BE512433A - - Google Patents

Description

       

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  IMPROVEMENTS RELATING TO A PROCESS FOR THE PREPARATION OF COMPOUNDS
CHEMICAL.



   The present invention relates to a process for the preparation of novel chemical compounds which are of interest in therapy and as intermediates in the production of other chemical compounds.



   The present invention relates more particularly to compounds having the formula
 EMI1.1
 formula wherein R is a hydrocarbonyl radical having 1 to 7 carbon atoms, Y is an aliphatic acylamino-carboxylic radical and X is S at SO2. The hydrocarbonyl radical R comprises: aliphatic, cycloaliphthic, arylated carbocyclic and benzylic radicals having from 1 to 7 carbon atoms and represented for example by: branched and unbranched alkyl radicals such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-heptyl, isoamyl, etc ...., alkenyl radicals such as allyl, methallyl, etc ...., cycloalkyl radicals, such as cyclohexyl, cyclopentyl, etc ...., the benzyl radical ;

   the phenyl radical; finally, the ortho-, meta- and paratolyl radicals.



  The acylamino radicals represented by X include both saturated and unsaturated aliphatic acylamino carboxylic radicals in which the aliphatic acylcarboxylic group can be considered to be derived from an aliphatic carboxylic acid. Thus, for example Y can be constituted by an alkanoylamino, haloalkanoylamino, nitroalkanoylamino, alkyl-mercapto, alkanoylamino, etc ... It is in particular preferred to use acylaminocarboxylic radicals lower aliphatic acyclic containing 1 to 4 atoms of carbon.

   This preferred group of acyl radicals includes, for example, the rec-

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 EMI2.1
 your acetylamino, dichloroacétylaminc, dibromoacétylamino, bromoac'tylam o, beta-chloropropionylemino5 difl..oroacétlamino, alpha-chloropropionylamino, trichloroacétylamino, nitroacétylamino5 méthßhercaptoacétylamino, methylsulphinyl fonylacétylamino, éthylmercaptoacétylamino, butynylamino, alpha-métbylpropio- nylamino, alpha-alpha-dichloroproçi, onylanino , iadoacetylamino, cyanoacetylamino, methoxyacetylamino, aorylylamino, alpha-hydroxypropionylamino; etc ...



   The groups below of the compounds to which the general formula given above relates represent the products in accordance with the present invention (in each case X means in the formulas below S or SO2):
 EMI2.2
 The 2-haloalkancrjlamino-l-lt, 4-alkvlmercaptbphênfl) -1,3-propanE, - diols and the 2mhaXoalkanoyiamino 1 (Ialkîsxlfony2.phenl), 3 propanediols, having the formula:
 EMI2.3
 
 EMI2.4
 The 2-alkanoylanino-1- (4-al.% Ylmercaptophenyl) -1,3-propanediols and the 2 = a1kanoylamino = 1 = 5-a1ky15'd.lfOIlylphenyl) -1,3 = propanediols, having the formula:
 EMI2.5
 
 EMI2.6
 The 2mhaZoaliLanoylaminc7m (/ a'ényïmercaptophény2) 1,3mpropanediols and the 2-haloalkanoylanino-1- (4-alkenyl-sulfonylphenyl) -1,3-propanediols, having the formula:

   
 EMI2.7
 
 EMI2.8
 The 2 ha3oalkanoylamiaolml = benzylmexcaptophenyl) 3, 3mpropanem diols and the 2-h8loalkanoylanino-1 - '(4-benzyl-sulfonylphenyl) -1,3-propanediols, having the formula:
 EMI2.9
 
 EMI2.10
 The 2 nit oa2kad.amïaoA (4mallmercs.ptophénr), 3 popa.em diols and the 2mnitroa3.ka; olamino.lna3kr.ms.l.fonylphép ;.)., 3propanedios; having the formula:
 EMI2.11
 
 EMI2.12
 The Zalkylakano.amino (4 a-lyimercaptophén) ml, 3mproparie diols, and the 2aalkvi.alkanaLsms.ao 14 aiky: L sv3fonyiphén) 1, propanediols, having the formula:
 EMI2.13
 

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 EMI3.1
 The 2-haloalkano, yiaminomL. (. Phenylmercapto-phenyl) -I, 3-propanediols and the 2-haloalkanoriaminoi - (.-Phenxi-sulfonyiphenyl) -1,3-propanediols, having the formula;

   
 EMI3.2
 
 EMI3.3
 2-Nitroalkanoylamino - I- (4-CYcloalkylmercaptophenyl) -1,3-pro- panediols and 2-Nitroalkanoylamino-1- (4-cycloslkylsulfonylphenyl) -1,3-pro- panediols, having the formula:
 EMI3.4
 
 EMI3.5
 The acylaminocarboxylel. (, Hydrocarbonyimercaptophenyl) 1., 3m propanediols bearing an aliphatic residue in 2 and the acy5.am.no-carboxyl I.



  (4 hydrocarbonylsulfor.plphenyl) 2,3mpropanediols bearing in 2 an aliphatic residue obtained by the process of the invention are useful as antibiotic agents and in particular as antimicrobial agents. They exhibit, for example, a bactericidal and bacteriostatic activity vis-à-vis gram-negative and gram-positive bacteria and vis-à-vis organisms of
Rickettsia. The new compounds are also useful as intermediates in the preparation of other valuable organics.



  Thus, for example, they can be hot hydrolyzed using mineral acids
 EMI3.6
 strong to obtain the corresponding 2-amino-1- (4 "hydrocarbonyl-mercaptophenyl) -1, 3-propanediols and the corresponding 2.am.no-1- (Ihydrocaxbonylsulfonylphenyl)., 3-propanediols. 2-amino-1 - (/ - hydrocarbonylmercaptophénx3.) - 1,3-propanediols constitute intermediate products which can be used in the production of 2dam..no1- {1-hydrocarbonylsulfonylphenyl) -1,3 = propanediols as will be discussed. show below.



   In accordance with the present invention, the carboxyls are obtained.
 EMI3.7
 acylaminom (1 hydrocarbonyl.mercaptaphenyl) 1,3-propanediols carrying a new aliphatic residue at 2 by means of the process which will be described now.



  An alpha-carboxyl acylamino .. (aliphatic) -4- bydrocarbonylmercaptoacetophenone of formula II is treated with formaldehyde in the presence of sodium bicarbonate or an equivalent alkaline condensation catalyst.
 EMI3.8
 which gives alpha-carboxyl-acylamino (a: Liphatic) -beta-hydroxy-4-hydrocarbonylmercaptopropiophenone (III); reducing the propiophenone derivative (formula III thus obtained by treating it with a lower aluminum alkoxide
 EMI3.9
 oxidizable to give 2-carboxyl-acylamino (aliphatic) -1- (4-hydrocarbonylmercaptophenyl) -1,3-propanediol (formula Ia).

   The reactions of the process of the invention are represented by the following equations:
 EMI3.10
 

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 EMI4.1
 In the initial phase of the process or hydrdxvmethylation, the formaldehyde is reacted in the gaseous state in the state of an aqueous solution because it is alcoholic or the para.formaldehyde with acylaminophenone (II) o - -This reaction takes place more advantageously at 20-50 C, although one can work at temperatures considerably above and below this range, for example of the order of 0-70 C, with results obtained. satisfactory. The amount of catalyst used is not critical, but it is preferred to use for best results the smallest amount of catalyst sufficient to achieve a reasonable reaction rate.



  Usually 0.01 to 0.10 moles of catalyst are sufficient to give satisfactory results.
 EMI4.2
 



  The last stage of the process according to the invention or the reduction can be carried out by treating the propiophenone (III) derivative obtained by hydroxynethylation with an oxidizable lower alkoxide of aluminum.



  This reduction phase is carried out in an organic solvent advantageously constituted by a lower secondary alkanol. For practical reasons, it is preferred to use a lower alkanol corresponding to the lower alkoxide. The reduction can be carried out by heating the reaction mixture at 20 - 100 C for several hours or until the reaction is
 EMI4.3
 completed. When using an infepier alkanol as the solvent, the reaction mixture is generally boiled while ensuring a slow distillation of the carbonyl compound, i.e. of the aldehyde or acetone, which separates. oxidation form of lower alkanol while reduction of the propiophenone derivative (III) takes place simultaneously.

   It is generally preferred to use as a reducing agent aluminum isopropoxide in isopropanol or aluminum butoxide (dry) in secondary butanol. Although as little as one equivalent of the alkoxide can be used for the reduction, it is generally preferred to use about 1.5 to 2.0 equiv.
 EMI4.4
 aluminum alkoxide values for one equivalent of the propiophenone derivative (III) in order to ensure optimum yields of reduction product (Ia).



  The alpha-carboxyl-acylamino (aliphatic) -4-hydrocarbonylmer-captoacetophenones (II) used as starting material in the process according to the invention are easily obtained, for example, by processing alpha-amino-4-hydrocarbonylmercaptoacetophenones ( formula IV) appropriate, in the usual manner with an aliphatic carboxylic acylating agent such as
 EMI4.5
 an acyl halide or an anhydride. The acylation can be carried out, for example, by heating the acylating agent and the amine (formula IV) in an anhydrous organic solvent or in an alkaline aqueous solution. The reaction temperature can vary within rather wide limits, but a range of 0 to 100 ° C. is generally satisfactory.
 EMI4.6
 



  The alpha-amino-4- (hydrocarbonylkercapto) acetophenones (Iv) are themselves advantageously prepared from the hydrocarbonyl-phenyl-sulfides conforming to the following reaction series:
 EMI4.7
 
 EMI4.8
 Car'boleacylaminomlm (4.ydro carbonylsulfonylphenyl) -1,3-propanediols carrying a new aliphatic residue in 2 in accordance with the invention can in general be obtained by oxidizing.; ¯ carboxyl-acylamino-l- (4-hy-drocarbonylmercaptophenyl ) -1,3-propanediol substituted in 2 by an aliphatic residue by treatment with a per-compound in an acid medium The reaction taking place in this process is represented by the following equation:

   

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 EMI5.1
 
The expression “per-compound” used during the present description denotes a hydrogen peroxide or a product derived therefrom and which confers at least two oxygen atoms linked together; that is to say a peroxide bond in accordance with the definition given in the work: Per-Acids and their salts by T.S.

   Price, page 1 and following, Longmans-Green edition (1911). The per-compounds suitable for obtaining the compounds in accordance with the present invention comprise, for example; Caro's acid (H2SO5), ammonium persulfate [(NH4) 2S2O8}, potassium persulfate, hydrogen peroxide, peracetic acid, perbenzoic acid, perphthalic acid, perborate sodium, sodium percarbonate, etc ....



  Generally, it is preferred to use as an oxidizing agent an organic peracid such as peracetic acid or perbenzoic acid. The oxidation is advantageously carried out in the presence of an organic solvent which is inert with respect to the per-compound used as the oxidant. The oxidation generally takes place more easily at temperatures between 10 and 1000 C depending on the oxidant chosen, but for the best yields it is preferable not to allow the reaction temperature to exceed about 65 C, when an organic peracid is used.



   The carboxyl-acylamino (2-aliph- tiques-1- (4-hydocarbonylmercato- (or sulfqnyl) phenyl) -1, 3-propanediols (I) according to the invention can easily be deacylated by treating them with hot mineral acids. to obtain the corresponding free amines (IVa) having the formula:
 EMI5.2
 
These new amines (IVa) readily acylate to give acylamino derivatives, and if desired can be easily converted back to the corresponding aliphatic acylamino-carboxylic derivatives (formula I). Amines (IVa) react with organic and mineral acids to form salts.

