BE487375A - - Google Patents

Description

       

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  Amino alcohol derivatives and processes for the preparation thereof.



   This invention relates to organic amino alcohol derivatives and processes for their preparation. More particularly, the invention relates to ketonic amino alcohol compounds having the general formula:
 EMI1.1
 Rl 0 NH-R M-bH-CH20R 'R2 N02 and the preparation of aminodiols having the formula:
 EMI1.2
 RI OH NH-R <| y¯ CH-CH-CH20H 7 - + - / CH-CH-CH2OH R2 N02

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 from these compounds, formulas in which R is a hydrogen atom or an acyl radical, R1 and R2 are the same or different and represent hydrogen, halogen, lower alkyl or lower alkoxy radicals and R 'is hydrogen or an acyl radical.

   The term "acyl" used herein includes lower aliphatic acyl radicals, lower aliphatic acyl radicals substituted with halogens, benzoyl, substituted benzoyl, araliphatic acyl and the like.



   From examination of the above formulas, it emerges that the acyleamidodiols and aminodiols compounds to which the invention relates can exist in structural isomeric as well as optical forms. The term isomer or structural form used herein refers to the cis or trans isomers, i.e. the planar arrangement of the polar groups attached to the two asymmetric carbon atoms. Compounds possessing the structural configuration are those for which the two more strongly polar groups of the groups attached to the two asymmetric carbon atoms lie on the same side of the plane of the two carbon atoms. Conversely, compounds having the trans configuration are those in which the most strongly polar groups are found on opposite sides of the plane of the two carbon atoms.

   For convenience, products having the trans structural form are referred to in the following as "pseudo" form to distinguish them from products having the cis or "regular" structural form.



   As is known, most chemical processes for the preparation of organic compounds which may exist in diasteriomeric forms result in the formation of products containing about equal amounts of the two structural isomers. When it is desired to obtain a diastereoisomer by-

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 In particular, the separation of these mixed products into their two components is often very difficult to achieve and in all cases gives rise to losses and to an increase in cost prices.

   For some inexplicable reasons, the process described below for the conversion of the keto amino alcohol compounds to the aminodiol compounds of the invention results in the production of a mixture containing a much greater proportion of the structural form pseudo aminodiols products than aminodiols having the cis form. In general, there is three to four times as much of the pseudo product in the mixture as there is the corresponding cis product and in the case where the amounts of material used are small, the cis product can be removed, if desired, for. separating the reaction product from the reaction mixture. When large amounts of the starting materials are employed, very simple processing of the reaction mixture product is only necessary to separate it into its components.

   Thus, it appears that the avoidance of the mixture of diastereomers generally encountered in the formation of compounds which may exist as diastereomers is of great importance, because this makes the separation of the mixture of isomers into its components. components much easier to perform and reduce to a minimum the losses characteristic of these separations.



   Due to the difficulty of representing structural differences of aminodiol products by graphical formulas, ordinary structural formulas are used and the following convention is adopted to denote the structural configuration. In cases where the formula is that of a compound specified without any designation of isomeric form being given, the product consists of an unseparated mixture of the two diastereomeric forms. Where a designation is given, the product consists of the particular isomer designated. On the other hand, when the formula is general, that is to say includes

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 more than one particular compound, it represents not only the mixture of diastereomers but also the individual isomer itself.

   Thus, for example, a general formula such as the second formula given above represents any one of the three products consisting of an unseparated mixture of (dl) -pseudo and (dl) -regular aminodiol compounds, the individual isomers (dl) -pseudo) and individual (dl) -regular isomers.



   This convention, applied to particular compounds such as (dl) -l-p-nitrophenyl-2-acetamido-propane-l, 3-diol can be represented by following: When the formula represented is as follows:
 EMI4.1
 0 OH MH-C-CHo N02 y V I IT-i-C-CH3 I N02 CH-CH-CH20H it denotes the mixture of isomers (dl) -pseudo and (dl) -regular.



  However, when a designation such as "(1) -psi" appears below or beside the formula, the designated product is the particular isomer, in this case the pseudo isomer.



   According to the invention, an onega-acylamidoacetophenone derivative containing a nitro group in the phenyl ring is condensed with formaldehyde in the presence of an alkaline condensation catalyst to obtain a ketone compound, having the formula.
 EMI4.2
 



  RI 0 NH-Acyl R2 N02 \ C-CH-CH20H R2 bio2 which can be transformed into the corresponding (dl) -acylamidodiol by reduction with an oxidizable aluminum alkoxide and, if desired, the last product is hydrolyzed to ( dl) -aminodiol free. Alternatively, (d1) -acylmaidoiol can be separated into regular and pseudo diastereomers and each isomer separately hydrolyzed into

 <Desc / Clms Page number 5>

   corresponding aminodiol (dl) -regular or (dl) -pseudo. The ketone compound can also be converted into other organic compounds, such as, for example, an acylamido acyloxy ketone of formula:
 EMI5.1
 Rl¯¯ 0 NH-Acyl, ## C-CH-CH20-acyl by treatment with an acylating agent.

   These transformations can be represented schematically as follows:
 EMI5.2
 R1 0 R2 <\ 2 J> - C-CHNH-acyl R2 NO2 0 1H A Alkaline condensation catalyst Ri 0 NH-acyl 1 acyl Ri 0 il NH-acyl 1 CI¯CH-CH20H ## - ##). "> # C-CH-CH2Q y¯ \ # / y # 'yçle R2 NO2 R2 acyl B (H Rl OH NH-acyl CH-uu-uh2u-n R2 ¯ NO2 CH 20 NH. (HX) 1 OH 1 EH 1 2 & (Hv,) n-1 N- CH-CH-CH20H R2 NO2 formulas in which R1 and R2 have the same meaning as above, HX represents an equivalent of a mineral acid and n is equal to 1 or 2 .



