BE550677A - - Google Patents

Description

       

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 EMI1.1
 



  The purpose of this statement is the preparation
 EMI1.2
 esters of formula;
 EMI1.3
 
 EMI1.4
 in which R and RU represent an alkyl residue,, Sw..S, é. o "v .'t # cy9 alcoyalcoy11que, a residue tàû, 'iotâ'," T ....

 <Desc / Clms Page number 2>

 
 EMI2.1
 saturated alkyl comprising this 1 to 7 carbon atoms and R may also be hydrogen, ROL hydrogen or an alkyl or alkoxy.leyl residue comprising at most 4 carbon atoms, preferably a methyl, ethyl or methoxyethyl residue or ethoxyethyler R21 of the hydrogen or a residue or ethyl, n as the number} 'n:; i:; 3r of a value of 7 s 15 indicating the number of the different residues or put in parentheses in the formulation, with this condition that in at least ni'2 remainders of formula:

   
 EMI2.2
 
 EMI2.3
 R "represents 1" hydrogen. Particularly valuable are compounds in which n is an integer with a value of 7 to 11. In this E compounds fi represents in particular 11: 'drogen or an alcoholic residue comprising from 1 to 7 carbon atoms and R' an alcoholic residue comprising from 1 to 7 carbon atoms, one of these R and R 'radicals being placed of
 EMI2.4
 preferably for an alkyl residue comprising at least 4 carbon atoms.



   These new esters present valuable
 EMI2.5
 Dharmacologîquz properties - ,,. This is how they have a marked effect of local anesthesia; they exert in particular a selective action on the receptors for elongation of the lungs.



  They can be used as medicaments, preferably as beakers. With regard to this use, these

 <Desc / Clms Page number 3>

 
 EMI3.1
 110lrV, t: i., T compn.:3I:h PJ: 'éfi51tm1i; â 9f - :: J notable advantages over those in which n denotes smaller or larger numbers fi ': ïid3.
 EMI3.2
 



  These new esters: are prepared in a
 EMI3.3
 she-leads known. CI is thus that one can t: ran6fo) !: 'ml des L1LY: â. "'. Ç3) (.". & 9 ':? "A.CS't3G-': de '3': 'ti? '
 EMI3.4
 
 EMI3.5
 where appropriate in the form of their reactive derivatives,
 EMI3.6
 their esters 8.'Je.c of the polyglycols of formula s
 EMI3.7
 
 EMI3.8
 Rol and If "'and n having the meaning indicated.



  A direct process is, for example, to react Eia9 benzoic acids in s ^; 3't a
 EMI3.9
 
 EMI3.10
 the appropriate in the form of their reactive derivatives, on due formula
 EMI3.11
 
 EMI3.12
 in which R to 3 'and n have the meaning indicated, optionally under the ez reactive derivatives.

   We can

 <Desc / Clms Page number 4>

 in this silo proceed by reacting the corresponding benzoic acids directly with the polyglycols indicated, advantageously using the usual esterification catalysts, or by reacting the benzoic acids, for example in the form of their anhydrides, their halides or their esters of readily volatile alcohols, for example methanol, on the polyglycols indicated, with advantage in the presence of basic condensing agents such as pyridine, metal alcoholates, possibly the corresponding polyglycolas themselves.

   However, it is also possible to react metal salts of the corresponding benzoic acids with reactive esters of polyglycols, in particular with esters of strong inorganic or organic acids, such as halogenated hydracids, or of sulphonic acids such as organic sulphonic acids. , for example ethanesulfonic acid or toluenesulfonic acid.



   Another embodiment of the process consists in transforming X into the group R-NH, in compounds of formula:
 EMI4.1
 in which R 'to R "' and n have the meaning indicated and X represents a residue convertible into a group R-NH, R having the meaning indicated. - even known, a group

 <Desc / Clms Page number 5>

 aminogen to a saturated monoalkyl-, cycloalkyl-, alkoxyalkyl-aminogen or oxacycloalkyl-alkyl-aminogen group, comprising from 1 to 7 carbon atoms, for example by reaction with reactive esters of corresponding alcohols. However, it is also possible to subject a compound comprising an aminogenic or free NO 2 group to reductive alkylation, in the presence of the corresponding oxo-starches.



