol) was added slowly with stirring to a cooled (0 C) solution of methylamine in benzene (84 , 5 ml of 7.33% solution, 0.2 mol). The reaction mixture was allowed to stand for 2 hours at 0 ° C, after which it was allowed to warm to room temperature. Water (50 ml) was added and the organic layer was separated. The aqueous layer was extracted once

 <Desc / Clms Page number 29>

 with ether and the ethereal extract was added to the benzene solution which was then washed with water and dried over magnesium sulfate.

   By evaporating the solution under reduced pressure, an oil (14.2 g) was obtained, which was converted to N- (3-benzenesulfonyloxy-6-chlorobenzyl) -methylammonium choride, by dissolving in a mixture of ether. and ethanol (20 ml, 1: 1) and by adding a slight excess of 5.6N ethanolic solution of hydrogen chloride.



  The salt (8.1 g, 46.5%) was obtained as colorless crystals, m.p. 212-215.



   The compound can be purified by recrystallization from ethanol, from which it separates in the form of platelets.



  M.p. 214.5-216.



  Preparation 3
The N- (3-Benzenesulfonyloxy-6-chlorobenzyl) -ethylammonium chloride required in Example 12 was prepared as described in B in Preparation 2, using ethylamine instead of methylamine. This compound was obtained in a yield of 51%, m.p. 142-143. Recrystallization from isopropanol gave colorless crystals, m.p. 146-147.5.



  Preparation 4
The N- (3-Benzenesulfonyloxybenzyl) ethylammonium chloride required for Example 14 was prepared as follows: A. 3-Benzenesulfonyloxybenzyl bromide
This compound was prepared as described in A in Preparation 2, from 3-benzenesulfonyloxytoluene. By recrystallization from methanol, colorless prisms were obtained (1.5 part vol / weight, m.p. 64-66 *, yield 60%).



  B. N- (3-benzenesulfonyloxy-benzyl) ethylammonium chloride
This compound was prepared as described in B in Preparation 2, from the product obtained in A in the present preparation. The compound was obtained as colorless crystals in a yield of 57%, m.p. 152-3,

 <Desc / Clms Page number 30>

 after recrystallization from ethanol.



  Preparation 5
The N- (3-benzenesulfonyloxy-6-bromobenzyl) - methylammonium chloride required for Example 17 was prepared as follows: A. 3-Benzenesulfonyloxy-6-bromobenzyl bromide
This compound was prepared as described in part A of Preparation 2, from 3-benzenesulfonyloxy-6bromotoluene. It crystallized as colorless prisms in ethanol. (3 parts vol / wt), m.p. 89-90 * 68% yield.
 EMI30.1
 



  B. N- (3-Benzenesulfonyloxy-6-bromobenzyl) -methyl-ammonium chloride
This compound was prepared in the manner described in B in Preparation 2, from the product obtained in A in the present part. This compound was obtained as colorless crystals with a yield of 76%, m.p. 195-200 *, after recrystallization from ethanol.



  Preparation 6 The N- (2-p-toluenesulfonyloxy-benzyl) -methylammonium chloride required for Example 20 was prepared as follows:
 EMI30.2
 A. 2-P-toluenesulfonyloxy-benzylidene-N-methylimine
P-Toluenesulfonyl chloride (50 g, 0.26 mole) is added fractionally over 10 minutes to a stirred solution of salicylaldehyde (30.5 g, 0.25 mole) in pyridine (100 ml), temperature being maintained at 0 C - 5 C using a cooling bath. The solution was left to stand at room temperature for 2 hours, then poured into 750 ml of water. The precipitated oil, which solidified by scraping, was filtered off, washed vigorously with water, after which the wet cake was suspended in ethanol (50 ml).

   A 33% ethanolic solution of methylamine (37.5 mL, 0.4 mole) was added and the mixture was stirred until a solid material had set.

 <Desc / Clms Page number 31>

 dissolved. After leaving the solution to rest for 1 hour at room temperature, it was diluted with water (100 ml) and the precipitated solid was filtered off, washed with a little isopropanol and recrystallized from isopropanol. isopropanol (75 ml). Colorless prisms were thus obtained, m.p. 88-88.5. Yield 58.7g (81.5%).



  B. N- (2-p-toluenesulfonyloxy -benzyl) -methyl-ammonium chloride
2-p-Toluenesulfonyloxy-benzylidene-N-methylimine (224 g, 0.775 mol), 5% platinum on charcoal (10 g) and ethanol (400 mL) were placed in a low-pressure autoclave. culant with a capacity of one liter and the apparatus was filled with hydrogen at a pressure of 80 atmospheres. After keeping the apparatus for 12 hours at 70 ° C., the pressure had dropped to 35 atmospheres (room temperature).



  The resulting brown solution was filtered off from the catalyst and ethanolic hydrochloric acid (100ml) = 30g HCl) was added. The colorless precipitate was filtered off and recrystallized from ethanol. Colorless needles were obtained, m.p. 194-5. Yield 142 g (56%).