   By performing the condensation designated by A on the

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 above, formaldehyde can be introduced into the reaction mixture in a number of different forms.



  For example, gaseous formaldehyde, aqueous or alcoholic solutions of formaldehyde, paraformaldehyde or other polymers which produce formaldehyde can be used.



   The relative amounts of the two reactants can be varied within rather wide limits, but it is preferable to use an excess of formaldehyde to ensure complete reaction. In general the best results seem to be obtained when about 3 to 5 moles of formaldehyde are used.
 EMI6.1
 per mole of nitro-substituted omega-acylsmidoacetophenone.



   A variety of solvents, alkaline condensation catalysts and reaction conditions can be used in the condensation reaction. As the solvent, water or aqueous or anhydrous lower aliphatic alcohols are particularly advantageous, but wet dialkyl ethers and dioxane-water mixtures can also be employed.

   The alkaline condensation catalysts used in this phase of the invention can be organic bases, inorganic bases or inorganic salts of acidic or pseudo-acidic organic compounds. Some representative types of these catalysts are alkali or alkaline earth metal hydroxides, oxides, carbonates, bi-carbonates and amides; alkali metal alkoxides; alkaline earth metal alkoxides; alkali metal phenolates; alkali metal salts of lower aliphatic carboxylic acids; organic tertiary amines and quaternary ammonium hydroxides of organic tertiary amines.

   In general, mildly alkaline catalysts are preferred such as sodium bicarbonate, potassium bicarbonate, calcium hydroxide, pyridine, triethylamine, N-ethyl morpholine, N, N-dimethyl-

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 aniline and analogous compounds because they make it easier to control the reaction.

   When employing strongly alkaline catalysts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium methoxide, sodium ethoxide and the like, care should be taken to separate or separate rendering the catalyst inactive as soon as the reaction is complete in order to prevent conversion of the desired product to the corresponding methylene-bis compounds by a dehydration and coupling reaction. Although the amount of catalyst is not critical, and may vary from a few hundredths or thousandths of a mole to one mole or more, it is preferable from the viewpoint of yield to use only what is sufficient to obtain about. a relatively quick reaction. In most cases 0.05 mole or less is sufficient.



   The temperature used to carry out this methylolation reaction, as well as the time required for it to be complete, vary with the catalyst employed. In general, the reaction can be carried out at a temperature between 0 and 75 C in a time varying from a few minutes to several hours. When strongly alkaline catalysts are used, the reaction is very rapid and is usually complete in a few minutes at room temperature or below. However, when moderately alkaline catalysts are employed, the reaction is not as fast and generally takes between 15 minutes and several hours at room temperature or slightly elevated, i.e. at about 25 to 50 ° C. .



   The reduction of α -acylimaid-ss -hydroxypropiophenone to the corresponding (dl) -acylamido glycol compounds, shown at B in the diagram above, is carried out using an oxidizable aluminum alkoxide as reducing agent. The reduction takes place

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 in an organic solvent which usually consists of a lower aliphatic alcohol and, preferably, that corresponding to the alkoxide. The use of secondary alcohol alkoxides such as secondary isopropanol and butanol is preferred because these alkoxides are more readily oxidized and therefore milder reaction conditions can be applied. Tertiary alcohol alkoxides such as tertiary butyl alcohol also give good results.

   In general, the reaction can be carried out within wide temperature limits, but for most purposes a temperature between about 20 and 125 ° C has been found satisfactory. Likewise, the amount of the oxidizable aluminum alkoxide relative to the amount of the ketone compound to be reduced can vary within rather wide limits. In most cases it is seldom necessary to use more than about three equivalents of the akoxide, but if desired, only as little as one equivalent can be used for up to twenty or thirty equivalents. .

   When using an alkoxide derived from a secondary aliphatic alcohol in a solvent consisting of the alcohol corresponding to the alkoxide, the preferred method of carrying out the reaction is to reflux the reaction mixture containing one or more little more than an equivalent of aluminum akoxide, and distilling off the oxidized alcohol, consisting of a lower aliphatic ketone, as it is formed in the reaction mixture.



   In some cases, it is desirable to hydrolyze the products of (dl) -acylamidodiols to the corresponding free (dl) -aminodiols. This transformation, shown at C in the scheme above, can be carried out using either the purified acyl-amidodiol mixture or the crude reaction mixture from the reaction stage as a starting material.

   If desired, the acylamidodiol mixture can first be separated into (dl) -psi-

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 acylamidodiol and (dl) -reg.-acylamidodiol by recrystallization from water, aqueous alcohols or alcohols, and hydrolyzing the individual isomers to (dl) -psi- or (dl) -reg.aminodiols. The reaction can be carried out with either alkaline or acidic reactants or catalysts. Dilute mineral acids such as dilute hydrochloric, hydrobromic, hydriodic, phosphoric and sulfuric acids are the preferred hydrolysis agents because they are more effective in achieving complete hydrolysis in a shorter time with less destruction of the cell. final product.

   When using acidic hydrolysis agents such as the mineral acids mentioned above, the product (dl) -1-nitrophenyl-2-amino-proae-1,3-diol is present in the reaction mixture under as an acid addition salt, and can be separated as such, or the salt can be neutralized and the aminodiol separated as the free base. Among the many alkaline reagents which can be used to effect hydrolysis are the hydroxides of alkali and alkaline earth metals, their oxides, carbonates, amides, a.lkoxides and phenolates; ammonium hydroxides, quaternary and strong tertiary organic nitrogen bases.
 EMI9.1
 



  The transformation of the compounds of Il -acyla.mido-1.3 -hydroxy-propiophenone into corresponding β-acyloxy derivatives, shown in D in the diagram above, can be carried out by treatment of the β-hydroxypropiophenone compound with a. acyl halide or an acyl anhydride under substantially anhydrous conditions, either alone or in the presence of an acylation catalyst such as an organic base, an alkali salt of an organic acid, a tertiary organic base , an aromatic sulfonic acid or sulfuric acid. The acylation can generally be carried out at a temperature varying between about 10 and 140 ° C. but the preferred temperature for the reaction is between about 60 and 120 ° C.