   When it is desired to obtain compounds according to the present invention in which the acylamino group is different from the acetylamino group, it is generally advantageous to prepare them by acylation of 2-amino-1- (4-hydrocarbonlermercaptophenyl) -1,3 -propanedol suitable obtained itself by hydrolysis of the corresponding 2-acetylamino-1- (4-hydrolcarbonylmercaptonphenyl) -1,3-propanediol. It should be noted that this acylation of the aminodical should be carried out under conditions which avoid the unwanted acylation of the hydroxyl groups.



  Thus, acylation should be carried out at temperatures below about 15 ° C. when an acid anhydride or an α-cylhalide is used as the acylating agent. When desired to prepare the dichloroacetyl derivatives of the amines (IVa), it is found that it is appropriate to use as dichloroacetylation agent. a lower alkyl dichloroacetate such as methyl dichloroacetate or ethyl dichloroacetate. Alternatively, the dichloroacetylating agent can be given rise in situ. Thus, the amines (IVa) are treated with chloral cyanohydrin or in an equivalent manner with a reaction mixture giving rise to this product, a mixture consisting of chloral hydrate and an alkali metal cyanide in the presence of an agent. neutralization of the acid.

   This acid neutralization agent can be constituted by an inorganic base such as calcium carbonate, sodium carbonate

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 or magnesium oxide or alternatively by a tertiary organic amine such as
 EMI6.1
 triethylamine, pyridine, or butyldiethylamine. When chloral cyanohydrin itself is used in the acylation, the reaction is preferably carried out at -20 ° C; when, on the other hand, a reaction mixture of chloral or chloral hydrate with an alkali metal cyanide is used, it is preferable to carry out the reaction at a slightly higher temperature, for example between 50 and 100 vs.

   The information below relates to this modification of the process, which is compliant. to the present invention.
 EMI6.2
 



  Although good yields of 2 = QiJchloroacéty1.amino- 1 = (4ethyrtlercaptophenyl) = 1.3px opanediol are obtained, for example, by using the common method of dichloroacetylation of alpha-amine = 4 = methylmercaptoacetophenone, then hydroxymethylation of this acylated product and reduction of the hydroxymethyl product, it is economically advantageous to dichloroacetylate 2-amino-1- (lethylnercaptophenyl) -1,3propanediol prepared by deacylation of 2-acetylaminolm (ln.ethylmercaptaphény) Z, 3 proparaediola It should be noted that in the preparation of carboxyacylamirfo (2-aliphatic) -1- (± -hydrocarbonylmercaptophenyl) -1,3-propanediols (Ia) according to the invention from intermediates, racemic or 'optically inactive , the final products are obviously obtained in racemic or optically inactive form.

   When it is desired to obtain the optically active forms of the acylaminodiols (Ia) in accordance with the invention, it has been discovered that it is generally
 EMI6.3
 Generally more interesting to acylate the appropriate optically active 2namino lm (4 hydroearbonyimercaptophenyl) -1,3-propanediol (obtained by separation, from the racemic aminodiol) by treating it with an ali- carboxylic acylchloride.
 EMI6.4
 phatic, anhydride or lower alkyl ester, as discussed above and in the examples which follow.



   It should also be noted that when a racemic or optically inactive form is used in the oxidation process as starting material
 EMI6.5
 carboxy-acylamino (2-aliphatic) -1- (4-hydrocarbonylmercaptophenyl) -1,3-propanediol (Ia), we obviously obtain a racemic form of carboxy-acylamine (2-aliphatic) -1- (4- hydroca-rbouylsulfonylphenyl) -1,3-propanediol (Ih) o
On the other hand, when the optically active form is used as raw material (Ia) in the process, the product (Ib) is likewise optically active.

   The optically active forms of the starting material (Ia) are easily obtained as below; a racemic form of compound (Ia) is deacylated by treating it with a hot mineral acid to give a
 EMI6.6
 racemic form of 2am3.no 2m (J 'droearbonyl) aercaptophény3 l, 3mpropanediol, which is separated using an optically active organic acid. The optically active forms of the amines thus obtained are then treated with an aliphatic carboxylic acylating agent to give the desired optically active forms of compound (Ia) o
A number of examples of implementation of the process will now be described, without implying any limitation.



   EXAMPLE 1, @
 EMI6.7
 9o-Chlorh drate alpha = 4-amino = I1lethYlmercaRtoacetophenoneo
110 g of thiophenol are added with stirring to a mixture of 90 cm3 of an aqueous solution of 35% sodium hydroxide and 400 cm3 of water in a 2-liter three-necked flask. 139 g of methyl sulfate are added dropwise to the resulting mixture using an introductory funnel at a rate such that the temperature of the reaction mixture does not exceed 60 ° C., while cooling the vessel. reaction from the outside with ice. The addition of the methyl sulfate takes about 5 to 10 minutes.



  After the completion of the addition of the methyl sulfate, the reaction mixture was continued to stir for about 1 hour, and then the mixture was cooled.



  The thioanisol which separates from the mixture is dissolved in about 400 cm3 of chloroform. The chloroform solution is separated; it was washed with 100 cm3 of dilute aqueous sodium hydroxide solution and dried over anhydrous calcium sulfate (In other tests, the isolation of the product from the solution was
 EMI6.8
 chloroform ion gives a recovery of thia-anisol with a yield

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 from 90% to 95% of theory, calculated with respect to the amount of thiophenol used).



   The chloroform solution of the calcium sulfate-free thioanisol is filtered directly into a 2-liter, three-necked flask, fitted with a stirrer, thermometer, introduction funnel and release tube (intended for to let the hydrochloric gas escape), the whole being protected against humidity by a drying tube. Sufficient anhydrous chloroform is added to the filtrate to bring the volume to about 800 cc and the solution is cooled by means of an ice-methanol bath.

   Then 165 g of aluminum chloride is quickly added to the chloroform solution while maintaining the temperature of the solution below 10 ° C., then 106 g of acetyl chloride is added to the solution by means of the funnel d. The introduction while still maintaining the temperature of the reaction mixture below 10 ° C. As the addition of the acetyl chloride progresses, a solid yellow product gradually separates from the mixture. (In some cases it has been found desirable to add an additional amount of dry chloroform to the mixture to facilitate agitation).



  When the addition of the acetyl chloride is complete, the cooling bath is removed and the reaction mixture is allowed to warm to 20 ° C. while continuing to stir vigorously. The thick reaction mixture is then decomposed by pouring it into a liter of ice and water containing 30 to 50 cm3 of concentrated hydrochloric acid, with vigorous stirring to ensure complete decomposition of the complex product. The chloroform layer is separated which contains 4-methylmercaptoacetophenone having the formula:
 EMI7.1
 and this product is used directly in the next phase. (In other tests, evaporation of the chloroform solution gives a yield of 96% to 98% of 4-methylmercaptoacetophenone of a high degree of purity).



   The chloroform solution of 4-methylmercaptoacetophenone is placed in a 3-liter three-necked flask fitted with a stirrer, an introduction funnel and an exhaust tube for the evolution of hydrobromic gas. The volume of the chloroform solution is brought up to about 1600 cc by adding chloroform. About 40 g of bromine was added to the solution and the mixture was allowed to stand until the reaction started, which was evidenced by the evolution of hydrobromic gas. The mixture is then stirred and a further 120 g of bromine is added over a period of 3 to 5 minutes.

   The reaction mixture is then subjected to reduced pressure with a water pump to remove most of the hydrobromic gas. The temperature of the solution, which contains alpha-bromo-4methylmercaptoacenone having the formula:
 EMI7.2
 gradually decreases due to evaporation to about 10 - 15.



  (A sample of this bromo-ketone isolated in another test is in the form of small white sheets which melt at 65.5 - 66.5 C, after recrystallization from methanol).



   140 g of hexamethylenetetramine are added to the cold chloroform solution of alpha-bromo-mercatptoacetphenene. The temperature of this mixture gradually rises to 30-35 ° C. and a solid white product separates from the mixture. The mixture is stirred for about 2 hours, then the solid product is combined on a filter and washed with chloroform. The product thus obtained is constituted by an addition product of alpha-bromo-4-methylmer-captoacetophenone and of hexamethylenetetrmaine having the formula:

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 EMI8.1
 product which melts at about 140 C when decomposing.
 EMI8.2
 



  The alpha-bromo-4-methvlmercaptoacetophemone-hexamethylenetetremine product obtained in the preceding phase is placed in a 3 liter flask containing 750 cm3 of ethanol and 375 cm3 of concentrated hydrochloric acid.



  On stirring the mixture a paste is obtained, the solid product gradually dissolving. Subsequently, the reaction product begins to separate from the solution. The reaction mixture is then cooled to 10 C; the filtered cake is filtered and washed with 100 cm3 of cold ethanol. We then paste
 EMI8.3
 the filter cake for a few minutes at L0 m 50 C with 600 em3 of water containing 25 cm3 of concentrated hydrochloric acid. After cooling the paste to 5-10 C, the white solid product is collected on the filter; it is washed with 100 cm3 of water containing 5 cm3 of concentrated hydrochloric acid and it is
 EMI8.4
 dried.

   135 to 141 g of alpha = amino "hydrochloride is thus obtained" 94411etbyl-mercaptoacetophenone having the formula:
 EMI8.5
 A sample of this product is recrystallized from water to give large white sheets which melt at 234.5-235 ° C (with decomposition).
 EMI8.6
 



  Bo-A1ha = Acetylamino = ethYlmercaptoacetophéDone.



  A paste of 11 g of alpha-amino = 4-methylmercaptoacetophenone hydrochloride is vigorously stirred in 50 cm3 of water containing 100 g of ice. 10 cm3 of acetic anhydride is added to this paste all at once, then a solution of 14.5 g of sodium acetate trihydrate in 60 cm3 of water.



  The temperature of the reaction mixture, which should not rise during the addition of acetic anhydride and sodium acetate, is allowed to return to room temperature (25 ° C.) and stirring is continued for a further period. 2 hours. Sufficient concentrated hydrochloric acid is then added to make the reaction mixture acidic to Congo Red paper (to dissolve any unreacted aminoketone), then the solid white product is combined on a filter with 30 cm3 of water and the mixture is filtered. dries it. This gives 10 g. alpha-
 EMI8.7
 acetylamino = 4 = methylmercaptoacetophenone having the formula
 EMI8.8
 product which melts at 133.2 = 134.6 C after recrystallization from acetone in the form of large white needles.
 EMI8.9
 



  Ca 0 Al-qha = acetlamino = beta, = bydro; KX = 4 = methrlmercaptoproRiophenone A mixture of 15 g of alpha acetylamino = 4 = metbylmercaptoacetophenone, 70 cm3 70 cm3 of ethanol, 25 C is stirred for 2 hours at 35 ° C. am3 of water, 10 cm3 of formalin (37% aqueous solution of formaldehyde and a solution of 0.3g of sodium bicarbonate in 10 cm3 of water The paste, thick at the beginning, gradually liquefies and after about 10 minutes, the reaction mixture is a pale yellow solution At the end of the two hours, the solution is cooled for about 10 hours.