   These reactions are carried out in the presence or absence of diluting agents and / or condensing agents or catalysts, at room temperature or at elevated temperature, in the open or in a closed vessel, under pressure.



   It should be noted that these new esters generally exhibit significant solubility in water.



  These solutions have the property, when heated, of becoming cloudy at a determined temperature depending on the concentration. This temperature, determined for a 10% solution, is called the "cloud point" and constitutes a. physical constant for the compound in question. The disorder is reversible; the solution clarifies again on cooling.



   The compounds indicated as starting materials are known or can be prepared according to methods known per se.



   The invention also embraces all the variants of the process in which one starts with compounds which can be obtained as intermediate products at any stage.

 <Desc / Clms Page number 6>

 of the process, then performs the still missing phases of said process. the present invention also relates, as new industrial products, to products conforming to those defined above.



   The invention is described in more detail in the following non-limiting examples, in which the temperatures are indicated in degrees centigrade.



   Example 1.



   Away from humidity, 2.23 g of 2- (n) -butoxy-4-amino-benzoate are heated for 3 hours in a 100 - 110 bath, under a water pump vacuum. of methyl after adding 9.6 g of nonaethylene glycol monomethyl ether and 0.15 cm3 of a 30% solution of sodium methanolate in anhydrous methanol. At the same time, 400 cc of anhydrous xylene are regularly introduced below the surface of the liquid and the resulting sapors are condensed in a reflux condenser.



   After allowing to cool, the reaction mixture is taken up in 100 cm3 of benzene and the extract is extracted twice successively with each time 20 cm3 of a 10% aqueous solution of sodium carbonate and with 20 cm3 of water.



  The aqueous layers are further washed twice with

 <Desc / Clms Page number 7>

 each time 100 cm3 of benzene. During the first extraction with sodium carbonate solution, the insoluble fractions separate which, after having been filtered and taken up in chloroform, give 0.8 g of a colorless product which solidifies in the state of a wax. After combining the aqueous layers, they are extracted three times with 100 cm 3 of chloroform each time. By combining the extracts and evaporating them, 4.75 g of regenerated nonaethylene glycol monomethyl ether are obtained.



   From the combined and dried benzene layers, 5.8 g of a brownish, viscous oil are obtained by evaporation under a partial vacuum, which essentially consists of a waxy product and of the 2- (n) -butoxy- ester. 4-Amino-benzoic acid of nonaethylene glycol monomethyl ether, of formula
 EMI7.1
 
Its purification can be carried out for example by chromatography on neutral aluminum oxide with carbon tetrachloride, benzene, methylene chloride and chloroform as solvents.

   This gives, in addition to a colorless by-product which solidifies into a waxy mass, the pure ester in the form of a colorless, viscous oil, which is easily soluble in water, and which separates from an aqueous solution to 10%, when heated above 49, as a milky cloudiness.

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   Example 2.



   Away from humidity and in a 100 - 110 bath, 2.8 g of 2- (n) -butoxy-4- (n) are heated for three hours under a water pump vacuum. -Methylbutylamino-benzoate, after adding 8.6 g of nona-ethylene glycol monomethyl ether and 0.15 cm3 of a 30% solution of sodium methanolate in absolute methanol. At the same time, 400 cc of anhydrous xylene are regularly introduced below the surface of the liquid and the resulting vapors condensed in a reflux condenser.



   After having allowed it to cool, the reaction mixture is taken up in 100 cm3 of benzene and extracted twice successively with each time 20 cm3 of a 10% aqueous solution of sodium carbonate and with 20 cm3 of sodium carbonate. water. The aqueous layers are extracted two more times in succession with 100 cm 3 of benzene each time. During the first extraction with the sodium carbonate solution, three layers are obtained, the two lower layers of which were allowed to flow into the second separating funnel where, by washing with benzene, only two layers are formed. After having combined them, the aqueous layers are extracted three times with 100 cm 3 of chloroform each time, and 5.1 g of nonaethylene glycol monomethyl ether are obtained.