   An inert organic solvent such as benzene, petroleum ether, toluene, or the like can be used to conduct the. reaction if desired, although in the

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 In most cases it is more convenient to dispense with the solvent and use only an excess of the acylating agent. Some of the catalysts which can be used to effect the reaction in less time are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate, pyridine, quinoline. , triethylamine, N-ethyl morpholine, N-methyl piperidine, N, N-dimethylaniline, p-toluene sulfonic acid and sulfuric acid.



   The products of the invention are particularly useful for the synthesis of organic compounds having antibiotic activity. For example, the products obtained in Examples
 EMI10.1
 1, 2 and 7 can be converted into (1) -psi-1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol, a compound which has remarkable and unique antibiotic properties. In addition to their utility in the preparation of antibiotics, certain acylamidodiols prepared by the methods described above are themselves useful in the treatment of diseases.

   For example, the acylamidodiol product of Example 7, (dl) -psi-lp-nitrophenyl-2-dichloracetamidopropane-1,3-diol can be used in the treatment of typhus, rocky mountain spotted fever, different urinary tract infections and typhoid fever.



   The invention is illustrated by the following examples: EXAMPLE 1.- (a) 71 g of p-nitro-omega-bromacetophenone dissolved in 300 cm3 of chloroform are added to a solution of 46 g of hexamethylene tetramine in 600 cm3 of chloroform . The solid product begins to separate almost immediately, and the temperature of the reaction mixture rises to about 50 C. After allowing the mixture to stand for about two hours, the p-nitro-omega complex is collected. bromoacetophenonehexamethylene tetramine, washed with a little chloroform and dried.

   The for-

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 mule of this product is as follows:
 EMI11.1
 0, ¯, il N02 - <f> C - CH2 (CH 2) 6N4Br
 EMI11.2
 The p-nitro-omega-bromoacetophenone-hexaïaethylc netetramine complex prepared above is mixed with a cold solution of 500 cc of absolute ethanol and 100 cc of concentrated hydrochloric acid and the mixture is stirred overnight at room temperature. .



  The solid product, which consists of the bromohydrate salt of p-nitro-omega-aminoacetophenone containing as an impurity small amounts of hydrochloride and ammonium chloride, is collected, washed with 200 cm3 of ice-water to separate the ammonium chloride. nique, and we dry. The formula of this compound is as follows:
 EMI11.3
 0 N02 C - CHNH.HBr
46 grs are mixed. p-nitro-omega-amino acetophenone hydrobromide prepared above at 200 cm3 of acetic anhydride and 25 grs. sodium acetate. Stir the mixture at room temperature, and add small amounts of ice and water from time to time. Stirring is continued until the mixture becomes clear and reaches a temperature of about 70 C.

   The solution is diluted with 900 cm3 of water, cooled to 5 C and
 EMI11.4
 collects p-nitro-omega-acetamidoacetophenone, which melts at 158-161 C and has the following formula:
 EMI11.5
 0 H 0 il 1 II N02 C - CH2N - C - CH3
 EMI11.6
 We mix It, 1 grs. of p-nitro-omega-acetaidoacetophenone to 55 cm3 of methanol and 17 cm3 of 36-38% aqueous formaldehyde. 0.4 gr is added. sodium bicarbonate and stir the

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 mixing at 35 ° C. for about an hour and a half, during which time the solid product separates. The mixture was cooled and stirred for half an hour, the solid product collected, washed with water and dried at 60 ° C.

   The product thus obtained is the
 EMI12.1
 p-nitro- el -acét8.J.llido- -hydroxypropiophenone, melting at 166-7 C, which has the following formula:
 EMI12.2
 u Il 0 NH - C - CH3 NO2 C - C - CH20H (b) 1.3 grams are added. of p-nitro- a .. - acetamido-ss-hydroxypropiophenone to 2 grs. of aluminum isopropylate in 75 dcm3 of isopropanol at room temperature and the mixture is stirred for two days at room temperature, while a stream of nitrogen is passed through the solution. Most of the isopropanol is separated from the dark red-brown mixture under reduced pressure and the residue is treated with 35 cm3 of water. The mixture is heated to boiling, filtered to remove aluminum hydroxide and the solution collected.



   The aluminum hydroxide is extracted with 35 cm3 of hot water and the extract is combined with the main solution of the reaction mixture. The combined extracts are cooled, filtered and the filtrates evaporated to dryness in vacuo. The residue is treated with a small amount of hot ethyl acetate and the crystalline material which does not dissolve is collected. The crystalline material consists mainly of (dl) -psi-l-p-
 EMI12.3
 nitrophenyl-2-acetamidopropane-1,3 diol and has the formula: 0 11 OR 1 N- C - CH3 NO2- <: CH - CH - CH20H. (dl) -psi shape.



  It can be purified by recrystallization starting from ethanol or

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 of ethanol-water mixture to remove small amounts of the product (dl) -cis; melting point 166-8 C.



   If an equivalent amount of propionic anhydride is used instead of acetic anhydride when converting
 EMI13.1
 tion of p-nitro-omega-aminoacetophenone in its acyl derivative, one obtains p-nitro-omega-propionamidoacetophenone, which can be transformed., by the process described above, into p-nitro- - propionamido- - hydroxypropiophenone, then in (dl) -psi-l, p-nit rophenyl-2-propionamidopropane-l, 3-diol.