   The solid crystalline product which separates from the cooled solution is combined on a filter and washed with 20 cm3.
 EMI8.10
 of water o In this way 10.5 g of a-pha acetylsnino = beta hydroxY4éthlmercapt propiophenone having the formula
 EMI8.11
 

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This product is purified by recrystallization from ethyl acetate to give light white needles which melt at 125.6-127.8 ° C.
 EMI9.1
 



  Do- 2 Acét .aminomlm .néth imerca to hén 1 ml ro anedio'lo A mixture of 5 g of alpha = acetylamino-betahydroXY = 4-methylmercaptopropiophenone, 20 g of isopropoxide is slowly distilled through a column of 37 cm aluminum and 120 cm3 of isopropanol; until no more acetone can be shifted in the distillate. This distillation takes about 7 hours. The excess isopropanol is then distilled from the reaction mixture and the residue is heated for 30 minutes with a solution of 10 g of sodium chloride in 100 cm3 of water. The suspension obtained is filtered while still hot and the residue of aluminum hydroxide thus collected is washed several times with 1-water. A solid white product separates from the filtrate in the form of thin sheets.

   This solid product is collected on a filter and washed with 15 cm3 of ether. 1.5 g of 2-acetyla-
 EMI9.2
 mino-1- (± -methylwercaptophenyl) -1,3-propanediol having the formula:
 EMI9.3
 
 EMI9.4
 product which melts at 167 - 168OC- Recrystallization in water, then in nitroethane brings the melting point to 172.1 = 173.5 Co E.- 2Acétvlamino - uêth lsuïfon 1 hén 1 ml m ro anedio.o On paste 1.95 g of 2 = acetylamino = 1- (4-methylmercaptophéDyl) -1,3-propanediol in 20 c.3 of acetone and add dropwise to this paste /.,

   5 cm3 of peracetic acid at 10o (The term "40% peracetic acid" is used in this example and in the following examples to denote a commercial preparation of peracetic acid consisting of an aqueous solution.
 EMI9.5
 containing approximately 10 peracetic acid, 5% hydrogen peroxide, 39% acetic acid and 1% sulfuric acid, all percentages given by weight). The temperature of the reaction mixture is maintained at 46 ° C or below by ice cooling the reaction vessel. After the completion of the addition of peracetic acid, the reaction mixture is continued to stir for 2 hours, after which it is cooled to 5 ° C. The white product which separates out is collected on a filter and washed. with twice 5 cm3 of cold acetone.

   This product is recrystallized from
 EMI9.6
 nitroethane, which gives 1.02 g of 2 = acetlaminoml = (4o.éthyi, su.fonqlghényl.) 1,3-propanediol in the form of white sheets which melt at 172.7 - 173, 7C and which have the formula :
 EMI9.7
   EXAMPLE 2.
 EMI9.8
 



  A.- 2 Am.ino Im néth imerca to hén 1 1 3m ro anediolo A mixture of 50 parts by weight of zacetylaminoml; 4..éthlraercaptophénrl) 1,3prop.nediol racemic obtained as described is heated in a water bath for 30 minutes above in Example 1, 100 parts by weight of concentrated hydrochloric acid and 500 parts by weight of water. The resulting solution was cooled to about 40 ° C. and made strongly alkaline by adding 35% aqueous sodium hydroxide solution. The alkaline solution is then cooled. The white product which separates from the cooled solution is collected on a filter. In this way 27 parts by weight of 2-amino-
 EMI9.9
 1- (l.étbImercaptophénlml, 3mpropanedioZ having the formula:

 <Desc / Clms Page number 10>

 
 EMI10.1
 
This product melts at 130.7-131.9 ° C. after recrystallization from methanol.



   A solution of 17.5 g of the 2-amino-1- (4-methylmercaptophenyl) -1,3-propanedol described above, which of course may be the racemic or optically inactive form of the compound, is mixed. in 100 cm3 of-methanol and a solution of 13 g of d-tartaric acid in 100 cm3 of methanol and the mixture is left to stand for about 6 hours at 15 '- 20 C. The solid product which is collected on a filter is collected on a filter. separates from solution during this period, the methanolic filtrate being set aside for processing as will be discussed below. In this way 18 g of a solid are obtained, the melting point of which is 190 - 196 C. This solid is suspended in 150 cm3 of water and a sufficient quantity of dilute hydrochloric acid is added to cause dissolution. of the solid product.

   50 cm3 of 35% aqueous sodium hydroxide solution was added to the solution thus obtained, which caused the separation of the solution of 11.7 g of a yellow solid product. This solid product melts at 127 - 135 C.



   Two recrystallized% ions in methanol give 1.5 g of large white needles which melt at 152 - 153 C. This product consists of the levorotatory form of 2-amino-1- (4-methylmercatponphéyh) -1.3 -propanediol whose rotation index is (a) 25 = - 21 (1% solution in 95% ethanol). D
The methane filtrate set aside to remove the methanol is distilled in a water bath; a dissolves the residue thus obtained in 50 cm3 of water and the resulting solution is treated with 15 cm3 of caustic solution at
35%. This causes the separation of 3.0 g of a white solid which melts at 141 - 150 C.

   This product is recrystallized twice from methanol, which gives. ne 1.0 g of white crystals consisting of the estrogyre form of 2-amino-1- (4-methylmercatponphenyl) -1,3-propanediol. product which melts at 152 - 153 C and has an index of (a) 25 = + 21 (1% solution in 95% ethanol) /
D
The racemic amine is also separated as follows: 33.0 g of racemic 2-amino-1- (4-methylmercatpophenyl) -1,3-propanediol and 34.6 g of dN-bezoylithrenine are dissolved (point melting 149 - 151 C, obtained by benzoylation of d-threonine) in 500 cm3 of methanol with heating.



   Crystallization is initiated by cooling the solution to 25 ° C. and scraping the interior walls of the vessel. The solution is cooled to 5 ° C for about 10 hours; then the crystals separated from the solution were collected on a filter, the filtrate (A) being set aside for the recovery of the dextrorotatory amine as described below. The solid product is washed on the filter with a few cm3 of cold methanol and dried at 70 ° C. In this way 31.3 g of 2-aminc-1- (4-methylmercaptophenyl) 1,3-propane salt are obtained. - levorotatory diol-dN-benzolythreonine which melts at 184 - 186 C. This amount of this salt is dissolved in 100 cm3 of water containing 6.2 cm3 of concentrated hydrochloric acid and the solution is made alkaline by adding 13 cm3 of 35% aqueous sodium hydroxide solution.

   20 g of sodium chloride are dissolved in this solution; then it is cooled to 5 tbsp. A heavy mass of crystals separates from the solution, which are collected on a filter, washed with a little saturated sodium chloride solution and dried at 70 C. In this way 15.0 g is obtained. of 2-amino-l- (4-methylmercaptophenyl) -1,3-propanediol crude levorotatory which melts at 147-150 C. This product is recrystallized in 150 cm3 of methanol which gives 11.9 g of pure levorotatory amine melting at 151-153 C.



   By concentrating the mother liquor, another 3.0 g of solid product is recovered, consisting mainly of racemic amine.



   The filtrate (A) set aside as above is evaporated under reduced pressure. The residue thus obtained is dissolved in 100 cm3 of water containing

 <Desc / Clms Page number 11>

 nant 62 cm3 of concentrated hydrochloric acid and this solution is made alkaline by adding 13 cm3 of 35% aqueous sodium hydroxide solution. We dissolve
 EMI11.1
 20 g of sodium chloride in this solution, then it is cooled to 5 Co. The heavy mass of crystals which separates from this solution is collected on a filter; it is washed with a few cm3 of saturated sodium chloride solution.
 EMI11.2
 dium and dried at 10 Ca. 13.5 g of crude dextrorotatory 2-amino-1- (4-methylmercaptophenyl) -1,3-propanediol are obtained. This product is crystallized in methanol to give 8.5 g of pure dextrorotatory amine which melts at 151-1530C.

   By concentrating the mother liquor, a further 5.0 g of a solid product is obtained, consisting mainly of the racemic amine.
 EMI11.3
 



  Ba- 2mD.ch.oroacétamino méth imerca to hén ZI m ro ataedio..o A mixture of 1.1 g of 2mam.ino-lm (4éthyinercaptophenyl)., 3 levorotatory propanediol, obtained is heated in a water bath for 3 hours. as described above under A, and 1.6 cm3 of ethyl dichloroacetate. The viscous yellow oil which is obtained is dissolved in 25 cm3 of ethylene chloride and filtered while still hot through animal charcoal, then the filtrate is allowed to cool to about 25 ° C., It separates from it. ci 0.92 g of thin white sheets which are collected on a filter.

   By recrystallization of this
 EMI11.4
 product, which consists of the dextrorotatory form of 2-dichloroacetylamino l- (4.n.éthy.mercaptophény i) i., 3propo: ned3ol having the formula:
 EMI11.5
 
 EMI11.6
 in nitroethane, the pure product is obtained which melts at 111.6 - 112.6 C 25
 EMI11.7
 and has a rotation index of (a) D = + - 12 '(1% solution in 95% ethanol) "In the same way, the 2-amino acid is acylated with ethyl dichloroacetate. -l- (4-methylmercaptophenyl) -l., 3-propanediol dextrorotatory to obtain the levorotatory form of 2dichSoroacety3.aminomSm (4nethynercaptophenyl) mi, 3mpro- panediol, which melts at 111, 6 - 112, 6 and has a rotation index of (a) 25 D = - 12 (1% solution in 95% ethanol).



   Likewise, the dichloroacetylation of the racemic amine with the
 EMI11.8
 Ethyl dichloroacetate similarly gives a racemic 2-dichloroacetylamino-1- (4-enethylmeroaptophenyl) -1,3-propanediol with a melting point of 101.2102.4 C.



   According to one variant, the dichloroacetylation of the amines is carried out as follows: In 60 cm3 of hot dioxane; 6.4 g are dissolved
 EMI11.9
 of 2maminoml (l, .nethylrnercaptophenyl) m1,3 levorotatory propanediol, obtained as described above under A. The mixture thus obtained is cooled to 20 C. To this solution is added 7.0 g of chloral cyanohydrin, then 6, 3 g of triethylamine, the latter reagent being added slowly dropwise while stirring the reaction mixture and providing sufficient cooling
 EMI11.10
 to keep the mixture at 10 - 20 ° C. After the addition of the triethylamine, the reaction mixture is stirred for a few more hours, then it is advantageously allowed to stand overnight at room temperature (about 16 hours at about 25 ° C. ).

   The reaction mixture is then poured into 75 g of ice-cold water and a sufficient quantity of concentrated hydrochloric acid is added to make the solution slightly acidic with Gongo Red. The acidified solution is cooled overnight and collected on a filter the product
 EMI11.11
 solid which separates from this solution.

   This gives 2-dichloroaoéty- Iamino = -1 (!. methylmereaptophényï.)., 3propane, dextrorotatory diol, melting point 111, 6 - 112, 6 c which is identical with the product obtained by treatment of the levorotatory amine with ethyl dichloroacetate, as described above.
 EMI11.12
 By replacing in this process the levorotatory amine by the 2 aminol- (. Methylmer captaphénvl)., 3p ops, dextrorotatory and racemic nediols, one obtains, respectively.