   From the combined and dried benzene layers,

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 6.5 g of a brownish viscous oil are obtained by evaporation under reduced pressure which, besides a little starting ester and impurities, consists essentially of the 2-n-butoxy-4 ester -n-butylaminobenzoic acid of the monomethyl ether of nomaethylene glycol of the formula
 EMI9.1
 
The crude proof can, for example, be purified by chromatography on neutral aluminum oxide, with carbon tetrachloride, benzene, methylene chloride and chloroform as solvents.

   Apart from a little methyl ester and by-products, the pure ester is thus obtained in the form of a colorless viscous oil which is easily soluble in water and which is separated from an aqueous solution to 10%, when heated above 39, as a milky cloudiness.



   Example 3.



   After having dissolved 4.2 g of o- (n) -hexoxy-p-dibenzylamino-benzoic acid in 40 cm3 of benzene, is added, protected from humidity, in a stirred flask, 10 cm3 of thionyl chloride, and heat the whole for 4 hours in a 90 - 1000 bath while stirring slightly, then evaporate the reaction mixture, stirring and protected from moisture, heating it moderately under vacuum water pump. To get rid of it as completely as possible

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 excess thionyl chloride, the acid chloride is further dissolved four times in each time 25 cm3 of anhydrous benzene, and evaporated again as above.



  The acid chloride is then dissolved in 30 cu. Of anhydrous benzene and added dropwise over 5 minutes, protected from humidity and with good stirring, to a solution of 15 g of monomethyl ether of nonaethylene glycol in 15 cm3 of anhydrous benzene, to which 7.5 g of anhydrous potassium carbonate was added. Then we stir again overnight.



   Then added 50 cm3 of benzene and stirred with 50 cm3 of water. The benzene solution was washed with a 5% aqueous sodium carbonate solution and with water until neutral, while the aqueous layers formed were extracted twice more simultaneously with 100 cm 3 of benzene each time.

   By evaporating the benzene extracts under reduced pressure, after having combined and dried them, 7.3 g of an almost colorless viscous oil are obtained, which essentially consists of the o- (n) -hexoxy-p- ester. dibenzyl-amino-benzoic acid of nonaethylene glycol monomethyl ether, of formula:
 EMI10.1
 If this product is allowed to flow as a 10% solution in ether through a column of 50 g of oxide

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 aluminum, the ester is then obtained in the pure state. The two benzyl groups of this ester can be split by hydrogenation by shaking it in 50 cm3 of glacial acetic acid with 2 g of a carbon containing 5% palladium in a hydrogen atmosphere.



   To purify the product, it is passed through a column of 50 g of aluminum oxide after separating it from the catalyst by filtration, evaporating and dissolving the residue in ether. On evaporation, the eluates give off a colorless, viscous oil which consists of the o- (n) -hexoxy-p-aminobenzoic ester of nonaethylene glycol mono-methyl ether of formula
 EMI11.1
 It is easily soluble in water and in many common organic solvents and is separated from a 10% aqueous solution, when heated above 37 as a milky haze.



   The o- (n) -hexoxy-p-dibenzylamino-benzoic acid used as a starting material can be obtained by heating 11.3 g of methyl o- (n) -hexoxy-p-aminobenzoate melting at 50 - 51 , 12.7 g of benzyl chloride, 8.2 g of anhydrous sodium acetate and 110 mg of iodine for seven hours at 110 - 130 and saponifying with an alkali. By recrystallization of the crude acid from methanol and cyclohexane, we obtained

 <Desc / Clms Page number 12>

 this acid in the form of colorless crystals which melt at 119 - 120.



   Example 4.



   As described in Example 3, 3.9 g is converted
 EMI12.1
 of m- (n) -butoxy-p-dibenzylamino-benzoic acid to acid chloride. During the reaction with 17 g of nonaethylene glycol monomethyl ether, instead of potassium carbonate, 2 cm3 of anhydrous pyridine is used and the remainder is carried out according to the indications given in the same example * To isolate the reaction product, the benzene extracts are first freed from pyridine by treating them with a 5% aqueous solution of hydrochloric acid.



   After having been combined and dried, the benzene extracts are evaporated under reduced pressure and thus obtain 6.9 g of a viscous oil which consists of the m- (n) butoxy-p-dibenzylamino-benzoic ester of ether. monomethyl of nonaethylene glycol of formula:
 EMI12.2
 
Purification and debenzylation are carried out as described in Example 3.