  (c) 3 grams are heated. of (dl) -psi-l-p-nitrophenyl-2-
 EMI13.2
 acetamidopropane-1,3-diol with 30 cm3 of 5% hydrochloric acid in the steam bath for half an hour. The solution is cooled, decolorized with charcoal, and the decolorized solution is made alkaline to pH 10-11 with sodium hydroxide solution. The free base of (dl) -psi-1-p-nitrophenyl- is collected.
 EMI13.3
 2-a-minopropane-1.3-diol., Of formula:
 EMI13.4
 OH NH2 1 N02- <::> - CH - CH -CH20H (dl) psi form which settles on standing, washed with cold water and dried: melting point 140-2 C. If desired, may recrystallize this product from water.



   (Dl) -psi-l-p-nitrophenyl-2-aminopro-pane-1,3-diol hydrochloride can be obtained by evaporating to dryness in vacuo the decolored solution obtained after hydrolysis of (dl) -psi-
 EMI13.5
 I-p-nitrophenyl-2-acetallido-propane-1,3-diol. This salt has a melting point of 177.5-8.5 C.



   (d) 2.5 grams are mixed. of p-nitro- a. -acetamido-ss - hydroxypropiophenone 1.5 grs. of aluminum isopropylate and 25 cm3 of dry isopropanol, and the mixture is heated under reflux A

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 for five hours. During the reflux period, the acetone formed separates out by distillation and a stream of nitrogen is passed through the solution. The isopropanol is distilled from the reaction mixture under reduced pressure, the residue is treated with enviroh 50 cm3 of water and separated from the solution as described above in (b), (dl) -psi-lp-nitrophenyl -2-acetamidopropane-1-diol.



   (e) 2.5 grams are mixed. of p-nitro- -acetamido-ss-hydroxypropiophenone at 1.5 grs. of aluminum isopropylate and 25 cm3 of dry isopropanol, and heat the mixture under reflux for five hours. During the reflux period, the acetone which forms is distilled off and a stream of nitrogen is passed through the solution. The isopropanol is distilled from the reaction mixture under reduced pressure and the residue is treated.
 EMI14.1
 containing (dl) -psi-l-p-nitrophenyl-2-acetamidopropane-1,3-diol per about 50 cm3 of dilute hydrochloric acid. A sufficiently concentrated solution of sodium hydroxide is added to the solution to dissolve the aluminum hydroxide which forms during the neutralization, and, after cooling, the solution is extracted with ethyl acetate.

   The ethyl acetate extracts are combined and concentrated in vacuo to the point of crystallization. The free base of (dl) -psi- is collected
 EMI14.2
 1-p-nitrophenyl-2-azninopropane-1.3-diol which separates on cooling, washed with cold water and purified, if desired, by recrystallization from water; melting point 140-2 C.



   (f) We heat 8 grs. of p-nitro- a acetamido-ss -hydro-xypropiophenone at about 75 C for half an hour with 20 cm3 of acetic anhydride containing a small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization.

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 tallization from methanol or ethanol. We thus obtain
 EMI15.1
 as the product of p-ni tro- a. -aceta.11ido-, B -acetoxypropiophenone
 EMI15.2
 which has the following formula: 0 II 0 NH - C - CH3 Il l '. "N0 C- CH1- CH20-C - CH3 2 Il 0 (g) 3 grs. Of p-nitro-q-acetamido-ss-hydro-xypropiophenone are heated in 150 cm3 of 5% hydrochloric acid under reflux for approximately two to three hours.

   The reaction mixture is evaporated to dryness in vacuo to afford the desired p-nitro-α -amin-ss-hydroxypropiophenone hydrochloride, having the formula:
 EMI15.3
 0 NHZ.HCl y v 1 NO2 C - CH - CHOH.



   If desired, this product can be neutralized with a slightly alkaline substance to obtain the free base which is rather unstable.
 EMI15.4
 



  (h) 50.6 grs are mixed. of p-ni tro- a -acetamido- jJ - hydroxypropiophenone at 41 grs. of aluminum isopropylate and 600 cc of dry isopropanol, and the mixture is heated under reflux for six hours. During the reflux period, the acetone which forms is distilled off and a stream of nitrogen is passed through the solution. The isopropanol is removed from the solution by distillation under vacuum and the residue is treated with 750 cm3 of dilute hydrochloric acid. The mixture is saturated with sodium chloride and extracted until exhaustion with ethyl acetate. The ethyl acetate extracts are dried and the acetate is distilled off in vacuo. The residue is extracted by several fresh portions

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 of hot ethyl acetate, the mixture was cooled and the residue collected.

   The ethyl acetate extracts are saved for further purification. Or. Recrystallizes from water the residue insoluble in ethyl acetate (melting point: 158-63 C) which consists of a mixture of (dl) -psi-1-p-nitrophenyl-2-
 EMI16.1
 acetamidopropane-1,3-diol and the corresponding isomer (dl) -reg., and 21 grs are obtained. of (dl) -psi-1-p-nitrophenyl-2-acetarrdopropane-1,3-diol, mp 166-7 ° C. The filtrate is allowed to stand for two days and the crystals which have separated are collected. These crystals are (dl) -reg.-1-p-nitrophenyl-2-acetamido-1,3-diol, which melt at 185 ° C. before recrystallization. After recrystallization, these crystals melt at 195 ° C. and weigh 3 grams.



   The ethyl acetate filtrate is evaporated to dryness in vacuo and the residue treated with about 75 cm3 of hot absolute ethanol. The alcoholic solution is left to stand and the crystalline material which settles is collected; this crystalline material consists of a mixture of (dl) -psi- and (dl) -psi reg.
 EMI16.2
 l-p-nitrophenyl-2-acetamidopropane-l, 3-diolx To separate it into its two components, it is recrystallized from water and 3 grs are obtained. of the (dl) -psi-crystallized isomer and the (dl) -reg isomer is separated. of the filtrate, allowing it to crystallize on prolonged standing.



  The yield of (dl) -reg isomer obtained at this time is 3 grs.