 <Desc / Clms Page number 12>

 
 EMI12.1
 vement, the 2md.ichloroacetylamino lm (4aethylmèrcaptophénI) ml, levorotatory and racemic 3propanediols, which are identical to the corresponding product resulting from the dichloroacetylation process using ethyl dichloroacetate.
 EMI12.2
 



  Co 2mDichloroacet lam.nomLm n. th lsulfon 1 hen 1 ml ro anediola - 7 g of levorotatory 2dichloroaeetylam.inoml (netr7snercaptophenyi) -1,3-propanediol, obtained as described above under 'A', are dissolved in 30 cm3 of acetone. 10 cm3 of 40% peracetic acid are added dropwise to this solution while stirring. During this reaction, the temperature is maintained at 39-45 C by cooling the reaction vessel. After stirring the mixture for 2 hours, dilute with 100 cc of water and allow the solution to stand for 48 hours in the cooler. The solid product which separates from the solution is collected on a filter; it is washed twice with ice water and dried. overnight at 70 C.
 EMI12.3
 



  This gives 6.2 g of 2dïchloroaeéttlam.no 7. (4n.étbylsulfonylphenyl) 2,3 levorotatory propanediol which melts at 164.3 - 166, 3 C and has a rotation index
25 of [a] D = - 12 (1% solution in 95% ethanol).



   The 2-dichloroacetylamino-l- (4, -
 EMI12.4
 dextrorotatory methflsulfonylphenyl) al, 3-çtopanediol by oxidizing 2-dichloroacetylamino - 1 m (/a.éthy7cç^ercaptophenyl) m1,3propanediol dextrorotatory obtained as described under B. This product melts at 165, 2 - 166, 6 C. , has an index of
25 rotation of (a] D = + 13 (1% solution in 95% ethanol) and the formula:

      
 EMI12.5
 
 EMI12.6
 Da- 2-Amino-l- (4-m.ethylsulfopYlphenyl) -1.3-Rropanediolo A mixture of 5 g of 2-dichloroacétrlaminoml.nêthylsulfonlphénl) m1,3-propanqd3ol dextrorotatory is heated for 1 hour as described above under C, 9 cm3 of concentrated hydrochloric acid and 40 cm3 of water o The water is removed from the solution obtained by vacuum distillation, leaving a light yellow syrup which solidifies on standing for For several days at room temperature (about 25 G) o This solid product is heated to 60 - 70 C with 20 cm3 of saturated sodium chloride solution until it is completely dissolved. The resulting solution is treated with 3.5 cm3 of a 35% aqueous sodium hydroxide solution and extracted while still hot with about 100 cm3 of n-butahol.

   On cooling and on standing it separates from the butanolic extract 0.9 g of crystals
 EMI12.7
 white. This product, which is levorotatory 2-amino-1- (4-nethylsulfonylphenyl) -1,3-propanediol having the formula:
 EMI12.8
 melts at 141.4 - 142.6 C and has a rotation index of [a] D = 1 19.8 (1% solution in 95% ethanol). This water soluble base forms a water soluble hydrochloride which melts at 200.4 - 202.6 C and has a rotation number of [a] 25 == 26.0 (1% solution in 95% alcohol).

   D
 EMI12.9
 Likewise, the dextrorotatory and racemic 2-amino-1- (4-nethylsulfonyl-phenyl) -l, 3-propanediols are obtained, respectively, when the 2-dichloro-2-dichloro is deacylated by treatment with concentrated hydrochloric acid. acetylamino 1- (ln.ethylmsulfonylpheryl) 1,3-propanediols levorotatory and racemic.

 <Desc / Clms Page number 13>

 
 EMI13.1
 



  E - 2D.choroacét lamino7! Eth lsulfox 1 hén 1 m1 - ro an io.a The dichloroacetylation of 2 = amino = 1 (4-methylsulfony.lphenyl) - 1,3-propanediols levorotatory, dextrorotatory and racemic, (obtained as described "above under D) by treatment with ethyl dichloroacetate or cbl cyanohydrin: are1 in the presence of an acid neutralizing agent or with a mixture of chloral hydrate and a cyanide of an alkali metal and in the presence of an acid neutralizing agent, such as triethylamine, calcium carbonate,
 EMI13.2
 sodium carbonate or pyridine, gives the 2-dichloroacetylaminoml (lnethylsulfor.l phenyl) 1,3propanedio.s dextrorotatory, levorotatory and racemic, respectively.

   These products obtained by acylation are identical to the corresponding acylaminated products described above under C. obtained by the oxidation process.



   EXAMPLE 3.
 EMI13.3
 



  ! .2 = 2 Dibromoacet Iaminoml = n.éth lmerca to hén 1 ml anediolo By boiling under reflux for about an hour, 2-amino-1- (4-methylmercaptophény1) = 1,3 = racemic propanediol described above under A (example 2) with methyl dibromoacetate in the presence of anhydrous ethanol as solvent for the reaction, the racemic 2mdibromoaeétylamino- 1- (4-methy:. mercaptophenyl) -1,3-propanediol is obtained having the formula:

   
 EMI13.4
 
 EMI13.5
 Likewise, dibromoacetylation of levorotatory 2aminomlm (l methy.m.ercaptophenyl) 11,3-propanediol (described in Example 2A) gives the dextrorotatory form of 2-dibromoacetylamino-l- (4-methylmercaptopheayl) -l, 3-'propaiidiol and the enantiomorphic dextrorotatory amino-diol gives 2-dibrcmoacetylemino-l- (4-methylmercap- tophenyl) -1,3-propanediol levogyreo Bo- 2Dibromoacet laminomlm n.eth lsulfon 1 hén l 1 3- ro anediolo The oxidation% ion of the racemic, dextrorotatory and levorotatory forms of 2-dibromoacetylamino-1- (4anethylmercaptophenyl) -1,3-propaùediol obtained as described under A gives the 2mdibromoa'cétylatnino1 (lethylsu.l.fonylphenyl) 1,3- propanediol racemic, dextrorotatory and levorotatory, respectively.



    EXAMPLE 40
 EMI13.6
 2o-Dichloroaceous lamino l.m n.eth lsu.l.fon. hén .l m2 ro anedïolo
 EMI13.7
 
 EMI13.8
 Ao- Alpha-dichloroacetylamino-4éthzlmercaptoacétohenoneo 217.7 g of alpha-amiDo-4ethylmercaptoacetophenone (hydrochloride), obtained as described under A of Example 1, are mixed with 4.5 liters of anhydrous benzene at 27 C. 166 g of dichloroacetyl chloride only once to this mixture and the latter is heated under reflux while stirring for 15 to 18 hours. After a while most of the solid product dissolved. The reaction mixture was filtered while hot in a preheated funnel and the filtrate was allowed to cool. The solid which separates from the solution is combined on a filter, washed with benzene.
 EMI13.9
 ne and dried.

   230 g of alpha-dichloroacetylamino-4-methylmer-captoacetophenone are thus obtained having the formula:

 <Desc / Clms Page number 14>

 
 EMI14.1
 Recrystallization of this product from acetone gives white needles
 EMI14.2
 which melt at 151, 'm 152, 9 Co - - Bo Al ha.dichloroaceous Iam.no beta = dro n.éth lmerca to ro io hénone-0 292.2 g of alpha-dichloroacetylsmino-4-enethylmercaptc- acetophenone with 14.5 liters of ethanol at 40C. To this mixture are added 15 g of sodium bicarbonate and 150 cm3 of formalin (37% aqueous solution of formaldehyde) while continuing to stir and maintaining the temperature of the solution at 40-50 C, until that all of the alpha-dichloroacetylamino-4-mercaptoacetophenone has gone into solution.

   It takes about 8 hours. The suspended sodium bicarbonate is then filtered off and the volume of the filtrate is reduced to 2-2.5 liters by evaporating the ethanol from the solution under reduced pressure. The residual solution, which is then orange in color, is cooled for about 10 hours.



  The solid which separates from this solution is collected on a filter. We
 EMI14.3
 thus obtain 232 g of alpha = dichloroacetylamine = betahydro: XY-4-metbylmercaptopropionic having the formula:
 EMI14.4
 Recrystallization of this product from ethylene chloride gives thin white sheets which melt at 147.7 ... 148.5 C.
 EMI14.5
 



  Ca-2-Dichloroac 'lamino1 neth lmerca to hén I l - ro anediol.



  322.2 g of alpha-die'hloroacetylaninobeta-hydroxy-4-methylmercaptopropiophenone, 420 g of aluminum isopropoxide, and 3 liters of anhydrous isopropanol are placed in a 5-liter flask and heated. mixing at a rate such that the distillation of the liquid through a 37 cm column corresponds to the passage of a drop every 3 to 5 seconds. The distillation is continued for 16 to 18 hours, after which time the distillate no longer contains acetone. (The presence of acetone is detected using a 0.1% solution of 2,4-dinitrophenylhydrazine according to the method described in the book "Organic Reactions", vol. II, page 200).

   Isopro- is eliminated. Panol remaining in the reaction mixture by evaporation under reduced pressure. The viscous dark red residue thus obtained is heated in a water bath for about 45 minutes with 2.5 liters of water containing 200 g of sodium chloride. Sodium chloride is added to reduce the tendency of the aluminum hydride to gel. We filter the still hot suspension
 EMI14.6
 to remove aluminum hydroxide.

   The aluminum hydrode thus collected is impasted several times with ether to remove the red oil which adheres to it and the ethereal extracts are combined with the filtrates. The combined ethereal solutions are dried over calcium sulfate. anhydrous and the ether was removed from the dry solution by distillation. 310-320 g of a dark red viscous oil were thus obtained. This oil is dissolved in 1600 cm3 of ethylene dichloride; filtered through animal charcoal and the filtrate cooled.



  The solid which separates from the filtrate consists of 180 to 195 g of 2-dichlo-
 EMI14.7
 roacetlamino-1- (In.éthplmercaptophénrl) - 1,3-propanediol having the formula:
 EMI14.8
 which melts at 98 - 100 C. This product is purified by recrystallization from 550

 <Desc / Clms Page number 15>

 cm3 of nitroethane and by a new recrystallization from e- chloride
 EMI15.1
 thylene. 125 g of crude product are thus obtained which melts at 101.2 - .02.1 C.



   In another test, the reduction is carried out as follows: A mixture of 9.6 g is heated under reflux for about 35 minutes.
 EMI15.2
 alpha-dichloro-acetylamino-beta = hydro-4ethylmercaptopropiophenQne; of 6.5 g of aluminum isopropoxide and 90 cm3 of anhydrous isopropanol, while arranging for the slow distillation of acetone and isopropanol from this solution. The remaining solvent is then removed by evaporation under reduced pressure. The residue thus obtained gives 5.8 g
 EMI15.3
 of 2mdichloroacety3.am5.no. (t ,. ethyimercaptophény3.) = 1.3 propanediol which melts at 101.2 = 102.4 C.



  Do - 2 ichLoroacét lamirol neth .sulfon 1 hén i ro aned.ol.a 21 cm3 of 40% peracétiqae acid are added to a stirred solution of 15.0 of 2mdichloroacéty.ami.noâ: (lnéthyn.ercaptophényl)., 3mpropanedioi in 44 cm3 of acetone. The reaction vessel is externally cooled with ice and the rate of addition of peracetic acid is controlled so that the temperature of the reaction mixture does not exceed 40 ° C. The reaction mixture is then stirred for. one hour and cooled to -5 ° C. The solid product separated from the solution is collected on a filter.