  Preparation 7
 EMI31.1
 A. 2- (p-toluencsulfonyloxy-benzylidene) -N-isopropylimine
Salicylaldehyde (73 g, 0.6 mole) in pyridine (270 ml) was treated with p-toluenesulfonyl chloride (114.3 g, 0.6 mole) at room temperature. The mixture was stirred for 1.5 hours, then poured slowly into 1.5 liters of water, while stirring. The solid which had formed was dissolved in ether and the ethereal solution was washed first with 2N hydrochloric acid, then with water. The ethereal solution was dried over sodium sulfate and evaporated to dryness. The residue was dissolved in isopropanol (250 mL) and isopropylamine (76 mL, 0.6 mole) was added to the solution.



   - 31 -

 <Desc / Clms Page number 32>

 The mixture was heated in a steam bath to ensure complete dissolution, after which it was kept at 5 ° C overnight. The product was filtered off and a second crop was obtained, by evaporation of the liquors. -mothers up to half the initial volume. 150 g (79%), m.p. 79 *. The pure compound crystallizes from isopropanol as prisms, m.p. 79.5-81.5 *.
 EMI32.1
 



  B. N- (2-p-toruenosuifonyloxybenzyl) -isopropyl-ammonium chloride
2-p-Toluenesulfonyloxy-benzylidene) -N-isopropylimine (3.17 g, 0.01 mol) dissolved in ethanol (20 ml) was hydrogenated at atmospheric pressure and room temperature in presence of 10% platinum on charcoal (300 mg). The catalyst was filtered off and the filtrate was evaporated to dryness at a pressure of 15mm. The residual oil was dissolved in ether (50 mL) and the filtered solution was added with a slight excess of a 7N ethanolic solution of chlorinated hydrogen.



  2.75 g, m.p. 173-176 *, of a solid was obtained which was collected and dried. The pure compound crystallizes from ethanol as colorless prisms, m.p. 189.5-190.5 '.



  Preparation 8 A. 2-Benzenesulfonykoxy-3-bromobenzyl bromide
This compound was prepared from 2-benzenesulfonyloxy-3-bromotoluene as described in A in Preparation 2.



  It was obtained in 66% yield, m.p. 114-116 * after recrystallization from a 1: 4 mixture of chloruform and petroleum ether (60-80). The compound crystallizes in the form of colorless needles, m.p. 117-118, in a mixture of ethyl acetate and petroleum ether (60-80).



  B. N- (2-benzenesulfonyloxy-3-bromobenzyl-methyl-ammonium chloride
This compound was prepared from 2-

 <Desc / Clms Page number 33>

 
 EMI33.1
 benzenesulfonyl-3-ban: renzyl with a yield of 70%, PF 167-169 * by the procedure of part B of preparation 2. It crystallizes in the form of colorless crystals PF 173-174 *, in isopropanol (12 parts vol / weight).



  Preparation 9
 EMI33.2
 A. 3-Benzenesulfony10xY-4-bromobenzyl bromide
This compound was prepared from 3-benzenesulfonyloxy-4-bromotoluene by operating as described in A in Preparation 2, but it could not be obtained in solid form.
 EMI33.3
 



  B. N - ($ - benzenesulfonyloxy-4-bromobenzyl) -methyl-ammonium chloride
This compound was prepared from the crude product obtained in A in the present preparation with a yield of 45%, mp 184-6 *, by operating as described in B in preparation 2. This product crystallized in the form of d. Colorless needles, melting at 185-6 *, in ethanol (10 parts vol / weight).



  Preparation 10
 EMI33.4
 A. N- (3-bromo-4-hydroxybenzyl) -methylammonium
A 33% ethanolic solution of methylamine (9.4 ml, 0.1 mole) was added to a suspension of 3-bromo-4hydroxy-benzaldehyde (10.05 g, 0.05 mole) in ethanol ( 40 ml). The resulting solution was heated briefly, cooled and added to a suspension of pre-reduced platinum (from 100mm PtO) in ethanol (10ml).



  The solution was reduced at room temperature and under pressure. Hydrogen uptake was complete after 1.25 hours.



   After filtering off the catalyst, ethanolic hydrochloric acid (11 ml = 3.3 g HCl) was added, then the filtrate was evaporated to dryness and the remaining gum was triturated with ether; a colorless solid was obtained, m.p. 185-189.

 <Desc / Clms Page number 34>

 



   By recrystallization from ethanol (8 parts vol / weight), colorless disms, m.p. 200-201, were obtained with a yield of 56%.