  EXAMPLE 2. - (a) A mixture consisting of 7.1 grs is heated. from p-
 EMI16.3
 nitro-omega-benzamidoacetophenone, 0.2 gr. of sodium bicarbonate and 1.5 grs. paraformaldehyde in 50 cm3 of methanol at 45 to 50 C for half an hour. The reaction mixture is left to stand for one hour and then poured into 300-400 cm3 of ice water.

   The precipitate produced is collected, washed with water and purified by recrystallitation from ethanol to obtain p-nitro-a,
 EMI16.4
 -ber¯zamido- / 3 -hydroxypropiophenone having the following formula:

 <Desc / Clms Page number 17>

 
 EMI17.1
 0 il 1., Yrlu- <i ::> Il NH j N02 <> - C - CH - CH2OH (b) We let stand at room temperature for about five minutes a cohsistant mixture in 7.1 grs. of p-nitro-omega-benzamidoacetophenone, 0.1 gr. of sodium and 1.5 grs. of paraformaldehyde in 50 cm3 of methanol. The reaction mixture is immediately poured into 300 cm3 of ice water, the mixture is separated.
 EMI17.2
 p-ritro-cL-benzamido- / 3-hydroxypropiophenone and purified as in (a).



   (c) A mixture consisting of 7.1 grams is stirred at room temperature for about 10 minutes. of p-nitro-omega-benzamidoacetophenone, 0.2 gr. of potassium carbonate and 3grs. of formaldehyde in a solvent mixture composed of 30 cm3 of methanol and 10 cm3 of water. The reaction mixture is poured into about 300 cc of ice water, the p-nitro-a-henzomoid-ss- -hydroxypropriophenone is separated and purified as in (a).



   (d) A mixture consisting of 7.1 grams is stirred at about 25 ° C. for five minutes. of p-nitro-omega-benzamidoacetophenone, 0.2 grs. of potassium carbonate and 3.75 grs. of para formaldehyde in 35 cm3 of methanol. The mixture is poured into 400 cm3 of ice water and the p-nitro-a-benzomid-ss-hydroxypropiophenone is separated and purified by recrystallization as in (a).



   (e) 6.3 grams are added. of p-nitro- a -benzomid-ss-hydroxypropiophenone to 4 grs. of aluminum isopropylate in 75 cc of dry isopropanol, and heat the mixture under reflux for about 6 hours. During the reflux period, part of the reaction mixture is continuously separated by distillation and occasional analysis of the acetone distillate. We

 <Desc / Clms Page number 18>

 the isopropanol is separated from the reaction mixture under reduced pressure and 150 cm3 of water are added to the residue. The mixture is heated to boiling, the aluminum hydroxide is filtered off and the filtrate is evaporated to dryness in vacuo. The residue was washed with several small portions of hot ethyl acetate, and the crystallized solid product which did not dissolve was collected.

   The crystallized solid product is recrystallized from water, which mainly consists of (dl) -psi-1-p-nitrophenyl-2-benzamido-propane-1,3-diol, having the following formula:
 EMI18.1
 0 Oh 1 NH - C - <> N0 <-CH - CH - CH20H forms (dl) -psi to separate the isomer (dl) -reg. and collects the product. The (dl) -reg isomer can be obtained. from the filtrate, if desired.



   (f) 3 grams are heated. of (dl) -psi-1-p-nitrophenyl-2-benzamidopropane-1,3-diol on a steam bath for one hour with 30 cm3 of 5% hydrobromic acid. The reaction mixture is decolorized with charcoal and the decolored solution is made alkaline to pH 10 with sodium hydroxide solution. We collect-
 EMI18.2
 le (dl) -psi-1-p-nitrophenyl-2- ^ inopropane-1,3-diol, having the formula
 EMI18.3
 OH NH2 #v! 1 NO2 CH - CH - CH2OH forms (dl) psi which precipitates, washed with cold water and purified, if desired, by recrystallization from water.

   Melting point 140-2 C

 <Desc / Clms Page number 19>

   EXAMPLE 3.- (a) 15 grams are mixed. o-methyl-p-nitro-omega-acetamido-acetophenone with 70 cm3 of methanol, 10 cm3 of water and 5.7 grams of paraformaldehyde; 0.5 gr is added. of sodium bicarbonate and the mixture is heated at 40 ° C. for an hour and a half. The mixture is poured into 600 cm3 of ice water, the o-
 EMI19.1
 methyl-p-nitroacêtaraido- / 3 -hydroxypropiophenone and washes with
 EMI19.2
 the water. The product has the formula 0 Il 0 Il Ni 1 -C - CH3 NO2.C - CH - cil 2OH CH3 it can be purified, if desired, by recrystallization starting from methanol.
 EMI19.3
 



  (b) 5.32 grams are added. of o-sethyl-p-nitro-a.-acetamido-fc -hydroxypropiophenone 4.8 grs. of aluminum secondary butoxide in 75 cc of dry secondary butanol and reflux the mixture under a nitrogen atmosphere while a small amount of the reaction mixture is distilled off. Refluxing is continued until the distillate no longer contains methyl ethyl ketone (about six hours) and then the secondary butanol is separated by vacuum distillation. The residue is treated with 200 cm3 of water, the mixture is heated to boiling and the aluminum hydroxide is separated from the solution. The solution is evaporated to dryness and the residue is extracted with several portions of hot ethyl acetate. The crystalline solid which does not dissolve in ethyl acetate is collected and dried in vacuo.

   This solid body is recrystallized from water which consists of a mixture mainly containing the (dl) -psi isomer with small quantities of the corresponding (dl) -reg product, to obtain the (dl) -psi-l-

 <Desc / Clms Page number 20>

 
 EMI20.1
 (o-ethyl-p-nitrophenyl) -2-acetamidopropanediol-1,3 having the
 EMI20.2
 formula: 0 II OH NH - C - CH3 N0 - <> - CH - CH -CHOH form (dl) -psi.