  14.0 g of a solid white product consisting of 2-dichloroa-
 EMI15.4
 cetylmino-l- (4-methylsuifonfiphén.vl) -1,3-propanediol which melts at 179, 4 - 180, 6 C and which has the formula:
 EMI15.5
 EXAMPLE 5.
 EMI15.6
 h- Alpha-amino = 4 =: ethx1mercaptoacetophenone (hydrochloride, ate)
337 g of ethyl sulfate are added dropwise via a funnel to a stirred solution of 200 g of thiophenol in 800 cm 3 of 10% aqueous sodium hydroxide. This mixture is then stirred for 2 hours.



  During this period, the temperature gradually rises to 65 ° C., then drops to room temperature (about 25 ° C.) and the product is separated from the mixture.
 EMI15.7
 desµré reaction which is ethyl-phenyl-sulfide in oily form. This oil is extracted from the mixture with 800 cm3 of chloroform. The chloroform solution of ethyl-phenyl-sulfide thus obtained was dried for several hours over anhydrous calcium sulfate. The dry solution is then placed in a 3 liter three-necked flask fitted with a stirrer, a thermometer and a drying tube. The solution is stirred, cooled to -10 C and 175 cm3 of acetyl chloride are added.

   Then 300 g of anhydrous aluminum chloride are added in portions while maintaining the temperature of the reaction mixture between 5 and 15 C. After the addition of the aluminum chloride, the reaction mixture is allowed to warm to 20 ° C. C and poured into about 2 kg of ice. The chloroform layer, which contains the
 EMI15.8
 The desired 4-ethyl mercaptoacetophenone is separated from the mixture and placed in a 5 liter three-necked flask fitted with a stirrer and an introductory funnel. 75 g of bromine are then added to the stirred solution.



  After the start of the reaction, which is manifested by the evolution of hydrobromic gas, a further 225 g of bromine is added as quickly as possible. The hydrobromic gas which evolves from the mixture is removed by the effect of the reduced pressure on the stirred solution, which contains
 EMI15.9
 alpha-bromo-4-ethylmercaptoacetophenone having the formula:
 EMI15.10
 

 <Desc / Clms Page number 16>

 (A sample of bromoketone isolated from another test melts at 74.4-
 EMI16.1
 75? 4 C after recrystallization from petroleum ether followed by recrystallization from methanol).

   To the residue thus obtained was added 256 g of hexanethylene tetramine and the mixture was stirred for 2 hours. - The solid and yellow addition product alphâ bromo4 - ethylmercaptoacetoacetophenone-hexamethylenetetramine having the formula is combined on a filter:
 EMI16.2
 it is washed with chloroform and drained to partial dryness on the filter. The adduct is mixed with 760 cm3 of concentrated hydrochloric acid and 1540 cm3 of ethanol. This mixture is stirred for about 6 hours.



  The suspension obtained is cooled to 5 ° C., filtered and washed with about 200 cm3 of ethanol. The solid product is then impasted with a liter of hot water containing 20 cm3 of concentrated hydrochloric acid. The suspension is cooled to 5 ° C., then filtered. The solid product collected is washed with about 300 cc of ice water and dried. We thus obtain 211 g of al-
 EMI16.3
 pha-amino-4-ethylmercaptoacetophenone (hydrochloride) having the formula. :
 EMI16.4
 This product melts at 186.5C (with decomposition) after recrystallization from water made slightly acidic with dilute hydrochloric acid.
 EMI16.5
 



  Ba A1pha-dichloroaceous \ vlamiAo = ethylmercaptoacetohenone A mixture of 200 g of alpha aminom4ethyln.ercaptoacetov phenone (hydrochloride) and 4.5 liters of benzene is placed in a 12-liter three-necked flask fitted with a stirrer and a condenser. at reflux to water siphon. The benzene is slowly distilled until no more water collects in the siphon. 147 g is added all at once to this mixture.
 EMI16.6
 of di chloroacetyl chloride and the resulting mixture is boiled under reflux for 15 hours. The evolution of hydrochloric gas ceases practically at the end of this period of time and all of the solid product contained in the mixture has dissolved. The still hot solution is filtered.

   On cooling, 139 g of solid white product separated from the filtrate which
 EMI16.7
 consists of alpha-dichloroacetylamino-4-ethyl-mercaptoacebophenone having the formula:
 EMI16.8
 This product melts at 127.6C-128.8 C after recrystallization from ethylene chloride. An additional 66 g of product is recovered by evaporating the filtrate to a volume of 600 cm3, cooled and the product collected. solid that separates within the solition.
 EMI16.9
 



  C.- A1ha "" dich1oroacetylamino = beta "" bydroX'f = 4 = eth: v: lmercatopropiophenoneo
A mixture of 200 g of alpha-dichloro = acetylamino-4-ethylmercaptoacetophenone, 100 cm3 of formalin (37% aqueous formaldehyde solution) is stirred. 1600 cm3 of ethanol and 10 g of sodium bicarbonate for 10 hours at 40-50 C. The mixture is left to stand at room temperature for about 15 hours, then cooled to 10 C. The mixture is combined on a filter. the solid product which separates from the cooled solution is washed with 150 cm3 of ethanol and dried.

   We obtain a; ipsi 204 G of alpha-dichloroaceous
 EMI16.10
 ty1amine = beta-hydroXY = 4-ethylmercaptopropiophenone having the formula

 <Desc / Clms Page number 17>

 
 EMI17.1
 product which melts at 150 - 152 C. After recrystallization from ethylene chloride, small white sheets are obtained which melt in the pure state
 EMI17.2
 at 153, 2 - 1540e3 Co om 2omDich'oroa:; ét lamino. = méth lmerea to hén i ml pr J; 1anediolo A mixture of 140 g of alpha-dichloroacetylamino-beta-hydroxy-4- is slowly distilled for 15 hours ethylmercaptopropiophenones 400 g of aluminum sopropoxide, and 1500 cm3 of isopropanol. The excess isopropanol is removed by distillation under reduced pressure.

   2 liters of water containing 200 g of sodium chloride are added to the viscous red residue and the mixture is heated for about 30 minutes on a steam bath. The mixture was filtered while still hot and the filter cake washed thoroughly with several 200 cc portions of ethyl ether. The dark red ethereal layer was separated from the filtrate, dried over anhydrous calcium sulfate and the ether was evaporated off. A residue of 128 g of red oil was thus obtained. This oil is taken up in 400 cm 3 of benzene and the hot solution is filtered in the presence of animal charcoal. Cooling the filtrate gives 84 g of a solid white product which separates from the solution.

   Recrystallization of this product from 300 cm3 of ethylene chloride gives 73 g of 2-cichloro-
 EMI17.3
 acetylaminol4dethylmercaptophenl) 1,3 = pure propanediol, having the formula;
 EMI17.4
 product which melts at 92.4 = 93 4 Co
 EMI17.5
 E.- 2mDicha.oroacet laminom.m eth lsozlfon 1 hén? 22 cc of peracetic acid at 10 ml are added dropwise to a stirred solution of 115 g of 2-dichloroacetylainino-l '- (4-ethyl mercapto-pehnljml9: propanediol dissolved in 50 cm3 of acetone. the vessel with ice and the rate of addition of peracetic acid is adjusted so that the temperature of the reaction mixture does not exceed 40 ° C.

   After the completion of the addition of the peracetic acid, the reaction mixture is stirred for one hour and then cooled to -5 ° C. The solid product which separates from the solution is combined on a filter and then cooled to -5 ° C. Wash it with twice 20 cm3 of cold acetone. We thus obtain
 EMI17.6
 17.5 g of 2-dochloroacetylamino-l- (4-ethylsulfonylphenyl) - '13-propanediol in the form of a solid white product which melts at 184 0 = 185.0 C and a la. formula -   @
 EMI17.7
 EXAMPLE 6.
 EMI17.8
 AT.

   Alpha = arîf.in.o.:; "4n = promr1meroaptoacetophenone (hydrochloride)
A suspension of 226 g of aluminum chloride in one liter of dry chloroform is placed in a 3 liter three-necked flask fitted with a stirrer, a drying tube, an introduction funnel and a thermometer. The suspension is stirred and cooled to 5 ° C., with stirring, then 145 g of acetyl chloride are added. This is then added dropwise.
 EMI17.9
 at 5 C 235, 5 g of n = propyi = phenyLmstg.if e o - The reaction mixture is stirred

 <Desc / Clms Page number 18>

 for 15 minutes after the addition of the sulfide, then poured into 1.5 kg of ice containing 25 cm3 of concentrated hydrochloric acid. The chloroform layer is separated from the mixture and the chloroform is distilled off from the solution.

   The residual oil is fractionated by distillation and the fraction which passes to 2070 C under 45-48 mm of mercury is combined. This gives 253 g of a colorless oil which solidifies on standing. This product is constituted by
 EMI18.1
 killed by 4-D-propylmereaptoacetophenone having the formula:
 EMI18.2
 and melts at 37.7 - 39.1 C.



   208 g of bromine is added to a solution of 254 g of 4-n-propyl-mercaptoacetophenone in 2 liters of chloroform. After 5 or 10 minutes, the evolution of hydrobromic gas from the reaction mixture has practically ceased and the mixture is then washed. with 2 liters of aqueous sodium bicarbonate solution containing ice. The chloroform layer is separated from the mixture and the chloroform is removed from the chloroform solution by distillation under reduced pressure. In this way, 300 g of alpha-
 EMI18.3
 bromo-4-n-propyl-mercaptoacetophenone having the formula:
 EMI18.4
 in the form of an orange oil which is used directly in the next phase of the process.

   Crystallization of a sample of this product from petroleum ether gives a white solid product which melts at approximately 43 ° C.
95 g of hexamethylenetetramine are added with stirring to a so-
 EMI18.5
 lution of 176 g of alpha brarn.o 4 nproprlmercaptoacetophenone dissolved in 850 cm3 of acetonitrileo The temperature of the reaction mixture rises from 28 to 42 C and a pale yellow solid product separates. After stirring the mixture for 2 hours, the solid product is combined on a filter; washed twice with 150 cm3 of acetonitrile and with 300 cm3 of water, then dried.



  In the form of a pale yellow solid product, 174 g of the product are thus obtained.
 EMI18.6
 addition alpha = brom () <=> 4 = n = propylmercaptoacetophenone-hexametbylenetetramine having the formula:
 EMI18.7
 which melts at about 135 C (with ** composition).
 EMI18.8
 



  92 g of the alpha-bromo-4-n-propylmer-captoacetophenone-hexametii. 71st, ne-lu-etramine adduct are mixed with a solution of 90 cm3 of concentrated hydrochloric acid and 225 cm3 of methanol; the mixture is stirred and refluxed for 30 minutes. At first the mixture turns dark red and after about 10 minutes it separates ammonium chloride in the solution. The ammonium chloride is removed by filtration and the filtrate is cooled to -5 ° C. The solid product which separates from the cooled solution is collected on a filter and dissolved in 125 cm3 of hot water.



  The aqueous solution is cooled to 0 ° C. and the solid product which separates from the solution is collected on a filter. In this way 27 g of chlorhy-
 EMI18.9
 alpha-amino-4 - n-propylmercaptoacetophenone drate having the formula:
 EMI18.10
 product which melts at about 1550 C (with decomposition).