   A viscous colorless oil is obtained with a good yield which consists of the ester
 EMI12.3
 m- (n) -butoxy-p-amino-benzoic acid of the monomethyl ether of

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 nonaethylene glycol of formula:
 EMI13.1
 It is readily soluble in water and in many common organic solvents, and separates from a 10% aqueous solution when heated above 430 as a milky haze.



   The m- (n) -butoxy-p-dibenzylamino-benzoic acid used as a starting material can be prepared as follows: @ The diethylamino-ethyl ester of m- (n) - butoxy-p- acid Amino-benzoic acid which can be obtained in the form of the hydrochloride salt under the trade name "Novesin" is converted into the free acid by saponification. 14.6 g of it are dissolved in 100 cm3 of methanol and while cooling and stirring, 40 cm3 of concentrated sulfuric acid are added dropwise. After heating at 60-65 for 4 hours, the reaction mixture is poured. cooled on a mixture of 500 g of ice, 100 cm3 of water and 70 cm3 of 25% ammonia, then using acetic acid, the whole is adjusted to a pH of 7.



  The precipitate thus obtained is filtered off, washed until neutral and dried. After recrystallization from methanol, the methyl ester is obtained in the form of colorless crystals which melt at 74-75. To further purify this compound,

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 it can still be taken up in 70 cm3 of benzene and filtered through 10 g of aluminum oxide. After evaporation, the residue is recrystallized from gasoline to give 12 g of pure methyl ester, with a melting point of 76-77. 11.2 g of this ester are dibenzylated in a manner analogous to that of Example 3, with 14 g of benzyl chloride, 9 g of anhydrous sodium acetate and 110 g of iodine, followed by hydrolysis.

   From the crude product, one obtains by repeated and alternating recrystallization from methanol and ethanol, the acid m- (n) -butoxy-
 EMI14.1
 Pure p-d1benzylam1no-benzoque as thick colorless prisms that melt at 155 - 157.



   Example 5.
 EMI14.2
 



  3.35 g of an-butQCt $ 7t03Cβ are carefully dried. methyl p-celopenty3.-amino-benoate and 12.9 g of nonaéthlneglco3 monomethyl ether. 0.2 em3 of a tetranormal solution of sodium methoxide in methanol is then added, then the mixture is heated as described in Example 1, while passing xylene. After 1 hour, at an internal temperature of 125 - 135, alcoholysis is complete? a test portion is soluble in cold water giving a clear solution.

   To isolate the reaction product, it is taken up in 150 cm3 of benzene and extracted successively with 130 cm3 of a 3% solution of sodium bicarbonate, 50 cm3 of a binormal solution of sodium carbonate and then twice more with each times 100 cm3 of a solution

 <Desc / Clms Page number 15>

 at 5% sodium chloride. All the aqueous layers are washed once with 50 cm3 of benzene marls. After having combined and dried over sodium sulfate, the benzene solutions are evaporated to obtain 6.8 g of the new ester of formula s.
 EMI15.1
 as a weak brownish oil. To purify it, it can be dissolved in 50 cm3 of ether, and filtered through 30 g of aluminum oxide, then wash with 300 cm3 of ether.



  On evaporation of the ether, 6.2 g of a colorless oil soluble in acetone, methanol and chloroform are obtained. A 10% aqueous solution shows a squint point of 35.



   During the alkaline saponification of this new ester, after the usual treatment, with an almost theoretical yield, a carboxylic acid is obtained which, after a single recrystallization from a mixture of benzene and gasoline 1: 2, melts at 69 - 70. Mixed melting point with acid
 EMI15.2
 Genuine o- (n) -butoxy-ethoxy-p-cyclopentyl-amino-benzoic acid is not lowered.



   The above carboxylic acid methyl ester, used as a starting material for preparing the new ester, can be obtained as follows:

 <Desc / Clms Page number 16>

 
In 300 cm3 of absolute isopropanol, are boiled under reflux for about 10 hours, protected from humidity, 45.2 g of butoxy-ethyl benzene-sulfonate, 46 g of the potassium salt of l Methyl o-hydroxy-p-acetylamino-benzoate and 2 g of potassium carbonate. The insoluble fractions are then separated by filtration and the filtrate evaporated under reduced pressure. To saponify, the residue is boiled at reflux for about 6 hours with 200 cm3 of ethanol, 100 cm3 of water and 70 cm3 of a decanormal solution of sodium hydroxide.