  CH 3 (c) 2 grs are heated. of (dl) -psi-l- (o-methyl-p-
 EMI20.3
 nitrophenyl) -2-acetamidopropane-1,3-diol in a steam bath with 20 cm3 of 5% hydrochloric acid for one hour. The solution containing (dl) -psi-l- (o-methyl- hydrochloride) is cooled.
 EMI20.4
 p-nitrophenyl) -2-aminopropane-.l, 3-diol, it is decolorized with charcoal and the decolorized solution is made alkaline to pH 10 with sodium hydroxide solution. The free base which precipitates, consisting of (dl) -psi-l- (o-methyl-p-nitrophenyl) -2-aminopropane-1,3-diol, is collected, washed with cold water and dried. in the void. This product has the following formula:
 EMI20.5
 OH NH NO2 CH - CH - CH20H CH3 forms (dl) -psi and can be purified, if desired, by recrystallization from water.



   (d) A mixture consisting of 10 grams is heated. from o-
 EMI20.6
 methyl-p-ni tro- a -acéta.111ido-; 3 -hydroxypropiophenone and 20 grs. Benzoic anhydride at 70 C for about half an hour to three-hour quartz. The mixture is cooled, treated with 75 cm3 of water and an excess of cold sodium hydroxide solution is added. After standing for a few minutes, the precipitate is collected, washed well with water and purified by recrystallization from methanol or ethanol. The product as well
 EMI20.7
 obtained is o-methyl-p-nitro- a -acetarido- / 9 -benzoxypropiophenone having the formula.

 <Desc / Clms Page number 21>

 
 EMI21.1
 



  0 #: l: OAUlq il 0 NH-C- CH3 0 #II II .¯¯.



  NOo <SN> # C - CH - CH - CH20 - C bzz CH3 EXAMPLE 4.- (a) A mixture consisting of 15 grams is heated for half an hour at 35 ° C. of m-methoxy-p-nitro-omega-p'-toluylamodoacétc phenone, 4.1 grs. of paraformaldehyde, 0.2 grs. of pyridine and 150 grs. of ethanol, then the mixture is poured into 750 cm3 of ice water. The m-methoxy-nitro-a -p'-toluylamido-ss-hydroxypropiophenone is collected, washed with water and purified by recrystallization from ethanol.

   The product has the following formula:
 EMI21.2
 0 il 0 NH - C - <C CH 3 Il N02- <; > C - CH - CH20H OCH3
 EMI21.3
 (b) 7.1 grams are added. of m-.m-ethoxy-p-r-itro-, z-p-1-toluylamido- / 2-b-ydroxypropiophenone at 4 grs. of aluminum isopropylate in 125 cc of dry isopropanol, and the resulting mixture is refluxed under a nitrogen atmosphere while a small portion of the condensate is distilled. Reflux is continued until the distillate no longer contains acetone, then the isopropanol is separated off under reduced pressure. The residue is treated with 200 cm3 of hot water, the precipitated aluminum hydroxide is removed by filtration, and the filtrate is evaporated to dryness in vacuo.

   The residue is washed with several portions of hot ethyl acetate and collected.
 EMI21.4
 (dl) -1 - (- tethoxy-p-nitrophenyl) -2-p'-toluyla? odopropane-7¯, 3- diol which does not dissolve in ethyl acetate, and has the formula

 <Desc / Clms Page number 22>

 
 EMI22.1
 . - 0 OH I NH - C CH3 N02 CH - CH - CH20H OCH3 This product can be separated by the methods described
 EMI22.2
 previously, in (dl) -psi-l- (m-methoxy-p-nitrophenyl) -2-p'-toluylamidopropane-1,3-diol and the corresponding (dl) -reg isomer.



  As in the previous examples, the mixture consists mainly of the (dl) -psi isomer.



   (c) A mixture consisting of 3 grams is heated in a steam bath. of (dl) -psi-l- (m-methoxy-p-nitrophenyl) -2-p'-toluyl aminopropane-l, 3-diol with 30 cm3 of 5% hydrochloric acid for about an hour and then evaporated to dryness in a vacuum. The residue, which consists of a mixture of p-toluic acid and (dl) -psi-l- (m-methoxy-p-nitro-phenyl) -2-aminopropane-l, 3-diol hydrochloride, is treated. per 15 cm3 of water, the mixture is made alkaline to a pH of 10 with a solution of sodium hydroxide, and the free base of (dl) -psi-l- (m-methoxy-) is collected.
 EMI22.3
 p-nitrophenyl) -2-aminopropane-1,3-diol. This product has for-
 EMI22.4
 mule: OH NH2 NO2- <)> C1 - C1 - CH2OH forms d1) -psi / OCH3 and can be purified, if desired, by recrystallization from water.



  EXAMPLE 5.- (a) Heated to 45 ° C. for about half an hour a
 EMI22.5
 mixture consisting of 16.3 grs. of 2-nitro -, 5-dimethyl-orga-phenacetamidoacetophenone, 4.5 grs. of paraformaldehyde and 0.2 gr. of calcium hydroxide in 150 cm3 of 95% ethanol. We pour

 <Desc / Clms Page number 23>

 the reaction mixture in 750 cm3 of ice water and collects
 EMI23.1
 crude 2-r.itro-, 5-dimethyl- a -phenacetamido- / 3 -hydroxypropiophenone. The raw product has the formula
 EMI23.2
 0 C - CH2 N02 1 0 t CHz 2 -S¯ # CH3P! - CH - CH20H CH3
It is washed with water and purified by recrystallization from ethanol.



   (b) 7.1 grams are added. of 2-nitro-4,5-dimethyl-a - phenacetamido - hydroxypropiophenone at 4.5 grs. of aluminum isopropylate in 150 cc of dry isopropanol, and the mixture is refluxed under a nitrogen atmosphere for about 5 hours, during which a small amount of the reaction mixture is continuously removed by distillation. When the reduction is complete, the isopropanol is removed by vacuum distillation.