 <Desc / Clms Page number 19>

 
 EMI19.1
 



  B. = Alhaichloroacetylamino = 4 = nrop.v1mercapoacetophenone.



  27 g of alpha-amino-4-D-propymeroàpto-ketophenone hydrochloride are added to 500 cm 3 of benzene and the resulting mixture is refluxed until no more water is distilled off in a separator. water. We add '.
 EMI19.2
 then 41 g of dichloroacetyl chloride and the mixture stirred with heating under reflux for 30 minutes. Meanwhile; all of the ketamine dissolves. The reaction mixture obtained is concentrated under reduced pressure and the residue thus obtained is cooled. The solid product which separates from the cooled solution is collected on a filter; it is washed with 5 cc of benzene and dried.

   In this way 16.5 g of alpha-dichloroa-
 EMI19.3
 netylamino-4-n-propylmercaptoacetophenone having the formula:
 EMI19.4
 product which, after recrystallization from benzene, forms a white solid which melts at 123.2 - 123.8 C.
 EMI19.5
 



  Q "rp.Jpha = dichlo9acéty1no = beta = h1dro = 4 = n = propY1mercaptoacetophenone.



  Stirred for 4 hours at .0 43 C a mixture of 13, g of a1-pha = dichloroacetylamino = 4 = n = propylmercaptoacetophenone, 100 cm3 of ethanol and 8 cm3 of formalin (37% aqueous solution of formaldehyde) containing 0.8 g of dissolved sodium bicarbonate. The reaction mixture is then cooled and the solid product which separates from this mixture is collected on a filter.
 EMI19.6
 solution. In this way 12.5 g of alpha = dichloroacétylamino-beta-hydroxy-4-n-proRylmeroaptoacétophénoney having the formula are obtained:
 EMI19.7
 After recrystallization from ethylene chloride, this product gives 10 g of compound in the pure state which melts at 133.4 - 136.8 C.
 EMI19.8
 



  D.- 2mdichloroacet iaminomla nm ro lmerea to hén I I o anediol A mixture of 9 g of alpha-dieh2oroacéfiiar..noebetamhrdroxt4 is slowly distilled for 3 hours. nmproplmercaptopropiophéxïone, 20 g of aluminum isopropoxide and 200 cm3 of dry isopropanol. Isopropanol remaining in the reaction mixture is removed by distillation under reduced pressure. The brown pasty residue obtained is heated with 200 cm3 of saturated sodium chloride solution, then filtered. The residual aluminum hydroxide is washed several times on a filter with ether. The residual ethereal layer is separated with ether. The ethereal layer is separated from the filtrate and dried over anhydrous calcium sulfate. The ether is then removed from the ethereal solution by evaporation under reduced pressure.

   The dark amber oil is taken up, which is obtained in 100 cm3 of hot benzene; it is filtered in the presence of animal charcoal and the filtrate is diluted with petroleum ether to the point where a permanent cloudiness forms. On standing, it separates from the solution 4 g of solid product which is recrystallized in -benzene, then in ethylene chloride. The product thus obtained which
 EMI19.9
 is 2mdzchloroacetylamino7m (l, .nproprlpercaptophénrl) l, 3mpropanediol ,, having the formula:
 EMI19.10
 bottom at 91, 8 - 94, 8 c.

 <Desc / Clms Page number 20>

 
 EMI20.1
 



  Eo # dichl.oroac't Iaminomh dnm ro lsulfon. hén I 1. m ro anedioia 2 g of 2-dichloroacetylamino-l- (4-n-propyliae: catophenyl) L, 3mpropanedio7 are dissolved. in 6 cm3 of acetone and to this solution is added 2 cm3 of 40% peracetic acid while cooling. After stirring the reaction mixture for about 1 1/2 hours, the solid product which separates from the solution is collected on a filter.

   This product, consisting of
 EMI20.2
 2-dichloroacetylamino- (4-n-proçylsulfonylphenyl) -1,3-propanedipl, weighs 1.2 g, melts at 182.9 - 184.5 C and has the following formula:
 EMI20.3
   EXAMPLE 7.
 EMI20.4
 Aa A1 ha amino- n bu imerca toaceto henone This compound is prepared in a manner analogous to that described
 EMI20.5
 in Example 6A above for the preparation of the compound nmprop, ylmereaptc corresponding 250 g of n-butyl-phenyl-sulfide are treated with 133 g of acetyl chloride in the presence of aluminum chloride. We thus obtain 206 g
 EMI20.6
 of 4-n-butylmercaptoacetophenone, having the formula:

   
 EMI20.7
 which boils at 1380 - 140 C under 0.8 mm and melts at 24 - 25 C after crystallization
 EMI20.8
 in petroleum ether at 0 ° C. * 110 g of 4-n-butylmercaptoacetophenone dissolved in one liter of chloroform are treated with 80 g of bromine, which gives 168 g of alpha-brcno-4-n-butylmercaptoacetophenone , having the formula:
 EMI20.9
 This compound is recrystallized from petroleum ether, which gives large colorless crystals which melt at about 63 ° C.

   60 g of alpha-bramo-
 EMI20.10
 4-n-bu'tyl mercaptoacetophenone in 300 cm3 of acetonitrile and treated with 30 g of hexamethylenetetramine, which gives 88 g of the adduct alpha-brcmo-4-m-butylmercapto-acetophenone-hexamethylenetetramine having the formula :
 EMI20.11
 which melts at about 113 C (with decomposition).



   A mixture of 86 g of the product is stirred for about 10 hours.
 EMI20.12
 addition of alµha-brcmo-4-n-butyl-mercaptoacetophenone-hexamethylenetoo tramine, 85 cm3 of concentrated hydrochloric acid and 170 cm3 of ethanol.



  Ammonium chloride which separates from this mixture as a solid white product is filtered off and discarded. After partial evaporation at room temperature under reduced pressure, the filtrate gives 13.5 g of a pale yellow solid which melts at 140-145 C (with decomposition). The volume of the filtrate resulting from this solid product was reduced by evaporation and a further 35 g of product was obtained as a brown, gummy solid product. This solid product gum = is suspended in 50 cm3 of acetone; The solution was cooled in an ice-methanol bath and the solid product which separated from the cooled solution was collected on a filter, then washed several times with cooled acetone. In this way 26.5 g of a yellow-brown solid product is obtained which melts at 140 - 145 C (with decomposition).

   The two portions of product melting at 140 - 145 C are combined

 <Desc / Clms Page number 21>

 and the 40 g of product are recrystallized in 100 cm3 of water containing 3 cm3 of concentrated hydrochloric acid.This gives 32.5 g of alpha-amino-4-n-butylmercaptoacetophenone hydrochloride having the formula:
 EMI21.1
 in the form of white fluffy crystals. A sample of this product, recrystallized from ethanol and then from water acidulated with hydrochloric acid gives the pure compound which melts at 175.5-179.30 (with decomposition).
 EMI21.2
 



  Be AlDha-dichloroacetylamino-.4-n-bu t: Vlmerca: pt, o, acetophenone.



  Stirred and heated for 15 minutes on a steam bath a mixture of 27 g of dry hydrochloride alpha-alin-4-n-bnlçyknercaptoacetophenone, 125 om3 of anhydrous benzene and 15 cm3 of dichloro chloride. acetyl. The reaction mixture is then cooled and the solid product which separates from the solution is collected on a filter. In this way 30.6 g of alpha-dichloroacetylamino-4-n-butylmercaptoacetophenone having the formula:
 EMI21.3
 Recrystallization of this product from benzene gives light white needles which melt at 127.4 - 128 C with slump at 120.2 C.
 EMI21.4
 



  C. Al) ha-dichlQroacé lamino-beta-hvdroxv-4-m-butvlmercaDtoDroDioDh * enonee A mixture of 47.5 g of alpha-dichloroacetylamino-4-n-bntylmercaptoacetophenone is heated at 40-45 C for 4 hours , 300 cm3 of ethanol and 2 g of sodium bicarbonate dissolved in 24 cm3 of formalin (37% aqueous solution of formaldehyde). The paste is cooled to 10 ° C., filtered and the solid residue washed with 40 cm3 of methanol, then dried. We obtain
 EMI21.5
 thus 41 g of alpha-dichloroac ethylamino-beta-h.vdroxy-L-n-butylmercaptopropiophenone having the formula:
 EMI21.6
 product which, recrystallized from benzene, forms small white crystals with a melting point of 123.0 - 123.8 C.
 EMI21.7
 



  Do- 2mdichloroacéi lam.inoml n but lmerca to hén 1 m1 ro anedioie A mixture of 35 g of alpha-dich10roacéty1amino-beta = bydroXY = 4-n-butylm.ercaptopropiophenone is slowly distilled over 15 hours; of 65 g of aluminum isopropoxide and one liter of dry isopropanol. The excess isopropanol is removed from the reaction mixture by evaporation under reduced pressure and the reddish residue thus obtained is heated for 30 minutes with 400 cm3 of water containing 40 g of sodium chloride. The aluminum hydroxide which separates from the solution is filtered off and the filter cake is washed thoroughly with ethero. The reddish ethereal layer is separated from the filtrate, dried over anhydrous calcium sulfate and dissolved. removing the ether from the ethereal solution by evaporation under reduced pressure.

   The viscous, light red oily redisu thus obtained is taken up in 120 cm 3 of benzene, it is filtered through animal charcoal and the filtrate is cooled. 11 separates from
 EMI21.8
 this filtrate 14 g of 2-dichloro-acetylamino-1- (4-n-butylmercaptophenyl) -1,3-pro- panediol, having the formula. :

 <Desc / Clms Page number 22>

 
 EMI22.1
 product which is recrystallized from benzene and then from ethyl chloride
 EMI22.2
 lene, resulting in a white waxy solid which melts at $ 5.5fl.¯ $ 7.0 C.



  E. - 2dichloroac 'Lami.n mh nmbut .sulfo 1 hén II o anediola 3.5 g of 2-dichloroacetylamino-l- (4-n'-butylmer- "captophenyl) -1,3-propanediol are dissolved in 10 cm3 acetone and 4 cc of 40% peracetic acid are added to this solution with cooling. This mixture is cooled after stirring for 1 hour at -10 C. The solid product which separates out is collected. this solution on a filtered We thus obtain 2.5 g of
 EMI22.3
 2mdiehloroaceous-tyLami.nomlm (l = n ^ 'butylsu.fonylphenyl) 1,3mrepanediol as a pure white solid which melts at 131.6 - 132.8 C. An additional 1 g of product can be removed. by evaporation of the filtrate. This product has the formula:
 EMI22.4
 EXAMPLE $
 EMI22.5
 AT.

   A1pha-amin-benzy1mercaptoacetophenone = ch10rhdrateo
340 g of benzyl-phenyl-sulfide are dissolved in 1200 cm3 of anhydrous chloroform and 120 cm3 of acetyl chloride are added to this solution.



  The resulting mixture is cooled to -10 ° C. and 226 g of aluminum chloride are added in portions at a rate such that the temperature of the reaction mixture does not exceed 0 C. After the addition of the chloride is complete. The mixture is stirred and allowed to warm to 21 ° C. The mixture is then poured into ice water. The red chloroform layer is separated from the aqueous layer, washed with 300 cm3 of dilute hydrochloric acid and dried over anhydrous calcium sulfate. The chloroform is then evaporated from the chloroform solution. This oil is dissolved in 1200 cm3 of petroleum ether and the solution obtained is filtered hot on animal charcoal. The filtrate is cooled in an ice bath. 154 g of a yellow solid separated from the cooled solution.