   The whole is concentrated to about a third of its volume, under reduced pressure, and acidified with glacial acetic acid * The amorphous precipitate is extracted with ethyl acetate and washed with a 10% chloride solution. sodium. After having dried over sodium sulfate, the ethyl acetate solution was evaporated under reduced pressure.



  From the residue, crystals, melting at 93-95, are obtained by recrystallization from a mixture of ethyl acetate and gasoline 2: 1. Further purification can be obtained by recrystallizing from 80% or 100% methanol or from benzene. The o-butoxy-ethoxy-p-amino-bensoic acid thus prepared pure for analysis melts at 95 - 960. For conversion to methyl ester, 15.2 g are stirred with 100 cm3 of methanol and while cooling, add 40 cm3 of concentrated sulfuric acid dropwise. Then boiled under reflux, laying two to four heifers, in a water bath.

   All in

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 stirring, the cooled mixture is introduced into a mixture of 500 g of ice, 70 cm3 of 25% ammonia and 100 cm3 of water. Using glacial acetic acid, the pH is adjusted to approximately 6. The crystalline precipitate is filtered off and washed with water. After recrystallization from a little methanol, while cooling to - 15, the new methyl ester is obtained, melting at 92 - 93. To introduce the cyclopentyl residue into the aminogenic group, 24.4 g of the ester are hydrogenated with 12. 6 g of cyclopentanone, in the presence of 250 mg of platinum oxide and 25 cm3 of binormal hydrochloric acid, in 250 cm3 of methanol.

   After six to eight hours? the catalyst is filtered off and the hydrochloric acid is neutralized with 10 g of sodium bicarbonate. The precipitated salts are filtered off and the solution evaporated in vacuo.



  The residue is taken up in ether and washed with sodium bicarbonate solution; by evaporation, 29.4 g of a weakly yellow-greenish oil are obtained, which oil is distilled under a high vacuum; it boils at 162 - 1640 under a pressure of 0.008 mm. By alkaline saponification of the ester, the above-mentioned carboxylic acid with a melting point of 69-70 is obtained.



   Example 6.



   1.68 g of methyl o- (n) -butoxy-ethoxy-p-cyclopentylamino-benzoate with 7.75 g of monomethyl ether are alcoholysed according to the method described in the previous example.

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 than undeca-ethylene glycol. After the treatment and filtration of an ethereal solution on aluminum oxide, 3.2 parts by weight of the new ester of formula are obtained
 EMI18.1
 as a weak yellowish oil which is soluble in acetone, chloroform and ethyl acetate; a 10% aqueous solution of this ester shows a cloud point of 47.



   Undeca-ethylene glycol monomethyl ether is obtained as follows:
64.3 g of nonaethylene glycol monomethyl ether, with a melting point of 13-14, are converted to ester of benzene-sulfonic acid. At 100-110, 65 g of this oily ester are added dropwise to a mixture obtained by dissolving 2.8 g of sodium in 60 cm 3 of diethylene glycol.



  It is left to stand overnight at 100-1100 under a nitrogen atmosphere. The reaction mixture is dissolved in water and extracted with benzene. The aqueous solution was extracted with chloroform and the chloroform solution washed several times with 1% sodium chloride solution. After drying over potassium carbonate and evaporation, 54.4 g of a light yellow oil are obtained. This crude product is heated for 16 hours in a steam bath.

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 with 50 cm3 of 25% ammonia.

   After having distilled the ammoniacal solution, and having dried under vacuum in a steam bath, the oily residue is taken up in 150 cm3 of water and filtered through a column filled with a mixture of 50 because of an activated acid exchange residue and 50 cm3 of a
 EMI19.1
 basic activated exchange resin. After elution with 500 μm of water, the combined filtrates are evaporated off under vacuum and dried at 100. In this way 51 g of a practically colorless oil are obtained. When distilling under a high vacuum of the order of 0.01 mm of mercury, 43 g of ether are obtained.
 EMI19.2
 pure monomethyllic of the undca-yng3co which goes to 236 - 238.

   When cooled strongly, this ether solidifies into a snow-white crystalline mass, very hygroscopic, which, in the absence of humidity, melts at 22.