  Treat the residue containing (d1) -1- (2'-nitro-4 ', 5'-dimethyl
 EMI23.3
 phenyl) -2-phenyl-acetamidopropane-1,3-diol per 100 cc of water and the mixture is acidified with hydrochloric acid. A sufficient amount of hot 10N sodium hydroxide solution was added to dissolve the aluminum hydroxide which separated by neutralization, and, after cooling, the solution was extracted with ethyl acetate. The combined extracts obtained were dried with ethyl acetate and concentrated to the point of crystallization.
 EMI23.4
 tallization. (Dl) -1- (2'-nitro-l, ', 5'-direthyl-phenyl) -2-aminopropane-l, 3-diol is collected, which separates from the solution on cooling, and which has for formula
 EMI23.5
 02 OH NIL, CH3 CH - CH - CH2OH - CH3

 <Desc / Clms Page number 24>

 and it is dried in a vacuum.

   If desired, the product can be recrystallized from water or alcohol to provide the individual diastereomers of arainodiol.



    EXAMPLE 6.- (a) A mixture of 18 grams is stirred at ordinary temperature. of 3-nitro-5-cM.or -omega (a. -chlorpropionamido) -acetophenone, 6 grs. of paraformaldehyde and 0.2 grs. of sodium carbonate in 200 cc? 70% aqueous methanol, for about an hour, then poured into 500 in? ice water. The precipitated product is collected, washed with water and purified by recrystallization from methanol or ethanol.

   The compound
 EMI24.1
 thus obtained is 3-nitro-5-chlor-a - (a '-chlorpropiona.rido) -i3
 EMI24.2
 -hydroxypropiophenone, and has the formula: 0 NO II 2 0 NH - C - CHCl.CH3 i C - CH - CH20H (b) 9.4 grs are added. of 3-nitro-5-chlor- <z - (a'-
 EMI24.3
 chlorpropionāmido) - / 3-hydroxypropiophenone at 6 grs. of aluminum isopropylate in 250 cc of dry isopropanol and the mixture is heated at 50 ° C. for about 24 hours by passing a stream of nitrogen through the solution. The isopropanol is removed by vacuum distillation and the residue is treated with about 200 cc of water. The mixture is heated to ensure complete precipitation of the aluminum hydroxide, the aluminum hydroxide is filtered off and the filtrate evaporated to dryness in vacuo.

   The residue is washed with several portions of hot ethyl acetate and the material which does not dissolve is collected.



    The solid is recrystallized from water to obtain (dl)
 EMI24.4
 -psi-l- (3'-nitro-5'-chlorphenyl) -2-ct-chlorpropionamidopropane-1,3-diol, having the form;

 <Desc / Clms Page number 25>

 
 EMI25.1
 0 Cl N02 OH NH - C - CH - CH3) ##. F 1 CH - CH - CH20H form (dl) -psi CI
The aqueous filtrate is allowed to stand and the (dl) -reg isomer is collected. which separates and is purified by recrystallization. Further amounts of the two isomers can be obtained from the ethyl acetate filtrate by the methods described in Example 1 (g).



   (c) A mixture consisting of 3 grams is heated. from (dl) -
 EMI25.2
 psi-1- (3'-n.itro-5'-chlorphenyl) -2- a, -chlorpropiona.idopropane- 1,3-diol and 30 cm3 of 5% hydriodic acid in a steam bath for half an hour . The solution is decolorized with charcoal and the decolorized solution is made alkaline to pH 10 with sodium hydroxide solution. The free base of (dl) -psi-l- (3'-nitro-5'-chlorophenyl) -2-aminopropane-1,3-diol is collected which precipitates and has the formula
 EMI25.3
 NO 2 UH N 2 h - CH - CH EH / "CH 2 O H This forms (dl) -psi and is purified, if desired, by recrystallization from water.



    EXAMPLE 7. - (a) A mixture consisting of 29 grams is heated at 35 ° C. for an hour and a half. of p-nitro-omega-dichloracetamidoacetophenone, 150 cm3 of methanol, 50 cm3 of 38% aqueous formaldehyde, and 0.5 gr. of sodium bicarbonate. The reaction mixture is cooled, the solid product is collected and washed with water.
 EMI25.4
 the water. The p --.- ni-tro-ct-dichloracet & -uido- / 3-hydroxypropio- is purified

 <Desc / Clms Page number 26>

 phenone thus obtained by recrystallization from ethanol or methanol.

   This product has the following formula:
 EMI26.1
 0 Il 0 NH - C - CHC2 II N02. :> - C - CH - CH20H (b) 16 grs are added. of p-nitro-a -dichloracetamcido-ss- -hydroxypropiophenone at 10 grs. of aluminum isopropylate in 250 cc of dry isopropanol, and the mixture is refluxed for six hours. During the heating period, a stream of nitrogen is passed through the solution, and a small amount of the reaction mixture is continuously distilled off.



  Isopropanol is removed by vacuum distillation, the residue is treated with 250 cm3 of water and the mixture is heated to boiling.



  The aluminum hydroxide is separated by filtration and the filtrate is evaporated to dryness in vacuo. The residue is washed with several small portions of ethyl acetate, the solid crystallized is collected.
 EMI26.2
 tallized containing the (dl) -psi-7.-p-ni trophenyl-2-dichloracéta.mido-propan-1,3-diol which does not dissolve, and recrystallizes it from water to obtain (dl) the desired psi-isomer, which has
 EMI26.3
 for formula: 0 11 OH NH - C - CHC12 NO2 .- <: CH - I CH - 1 CH20H form (dl) -psi.



  It can be recrystallized, if desired, from ethylene dichloride.