  Preparation 11
 EMI34.1
 N- (3-Benzenesulfonyloxybenzyl} -isopropylnmmonium chloride This compound was prepared from isopropylamine 3benzenesulfonyloxybenzy1let bromide in 85% yield, m.p. 180-2, by the method of Part B of Pre-
 EMI34.2
 "'-pdtiïn -:" "3T crystallized as colorless crystals, m.p. 183.5-184.5', in ethanol. Preparation 12
 EMI34.3
 N- (3-benzeneT; ulfonyloxybenzyl) -cyclopropylammonium chloride
This compound was prepared from 3benzenesulfonyloxybenzyl bromide and cyclopropylamine in 81% yield, PF 151-153 as described in B in Preparation 2. This product crystallized as small colorless sticks, melting at 156-157 C, in iso # propanol (5 parts (vol / wt).



   CLAIMS.



  1.- As new compounds, the hydrazine derivatives corresponding to the following general formula:
 EMI34.4
 in which X represents a halogen atom, n represents 0, 1, 2 or 3, and R represents an alkyl radical containing 1 to 4 carbon atoms as well as the addition salts with acids of these derivatives.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

2. - As new compounds, the hydrazine derivatives corresponding to the following general formula:; <Desc / Clms Page number 35> EMI35.1 wherein X and n have the meanings given in claim 1 and R "denotes an acyl group, as well as the acid addition salts of these derivatives. 3. - As new compounds, the hydrazini derivatives EMI35.2 ques answering. the general formula-given -in claim 1 or in claim 2, in which R denotes a cycloalkyl radical having 1 to 4 carbon atoms and X, n and R "have the meanings indicated above. 4.- N- (3-hydroxybenzyl) -N-methylhydrazine. EMI35.3 5.- Di-, N- (3-hydroxybenzyl) -N-methylhydrazinium oxalate (i + L7. 6. - Process for preparing a hydrazine derivative according to claim 1, characterized in that an N-nitrosamine corresponding to the following general formula is reduced: EMI35.4 wherein X, n and R have the meanings given in claim 1. 7. A process for the production of a hydrazine derivative according to claim 2, characterized in that an N-nitrosamine of general formula is reduced: EMI35.5 wherein X, n, R and R "have the meanings given in claim 2. 8. A process according to either of claims 6 and 7, characterized in that the N-nitrosamine is a compound in which R denotes a cycloalkyl radical containing 1 to 4 <Desc / Clms Page number 36> carbon atoms and X, n and R "have the meanings given in claim 2. 9. A method according to claim 7, characterized in that the N-nitrosamine is N- (3-hydroxybenzyl) methyl-nitrosamine. 10. - Process according to one or the other of the claims 7 to 9, characterized in that the reduction is carried out with zinc in the presence of acetic acid. 11.- Method according to one or other of the claims 6, 7 and 9, characterized in that the hydrazine is isolated in the form of a hydrazone formed from a volatile aldehyde in the presence of water vapor, this hydrazine then being regenerated by subjecting it to the action of an aqueous acid at high temperature, the aldehyde thus formed: being removed by distillation with water vapor. 12. - Process according to either of the claims 8 and 10, characterized in that the hydrazine is isolated in the form of a hydrazone formed from a volatile aldehyde in the presence of water vapor in that it is then regenerated by subjecting the hydrazone to the action of an aqueous acid at high temperature, the aldehyde thus formed being removed by steam distillation. 13. - Nitrosamines corresponding to the following general formula: EMI36.1 wherein X, n and R have the meanings given in claim 1. 14.- Nitrosamines corresponding to the following general formula: EMI36.2 <Desc / Clms Page number 37> wherein X, n, R and R "have the meanings given in claim 2. 15.- Nitrosamines corresponding to the general formula given in claim 13 or in claim 14, R denoting a cycloalkyl radical containing 1 to 4 carbon atoms and X, n and R "having the meanings indicated above. 16. - N- (3-hydroxybenzyl) methylnitrosamine. 17.- A process for the production of a nitrosamine according to claim 13, characterized in that a secondary amine is reacted having the general formula: EMI37.1 wherein X, n and R have the meanings given in claim 1, with nitrous acid or with lower alkyl nitrite, in the presence of an acid. 18. A process for the production of a nitrosamine according to claim 14, characterized in that a secondary amine corresponding to the following general formula is reacted: EMI37.2 wherein X, n, R and R "have the meanings given in claim 2, with nitrous acid or with lower alkyl nitrite, in the presence of an acid. 19. A method according to either of claims 17 and 18, characterized in that the secondary amine is a compound in which R denotes a cycloalkyl radical containing 1 to 4 carbon atoms and X, n and R " have the meanings given above. <Desc / Clms Page number 38> 20.- Process for the production of an N- (3-hydroxybenzyl) methylnitrosamine, characterized in that the N- (3-hydroxybenzyl) methylamine is reacted with a lower alkyl nitrite, in the presence of a acid. 21.- Pharmaceutical compositions, characterized in that they contain, as active ingredients, at least one hydrazine derivative according to either of claims 1 to 5 or an addition salt with a therapeutically acceptable acid of these derivatives .