 <Desc / Clms Page number 20>

 



     Bxample 7
In the presence of catalytic quantities of sodium methoxide, alcoholysis is carried out, according to the process described in Example 8.
 EMI20.1
 5, 1.40 g (Cl (o-methoxy-p -tetrahydr.) ..... methyl pyranyl- (2) -methyl-amino-benzoate with 8.6 g of nonaethylene glycol monomethyl ether. After having distributed the reaction mixture between benzene and the aqueous solutions mentioned in Example 5, 2.8 g of the new ester of formula are obtained:
 EMI20.2
 as a yellowish oil. To purify it, it can be taken up in ether and the whole thing filtered through an aluminum oxide column.



   From the ethereal solution, 2.3 g of the new compound are obtained by evaporation as a very slightly yellowish oil which, except in aliphatic hydrocarbons, is readily soluble in almost all organic solvents. The squint point of a 10% aqueous solution is 62.
 EMI20.3
 



  Methyl o-mdthoy-p-ttra-hydro-pyranyl-2-mthyl-amino-benzoate used as a starting material can be obtained as follows:

 <Desc / Clms Page number 21>

 Stirred for 20 hours at 150-160, 11.15 g
 EMI21.1
 methyl o-methoxy-p-amin.o-berazvate, 40 cm3 of 2-tetra-hydropyranyl-carbinol and 6 g of Raney nickel. The insoluble fractions are then separated by filtration and washed well with hot methanol. From the combined filtrates, 12 g of a residue are obtained by evaporation in vacuo, which residue is washed in ether, normal hydrochloric acid and saturated sodium bicarbonate solution.

   The 4.4 g of the residue from the ether solution are then subjected to alkaline hydrolysis, to obtain the free carboxylic acid directly. After crystallization from a mixture of ethyl acetate and ether, petroleum 1: 1. and in 90% methanol, 2.4 g are obtained
 EMI21.2
 o-methoxy-p¯tetrahydro-pyranyl- (2) -methylamino-benzoic acid, a melting point of 102-103. The methyl ester is obtained with diazomethane. It melts at 1080.



   Example 8
Following the indications of Example 3, we transfer
 EMI21.3
 forms 3.9 g of m- {n) -buto2cy-p-dibenzyl-amino-benzo ± acid as acid chloride which is reacted, after dissolution in 30 cm3 of dry benzene, with 17.5 g of heptaethylene glycol, in 35 cm3 of anhydrous benzene, in the presence of 2 cm 3 of pyridine, as described in the example indicated.

   By treatment
 EMI21.4
 analogous to that indicated in this example, 6.2 g of a slightly colored viscous oil is obtained, which consists of

 <Desc / Clms Page number 22>

 
 EMI22.1
 mOIlo-e ..; tü.t "m- (n) -butoxy-p-dibel1zylamlno-benzoY.que of heptaethylene glycol, of formula:
 EMI22.2
 
To purify it, this crude product, dissolved in ether, is allowed to flow through a column of 200 g of aluminum oxide, a very small amount of impurity being eluted. Other by-product fractions can be eluted with methylene chloride, while the monoester is obtained by eluting with methylene chloride containing increasing levels of chloroform.



   The hydrogenating debenzylation of the monoester in a manner analogous to that indicated in the example above,
 EMI22.3
 provides the monoester of m- (n) -butoxypwamino'betzo5 acid: than with heptaethylene glycol, of formula:
 EMI22.4
 It is easily soluble in water and in some of the usual organic solvents, and is separated from solution.
 EMI22.5
 10% aqueous, when heated above 420, as a milky cloudiness.

 <Desc / Clms Page number 23>

 



   Example 9
In the presence of catalytic quantities of sodium methoxide, alcoholysis is carried out, according to the method described in
 EMI23.1
 Example 5, 2e8 g <3'o- (n) -butoxy-p-butyla! Sino'.benEoate of methyl with 18 g of purified technical monomethyl ether of polyethyleneglycol 0o'da average molecular 750. The mixture is purified. reaction mixture by partitioning between benzene and a saturated solution of sodium bicarbonate and, by evaporating the benzene solution, 9.8 g of the new mixture of esters @ - formula:
 EMI23.2
 in the form of a viscous, almost colorless oil, which is soluble in water at body temperature of animals at
 EMI23.3
 hot blood.