   (c) 5 grs are heated. of (dl) -psi-1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol on a steam bath with 50 c3 of 5% sulfuric acid for about fifteen minutes. The mixture is decolorized with charcoal, made alkaline to pH 10 to neutralize the sulfuric acid salt of the desired amindiol, and the precipitated product is collected. This product consists of

 <Desc / Clms Page number 27>

 
 EMI27.1
 (dl) -psi-1-p-nitrophenyl-2-aminopropane-1,3-diol, and has the formula:
 EMI27.2
 OH NT32 NO2- <: H-CH-CH2OH form (dl) -psi It can be purified by recrystallization from water; melting point 140 C.
 EMI27.3
 



  The oga.-acylamidoacetophenone derivatives used as starting materials in the practice of the invention can be prepared by hydrolysis of a complex of nitro-oniega-haloaceto-phenone-hexamethylene tetramine to the corresponding nitro-omega-aminoacetophenone and acylation of the same. amino ketone with a suitable acylating agent. A special example of the preparation
 EMI27.4
 p-nitro-orga-acetamidoacetophenone by this method is described in Example 1 (a) above.

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


    

Claims (1)

CLAIMS 1.- Process characterized in that one condenses a compound of formula: EMI27.5 R10 'C-CH2NH-acyl R2 NO2 with formaldehyde in the presence. of an alkaline condensation catalyst, to obtain a ketone compound of formula EMI27.6 R1 0 il NH-adyl 1 R2 NO 1 2> UH-CH20H where R1 and R2 are the same or different and represent hydrogen, halogen, lower alkyl or lower alkoxy radicals. <Desc / Clms Page number 28> 2. - Process according to claim 1, characterized in that the condensation is carried out in the presence of a solvent. 3. - Process according to claims 1 and 2, characterized in that the condensation is carried out in water, in a lower aliphatic alcohol or in a mixture of the two. 4. A process according to any one of the preceding claims, characterized in that an excess of formaldehyde is employed in the condensation. 5. - Method according to any one of the preceding claims, characterized in that the condensation is carried out at a temperature between 0 and 75 C. 6. - Process according to any one of the preceding claims, characterized in that the condensation is carried out in the presence of a slightly alkaline agent. 7. A process according to any one of the preceding claims, characterized in that the keto compound thus obtained is reduced with an oxidizable aluminum alkoxide in an organic solvent, to obtain a (dl) -acylamido diol having for formula EMI28.1 RI OH NH-acyl -CH-Cli-CH20H R2 NO2 in which R1 and R2 are the same or different and represent hydrogen, halogen, lower alkyl radicals or lower alkoxy radicals. 8. A process according to claim 7, characterized in that the reduction is carried out under substantially anhydrous conditions in a lower aliphatic alcohol corresponding to the alkyl radical present in the oxidizable aluminum alkoxide. 9. A process according to claims 7 and 8, characterized in that the oxidizable aluminum alkoxide is derived from a secondary aliphatic alcohol. <Desc / Clms Page number 29> 10. - Process according to claims 7, 8 and 9, characterized in that the reduction is carried out at a temperature between 20 and 125 C. 11. A process according to any one of the preceding claims, characterized in that the (dl) - acylamidodiol of formula is then hydrolyzed. EMI29.1 Rl OH NH-acyl 1> -CE-CH-CH20H R2 N02 thus obtained in the corresponding free aminodiol or one of its addition salts with an acid, this free aminodiol having the formula EMI29.2 RI OH NH2 1> CH-CH-CH20H R2 NO2 in which R1 and R2 are the same or different, and represent hydrogen, halogen, lower alkyl or lower alkoxy. 12. - Process according to claim 11, characterized in that the hydrolysis is carried out using an acid hydrolysis agent. 13. - Process according to claims 11 and 12, charac- terized in that the hydrolysis is carried out using a dilute mineral acid as hydrolysis agent. 14.- Process according to claims 11, 12 and 13, characterized in that separating (dl) -acylamidodiol into its diastereomeric forms before hydrolysis. 15. - Process according to claims 11, 12, 13 and 14 characterized in that the hydrolyzed (dl) -acylamidodiol is the pseudo diastereoisomer. 16. - Process according to any one of the preceding claims, characterized in that R1 and R2 represent hydrogen and that the aromatic -NO2 substituent is in position. <Desc / Clms Page number 30> para of the ring.phenyl relative to the ketone or alcohol radical. 17.- Process according to claims 1 to 6 inclusive, characterized in that the ketone derivative obtained is then acylated to obtain an alpha-acylamido- -acyloxypropiophenone having the formula: EMI30.1 R1 ¯¯¯ 0 Il NH-acyl -C-CR - CH20acyl R2 NO2 in which R1 and R2 are the same or different and represent hydrogen, halogen, alkyl radicals or alkoxy radicals. 18. - Ketone am8noacool compounds having the formula EMI30.2 RI 0 NH-R C-CH-CH20R 'R2 NO2 where R1 and R2 are the same or different and represent hydrogen, halogen, lower alkyl or lower alkoxy radicals and where R and R' are the same or different and represent hydrogen or an acyl radical, prepared or produced by the processes according to any one of the preceding claims or by a chemically equivalent process. 19. - Compounds of aminodiols having the formula: EMI30.3 R1 OH NH-R ¯¯¯¯ <* \ -CH-CH-CH20H R2 N02 where R1 and R2 are the same or different and represent hydrogen, halogen, alkyl or alkoxy radicals and where R is l 'hydrogen or an acyl radical, and acid addition salts of products where R represents hydrogen, prepared or produced by the processes according to claims 1 to 17 inclusive or by a <Desc / Clms Page number 31> chemically equivalent process. 20. - Individual structural isomeric forms of aminodiol compounds according to claim 19, prepared or produced by the processes according to claims 1 to 17 inclusive or by a chemically equivalent process.