   This product is recrystallized twice from ethanol and once from petroleum ether. In this way, in the form of fine white needles, which melts at 113.9 - 115.3 0, 4-benzylmercaptoacetophenone is obtained, having the formula:
 EMI22.6
 
 EMI22.7
 95 g of this 4 benylmercaptoace-Gophenone are dissolved in one liter of chloroform and this solution is treated with 62.5 g of bromine using a method analogous to the bromination already described in Example 1A.

   
 EMI22.8
 56 g of hexamethylenetetramine are added to the alpha-bromo-4-benzyl-mercaptoacetophenone solution thus obtained, and the mixture is stirred for two hours. The pinkish white product which separates on a filter is combined and the mixture is stirred. washes it with 200 cm3 of chloroform The crude product obtained, which is the product
 EMI22.9
 alpha-bromo-4-benzylmercaptoaceous * toplienone-hexamethylenetetrmin addition has the formula:

 <Desc / Clms Page number 23>

 
 EMI23.1
 product which is hydrolyzed directly by stirring for about 10 hours at room temperature (about 25 ° C.) with 180 cm3 of concentrated hydrochloric acid and 360 cm3 of ethanol. The reaction mixture is then cooled to 10 ° C. The solid product is collected on a filter and dried.



  145 g of crude reaction product are thus obtained. The aluminum chloride is removed from this product by impregnating it with 400 cm3 of hot water for 10 minutes, then cooling this solution thus cooled. This product is further purified by recrystallization from water containing a small amount of hydrochloric acid. This gives alpha-amino-4- hydrochloride.
 EMI23.2
 benz, vlmercaptoaceous: tophenone having the formula:
 EMI23.3
 in the form of white sheets which melt at 214.5 ... 216.5 C (with decomposition).
 EMI23.4
 



  .-A1nha-acetxlamino-4-benzxcatoacetophenone.



  52 g of alpha-amino-4-benzylmercaptoacetophenone (hydrochloride), 250 cm3 of water and 500 g of ice, 40 cm3 of acetic anhydride are added to a paste and then immediately after a solution of 60 g of sodium acetate trihydrate in 250 cm3 of water. The reaction mixture is stirred and allowed to warm to room temperature (about 25 ° C), then made acidic in Congo Red by adding hydrochloric acid. The solid product is filtered off from the mixture, washed with water, and dried.

   A small sample of this product is purified by recrystallization.
 EMI23.5
 in acetone; we thus obtain alpha-acetylamino-4-benzylmercaptoacetophenone, having the formula:
 EMI23.6
 in the form of white needles which melt at 162.6 - 163.8 C.
 EMI23.7
 Ca A1: pha-acetylamino-beta-hydroXY'-9: -benzy: lmercaptopro: Riophenone.



   The crude product obtained according to B is impasted and heated to 40 ° C. with 3.5 liters of ethanol. 45 cm3 of formalin) (37% aqueous formaldehyde solution) and 4 g of sodium bicarbonate are added to this mixture.



  Stirring of the reaction mixture is continued at 40 ° C. for 24 hours. The sodium bicarbonate suspension is filtered off from this solution and the filtrate is evaporated to a volume of about 100 cm 3, diluted with water and the solid white product which separates from the solution is collected on a filter. this solution. 49 g of a pale yellow solid product are thus obtained.



  This product is recrystallized once from ethylene chloride and once
 EMI23.8
 in nitroethane. We thus obtain alpha-acetyl-amino-beta-hydroxy-4-benzylmercaptopropiophenone, having the formula:
 EMI23.9
 which melts at approximately 1610 C.
 EMI23.10
 . Do - 2-acet lam.i.n 1 ben Zm.erca to hei 1 ,, - .. urQpanediol A mixture of 23 g of alpha-acetylamino-be- is refluxed.

 <Desc / Clms Page number 24>

 
 EMI24.1
 ta 4 benlmercaptopropiophénoe9 of 30 g of isopropoiwde dyaluminum and one liter of dry isopropanol for 18 hours.

   During this time, the iL sopropanol and the acethne are allowed to slowly distill from the reaction mixture. The remaining isopropanol is then distilled off under reduced pressure and the red residue is heated for 30 minutes with about. 200 cm3 of a 5% aqueous solution of sodium chloride on a water bath. The mixture is filtered and the residue thus collected is heated with 200 cm3 of ethylene chloride. The still hot mixture is filtered to remove aluminum hydroxide and the filtrate is cooled. 11 g of solid product separated from this cooled filtrate.

   This solid product is collected and purified by recrystallization first from nitroethane then from isopropanol and finally again from nitroethane.
 EMI24.2
 white sheets which melt at 157, o ± 158, o C, 2-acetylamino-l- (4- 'benzylmercaptophenyl) -1.3 propanediol, having the formula:
 EMI24.3
 
 EMI24.4
 En- 2 Acet laminoml benzvLsüïfon 1.1, - ro anediaïo 0.6 g of 2-acetylamino-1 ((4-benzylmercap- tophenyl) -1,3-propanediol in 3 cm3 of acetone is added to a paste ( at 20 ° C.) 2 cm3 of 40% peracetic acid at one time The temperature of this mixture rises to 55 ° C. and the solution becomes clear to give rise, in general immediately, to the separation of a solid product. .

   The mixture is stirred for a further 30 minutes, then cooled to 10 ° C. The solid product is collected on a filter and washed with three times 2 cm3 of acetone. 0.6 g of a solid white product is thus obtained. The recrystallization of this solid product in 70
 EMI24.5
 cm3 of nitroethane gives small white sheets of 2-acetylamino-1- (4- benzylsulfonylphenyl) -1,3-propanediol, which melt at 222.9 - 223.9 C and correspond to the formula:
 EMI24.6
 EXAMPLE 9.
 EMI24.7
 



  A.- 2diehloroacé lam.ino1 = .mbenz imerca to hén 1 1 m ro anediola 12 g of alpha-amino hydrochloride = 4-benzyJ.mercaptoacetophenone (obtained as described above under example) is heated under reflux for 7 hours. 7A), 8 g of dichloroacetyl chloride and 500 cm3 of dry benzene. The hot solution is then filtered, 5 g of solid residue is collected on a filter and from the benzene filtrate is removed by cooling an additional 8 g of the same product which is constituted by
 EMI24.8
 alpha-dichloroacetylamino-4-benzylmercaptoacetophenone, having the formula
 EMI24.9
 After purification by recrystallization, first in ethylene chloride and then in nitroethane, this product melts at 185.6 - 186.4 C.



   By proceeding as indicated in the examples above,
 EMI24.10
 The hydroxymethylation of alpha-dichloroacetylsmino-4-benzylmercaptoacetophenone by treatment with formaldehyde in the presence of an alkaline condensation catalyst gives a1.pha = dichloroacetylamino-beta = hydroXY-4-benzylmer- captophenylacetophenone , having the formula:

   

 <Desc / Clms Page number 25>

 
 EMI25.1
 The reduction of this compound with aluminum isopropoxide at
 EMI25.2
 within isopropanol gives 2-dichloroacetylamirio-l - = (4 -t) enzylmeroaptophéayl) -13 "'propanediolo 0 2 = dichloroact laminom mt benz lsxlfon 1 hénvl Z o anedioln-¯ When replacing 2- acetylamino-'l "(4-'beDzylmercaptopheayl), 1,3-propanediol used as a reactive agent in the oxidation process described in Example 8E by 2d.ichloroacétviam: ino1 (l ,. benzyi.mercaptophenyl} m 1, 3-propanediol, the final product is 2-dichloro-acetylamino-1- (4-benzylsulònylphenyl) -1,3-propanediolo EXAMPLE 100 2-dichloroac'étvlino-1 - '(, A - ohênvlsulfo = lphenyl) -l, âzUroDanediol.
 EMI25.3
 
 EMI25.4
 



  Ao = alpha = amino = 4 = "Qhen: vlmercaptoaoetophenone (hydrochloride).



  Stirred and cooled to 5 ° C a mixture of 190 g of diphe-
 EMI25.5
 nrlmsu'1 fure, 146 g of aluminum chloride and one liter of anhydrous chloroform. 80 g of acetyl chloride are added slowly to this mixture while maintaining its temperature, between -5 C and + 5 C. When all of the dacetyl chloride is added, stirring is continued for one hour while allowing the reaction mixture to warm slowly to room temperature. The mixture is then poured into ice water. The chloroform layer is separated from the mixture and the chloroform is removed from the chloroform solution by distillation under reduced pressure. The residue thus obtained is dissolved in a hot mixture of 150 cm3 of benzene and 150 cm3 of petroleum ether.

   After cooling the solution, 158 g of 4-phenylmercaptoacetophenone having the formula:
 EMI25.6
 this product melting at approximately 66 c.



     A solution of 53 g of 4-phenylmercaptoacetophenone in 500 cm3 of chloroform is treated with 36 g of bromine at room temperature.



  After completion of the bromination and removal of excess bromide gas from the reaction mixture, a sufficient amount of aqueous sodium bicarbonate solution is added to make the mixture alkaline to sunflower.



  The chloroform layer is separated and distilled under reduced pressure to remove the chloroform therefrom. In this way, in the form of an oil, 69 g is obtained
 EMI25.7
 crude alpha-bromo-4-phenylmercaptoacetophenone, having the formula:
 EMI25.8
 These 69 g of oil are dissolved in 400 cm3 of acetonitrile and
 EMI25.9
 32.6 g of hexamethylenetetramine are added to the solution. The mixture was stirred for 30 minutes and the creamy white solid was collected on

 <Desc / Clms Page number 26>

 
 EMI26.1
 a filter. In this way 100 g of the crude aljha-bromo-4-phemylmercaptoacetophenone-hexanethyl] 2etetramine adduct is obtained, having the formula:
 EMI26.2
 which melts with decomposition at around 206 C.

   This product is stirred and heated on a water bath for 15 minutes with 250 cm3 of ethanol and 120 cm3 of concentrated hydrochloric acid. The aluminum chloride which separates from the mixture is removed by filtration and the filtrate is left to stand. for several hours at room temperature o The white solid product which separates from the solution is collected on a filter, dissolved in hot anhydrous ethanol, filtered hot in the presence of animal charcoal and the filtrate cooled .

   It thus separates from the cooled solution 22 g
 EMI26.3
 alpha-xmino-4-phenylmercaptoacetophenone hydrochloride, having the formula:
 EMI26.4
 product which melts at 216.7 - 217.0 C (with decomposition)
 EMI26.5
 Ba alppa-dichloroactvlamino4-phenYlmercaptoacetophenoneo A mixture of 22 g of alpha-amino-4-phenylmercaptoacetophenone hydrochloride, 37 g of dichloroacetyl chloride and 150 cm3 of dry benzene is heated under reflux for 30 minutes. The still hot reaction mixture is then filtered. It separates 12 g of alpha-dichloroaceous
 EMI26.6
 tyl-amino-4-phenylmercaDtoa.cetophenone from the filtrate by cooling. This product melts at 13.5 m 19, 'Co C 0- al: p "ha-dichloroactylamino-beta = hydroxy: ,, 4-: phenylmerca: ptoprop" iophen9n.e.



  Stirred and heated for one hour at 40 C a mixture of 17 g of alpha-dichloroacetylamino-4-phenylmercaptoacetophenone, 125 cm3 of ethanol, 10 cm3 of formalin (37% aqueous solution of formaldehyde) and 1 g of sodium bicarbonate, then this mixture is left to stand for several hours at room temperature (25 C) a The mixture is then warmed to 40 C, it is filtered to remove the sodium bicarbonate and the filtrate is cooled. separated from the cooled filtrate. 1 g of solid product.