   The sign; = 17 means that the new ester mixture contains on average about seventeen links per
 EMI23.4
 polyethylene glycolic chain. The purification of the starting polyethyleneglycol is known and described for example in French patent No. 1,032,512 by the applicant, applied for on February 15, 1951,
Example 10
As described in Example 3, we transform 4.2 @
 EMI23.5
 o- (n) -hexoxy-p-dibenzylamino-bonzoque acid to chloride

 <Desc / Clms Page number 24>

 esterified with 20 g of ether #, # '- di- [2-hydroxy-n-propyl- (1)

  ] of heptaethylene glycol and isolates the reaction product as indicated in this example. After removing the two benzyl residues by catalytic hydrogenolysis and chromatography as described in example 8 (for the elimination
 EMI24.1
 c "1-zïïotz), at t" *, 11, {..... 1. ",:" "": '"1 new ........ t.! ..." ;, ,,, 1 3 formula:
 EMI24.2
 
 EMI24.3
 under the for-r.:o ('.:. ::: j8 oil ..: -. gt: "' e soluble ê:.: 'c water at Su body temperature clcc" "' ''. 1 '' - Ht '' warm blooded.



  R '0'hcr çC4 sf.- 2-8ai'y'G' 'â'à - n-ppo C'6.Ei''ue- Ce l'n.c: pt: 8G'; Yll: - .: g:,: col uses coHES-e starting material in this little er-ssnipls ". ;; r $ obtained in the following way A 260 in 'of t1étnYlèneg1ycol e solution in 2000 cm3 of bj sir.o9 is added regularly , over 2 hours - / 2, stirring well and cooling from time to time to 30-35, 800 cm of bsnsene sulfochloride and 400 g of powdered sodium hydroxide. Stirring is continued for 24 hours, then allowed to stand During mild days Adding 2500 cm3 of water completely dissolves the reaction mixture in two layers.



    The two layers are separated and the aqueous layer is extracted by stirring it with 400 cm3 of benzene. After combining the benzene solutions and adding 200 cm3 of a solution

 <Desc / Clms Page number 25>

 25% aqueous ammonia * stirred in a machine for 4 hours. Then add 200 cm3 of a binormal solution of sodium hydroxide and shake again for a short time.



  The aqueous layer is separated and extracted by stirring it with 400 cm3 of benzene. The two benzene layers are washed and stirred with 200 cm3 of a binormal solution of sodium hydroxide and then with 200 cm3 of water. After having combined and dried over sodium sulfate, the benzene is removed by evaporation under a partial vacuum and thus obtained 820 g.
 EMI25.1
 of crude dibenzene-sulfonic ester of trlethylene glycol which is recrystallized from 10,000 cm 3 of methyl alcohol. Cooling slowly to -17 gives 690 parts by weight of the crystalline diester, melting at 38-39.



   215 g of this diester are liquefied by mixing it with a little ether and adding everything dropwise over 4 hours at a bath temperature of 110, stirring well and away from humidity. , 350 cm from a 2.85-nor- solution
 EMI25.2
 male of dlethyleneglycol, sodium iate in diethyleneglycol.



  Heat for another 24 hours at 100-110.



   The cooled reaction mixture is extracted to exhaustion with ether. 442 g of an almost colorless oily residue and 200 g of crystalline sodium benzenesulfonate are thus obtained. 100 cc of a 25% aqueous ammonia solution is added to the extract and left to stand overnight, then slowly heated to 100. We heat

 <Desc / Clms Page number 26>

 for two hours at 1000 and then evaporate completely under the vacuum of the water pump.

   442 g of an almost colorless oil remain which is passed through an aqueous column of mixed bed exchangers consisting of
100 cm3 of Amberlite JR 120 and per 100 cm3 of Amberlite JRA 410.



  Elution is carried out until exhaustion with water and, by evaporation of the water under the vacuum of the water pump, 436 g of an oil which is only slightly colored and from which is obtained is obtained. by distillation under a high vacuum, 303 g of triethylene glycol and, under a pressure of 0.008 mm and at 157, 104 g of heptaethylene glycol. Finally, 6 g of dodecaethylene glycol as the main high-boiling point by-product can be separated at 2250 and under a pressure of 0.03 mm from 3 g of distillation residue.