   This product is recrystallized from ethylene chloride to give 10.5 g of alpha-dichloroacetylamino-beta-hydroxy-4-phenylmercaptoacetophenone, having the formula:
 EMI26.7
 product which melts at 128.5 - 129.5 C.
 EMI26.8
 i3 2dichlor ac am.nomlm mh 'erca to hén 1 ml ro anediolo A mixture of 10 g of alpha-dichloroacetylmino-beta-hydroxy-4-phenyl-mercaptopropiophenone, 20.4 g of aluminum isopropoxide and 100 cm3 of dry isopropanol. The excess isopropanol is then removed by distillation under reduced pressure and the residue is heated for 30 minutes with 100 cm3 of 15% aqueous sodium chloride solution.

   The aluminum oxide which separates from the mixture is combined on a filter, and washed thoroughly with ethero The aqueous filtrate is also extracted with ether, the washings and the ethereal extracts are combined, then they are dried over anhydrous calcium sulfate. The ether of the filtrate is distilled off under reduced pressure. In this way 5.0 g of 2-dichloroacéty-
 EMI26.9
 amino- (4-phenylmeroaptophenyl) -1, 3-propanediol, having the formula:

 <Desc / Clms Page number 27>

 
 EMI27.1
 
 EMI27.2
 in the form of a red oil.
 EMI27.3
 dl'th This oil is dissolved in about 40 cm3 of dichloride
 EMI27.4
 ethylene, the solution is treated with animal charcoal and filtered.

   The filtrate is cooled for several hours and the solid product which separates from the solution twice is recrystallized from ethylene bichloride.
 EMI27.5
 



  4 g of 2-dichloroacetylanino-1- (4-phenylmercaptophenyl) -1,3-proanedioi are thus obtained. which melts at 90.60 - 97., 40 On E 2 diohioroacet .amino. ohén ïsuifon i hénrl.,) aix .roPānedïo.o Ooeydation of 2-dichloroacetylamino-l- (4-phenylmercaptophenyl)
 EMI27.6
 -1,3-propaned.iol with peracetic acid analogously to the methods
 EMI27.7
 oxidation already described in the examples above gives 2-dichloroaeéty- lamino. = (4 phenisz.fonviplénr ..) ,, 3 propaaaedio., before the formula:

   
 EMI27.8
 
 EMI27.9
 12.7 g of 2 dfichlroacetylaznino 1.m (f phenyl mereaptophenyl) -1,3-propanediol are thus suspended in 125 cm3 of water and one adds to this suspension.
 EMI27.10
 16.3 cm3 of 40% peracetic acid, the solid product obtained by this reaction is recrystallized twice from nitroethane using
 EMI27.11
 animal black. There is thus obtained g, 5 g of 2-dichloroacetylamino-l- (4-phenyl-su.fony: Lphenyl) =., 3propanediol qc.i melts at 124; 9 - 127.3 C.
 EMI27.12
 



  By using the procedures in accordance with the prescriptions of the above examples, the following compounds can be further prepared as well as the corresponding mercapto compounds:
 EMI27.13
 2-Iodoacetyî-1- ln = (mtoïy.sulfony7 ..) pheny3.,% -1,3-propadediol, by oxidizing 2-iodoa'3etyl = 1- (4 = (p = tolylmercapto) phenyl) = 1,3-propanediol, which is prepared in hydroxymethylaat i. ' alpha iodoacetriamino4m (pmtoxylm mercapto) -acetophenone and reducing the alpha-iodoacetylamino-beta-hydrox¯v4- (p-tolylmet'capto) -propiophenone thus obtained.



  2-beta-chloropropionylamino-l - '(4' 'ccyolohexyl- = sulfo'aylphenyl) -1,3-propanediol, by oxidizing 2-beta-chloropropionylamino-l- (4-cyclahexyl mercaptophényi) 1,3propanediol that l 'is prepared by hydroxymethylating alpha-beta chloropropïony3.amino) lmcyc.ohexr7x.ere.pto acetophenone and reducing alpha-beta-chloropropionylanino) -beta-hydroxy-4-eyclohezybaercaptopropiophé
 EMI27.14
 none thus obtained.
 EMI27.15
 



  2 acetlaminom: i (/ métya..ylsulfonylphény3) 1,3propanediol, by oxidizing 2acétylanïnoml (.néhay.m.ercaptophénvw) 1,3propaned.ol., Which is prepared by l1ydroxyméthy1.ant alpha = acetylamino- 4 = methallylmercaptoacetophenone and reducing alpha = acetylamine = beta-hydroxy-4 = methallylmer-
 EMI27.16
 captopropiophenone thus obtained
 EMI27.17
 2-triiluoroacetylanino-1- (4-methallylsulionylphenyl) -1,3-propanediol, by oxidizing 2-trifluoroacetylanino-1- (4> + 1ethallylmercaptophenyl) - 1,3-propgnediol which is prepared by reacting the trifluoroacetate ethy- le with mam.noml (4.étha.ly3raercaptophenyl) ï., 3mpropanedioi that we obtain
 EMI27.18
 holds by deacylating the corresponding 2-acetyl-amino compound.
 EMI27.19
 



  2 (alphan.ethylpropionylamino) l (.ïsabztylsulfoxtlpheny.) M 1,3-propanediol, oxidizing 2 = (a.phanethylpropionylam.ino; l (,. Misobutylraer eaptophenyl) -1,3-propanediol, prepared by reacting 2aminoi (1-ISO b.aiylmercaptophé; yl) -1,3-propanediol with alpha-methylpropionyl chloride.

 <Desc / Clms Page number 28>

 
 EMI28.1
 



  Finally, (a.Ipha betadichloroprogiy3ninmlm (fmtèrt bû.tyï- sulfonylphenyl) -1,3-propanediol, by oxidizing 2- (alpha-beta-dichloropropionylamino) mi.m (l-terto butylrnercaptophêny.) I., 3mpropanediol, which is prepared by hydroxymethylating alpha- (alpha = beta-dichloropropionylanino) -4-tertobutyl- mercaptoacetophenone and reducing alpha (a7.pha beta-dich2oropropionvla- mino) -beta-hydroxq-4-terto -butyInercaptopropiophenone thus obtained.



  The racemic and dextrorotatory forms of the carboWacylamino-1- (l hxrdronarbonylmsulfonyiphênrï) I, 3prapauedio.s (2-aliphatic) in accordance with the invention exhibit particularly high antibiotic activity against Gram-negative and Gram-positive bacteria as well. that organizations from Rickettsieso
In general, the dextrorotatory form is more active than the racemic form. In some cases, the dextrorotatory form has anti-bacterial activity twice as strong as that of the racemic form.



    CLAIMS.
 EMI28.2
 



  1. Process for preparing acyleminodiol compounds, in which a compound is reduced before the following formula (III):
 EMI28.3
 in order to obtain a compound having the following formula (Ia):
 EMI28.4



    

Claims (1)

2. The method of claim 1, wherein the compound having the formula (III) is treated with an oxidizable lower aluminum alkoxide. 3. A method according to either of the claims. 1 and 2, wherein in the above formulas Y represents a haloalka- group. EMI28.5 Noylamino, for example the dichl.oroacétIam.inoo group A process according to either of claims 1 and 2, wherein alpha-dichloro-acetylanino-beta-hyàroKy-4-methylmer-captopropiophenone is treated with ' aluminum isopropoxide in isopropanol to obtain 2mdichloroacâtylaminolm (lnethrlmercaptophenl) l, 3mpropanediola 5. Process according to any one of the preceding claims, in which the starting compound is prepared before the formula (III) by hydroxymethylation of a compound having the following formula (II): EMI28.6 6. A process according to claim 5, wherein the compound having the formula (II) is treated with formaldehyde in the presence of a small amount of sodium bicarbonate. 7. Process for preparing acylaminodiol compounds; in which a compound having the following formula (IVa) is acylated: EMI28.7 <Desc / Clms Page number 29> in order to obtain a compound having the following formula (I): EMI29.1 8. A process according to claim 7, wherein the compound having formula (IVa) is treated with an aliphatic carboxylic acylating agent. 9. The process of claim 8, wherein the compound of formula (IVa) is treated with an acylating agent under conditions which allow an amino alcohol to be acylated with nitrogen. The * A method according to either of claims 8 and 9, wherein the acylating agent is a haloalkanoylation agent, such as for example a dichloroacetylating agent. 11. Process according to any one of claims 7 to 10, in which R is an alkyl group, for example a methyl group * 12. A process according to any one of claims 7 to 10, wherein R is phenyl. 13. Process for preparing acylaminodiol compounds, in which a compound having the formula (Ia) is oxidized in order to obtain a compound having the following formube (Ib): EMI29.2 14. The method of claim 13, wherein the compound having formula (Ia) is treated with a peroxide compound in an acidic medium. 15. A method according to either of claims 13 and 14, wherein Y is represented by a haloalkanoylamino group, such as for example the dichloroacetylaminoo group. 16. The following process: Either of claims 13 to 15, wherein R is represented by an alkyl group, for example by a methyl group. 17. A method according to any of claims 13 to 15, wherein R is represented by a carbocyclic aryl group, for example by the phenyl group. 18. A process according to any of claims 13 to 17, in which the compound having the formula (Ia) is treated with an organic peracid, for example with peracetic acid. 19. A process for preparing acylaminodiol compounds, of formula (I), in substance, as described in the examples. 20. Acylamino-diol compounds of formula (I), when they are prepared by the process according to any one of the preceding claims. 21. A process for preparing acylaminophenone compounds, in which a compound having the formula (II) is hydroxymethylene to obtain a compound having the formula (III). 22. The method of claim 22, wherein the compound having formula (II) is treated with formaldehyde in the presence of a small amount of sodium bicarbonate. 23. A process according to either of claims 21 and 22, wherein R is represented by an alkyl group, for example by the methyl group and Y is represented by a haloalkanoylamino group, for example the dichloroacetylamino group. . <Desc / Clms Page number 30> 24. Process for preparing acylaminophenone compounds of formula (III), in substance, as described in the examples. @ 25. Acylamino-phenone compounds of formula (III), when they are prepared by the process according to any one of claims 21-24. 26. A process for the preparation of amino-diol compounds having the formula (IVa) in which a compound having the formula (I) is deacylated or hydrolyzed. 27. The method of claim 26 wherein the compound having formula (I) is treated with a hot mineral acid. 28. A process according to either of claims 26 and 27, wherein R is represented by an alkyl group, for example by a methyl group. 29. Process for the preparation of amino-diol compounds of formula (IVa), in substance, as described in the examples. 30. Amino-diol compounds of formula (IVa), when they are prepared by the process according to any one of claims 26 to 29. 31. Acylamino-diol compound of formula (I). 32. A compound according to claim 31, wherein Y represents a haloalkanoylamino group, for example dichloroacetylamino. 33. A compound according to either of claims 31 and 32 wherein R is an alkyl group; for example methyl, 34. A compound according to either of claims 31 and 32, wherein R is a carbocyclic aryl group, such as phenyl. 35. Acylamino phenone compound of formula (III). 36. Amino-diol compound of formula (IVa). 37. A compound according to claim 36, wherein R is an alkyl group, for example methyl.