   In 100 cm3 of benzene, 32.7 g of hepta ethylene glycol are dissolved and added regularly, over one hour, with agitation. both vigorously and cooling from time to time at D25-300, 40 cc of bensene sulfochloride and 20 g of powdered sodium hydroxide. The mixture is stirred for three more hours and the temperature is allowed to rise to a maximum of 40 without cooling.



   After leaving to stand overnight, the salts are dissolved by adding 120 cm3 of water and the two layers are separated. The aqueous layer is then extracted with 20 cm of benzene. The benzene solutions are combined, add

 <Desc / Clms Page number 27>

 10 cm3 of 25% ammonia and shake for 4 hours in the machine. Another 10 cm3 of a binormal sodium hydroxide solution is added and further shaking for a short time.



  The aqueous layer is separated and extracted with 20 cm3 of benzene. The two benzene layers are washed by shaking them with 10 cm3 of a normal solution of sodium hydroxide, then three times with 10 cm3 of water each time. From the combined benzene solutions and dried over sodium sulphate, by evaporation of the benzene under partial vacuum, 58 g of the di-benzene-sulphonic ester of hepta-ethylene glycol, oily, slightly yellowish, are obtained.



   A solution of 56.7 g of this diester in 100 carbons of absolute benzene is added dropwise over one hour at a bath temperature of 80, with stirring and protected from humidity. 70 cm3 of a 2.85 -normal solution of sodium 1,2-propylene glycolate in 1,2-propylene glycol.



  Further heat for 20 hours at 80 with gentle stirring.



   After allowing to cool, the separated benzene tallow sodium wadding is dissolved by adding 75 cm 3 of water and the aqueous layer is separated. It is extracted three times, shaking it each time with 250 cm3 of chloroform. By evaporation of the dried and combined chloroform solutions, 48.2 g of a crude product are obtained, which product is left to stand for two days after adding 50 cm 3 of an aqueous solution thereto.

 <Desc / Clms Page number 28>

   to 25% ammonia, and then slowly heated to 800.



  The water and ammonia are filtered off under a water pump vacuum and the residue is allowed to flow through a mixed, wet bed of exchangers, consisting of 25 cm3 of Amberlite JR 120 and 50 cm3 of 'Amberlite JRA 410. The column is washed with water until exhaustion and obtained / by evaporation of the eluates, 44 g of a brownish oil from which is distilled under a
 EMI28.1
 high vacuum 32 g of heptaethyleneglycol <o, <R'-di-2-hydroxy-H-propyllque- (l)] ether in the form of a colorless oil passing to 1820 under a pressure of 0.01 .



   Example 11
 EMI28.2
 ..,. ¯¯¯..¯ ... ¯..¯
In a stirred autoclave, 110 g of monomethyl ether are heated to 170-180, in a nitrogen atmosphere.
 EMI28.3
 polyethylene glycol, technical, dry, of an average molecular weight of 550, with 0.2 g of potassium hydroxide. 52 g of 1,2-epoxy-propylene are then passed slowly under pressure with nitrogen. Condensation is terminated after a short time, which can be seen from the pressure drop
 EMI28.4
 due to the consumption of epOx1-POPYlene.

   To purify the brown contents of the autoclave which, after heating for half an hour at 100 under a pressure of 10 mm of mercury, weighs 161.6 g, it is dissolved in 750 cm3 of water and shaken for 3 hours with 8 g of activated carbon. Filtered, the residue washed with 120 cm3 of water and added. To the filtrate 100 g of chloride.

 <Desc / Clms Page number 29>

 sodium. By extracting with chloroform until exhaustion, after evaporation and drying at 1000 BUS empty, 157 g of a light yellow oil with a molecular weight of 810 are obtained, based on the determination of the hydroxyl number.



  The polyether alcohol thus obtained is a mixture of various stages of polymerization of formula:
 EMI29.1
   n having an average value of 12 and la as n @ y an average value of 15.



   19 g of this product are esterified with 4 g of m- (n) -butoxy-p-dibenzyl-amino-benzoyl chloride according to the Method described in Example 3, then the reaction product is isolated. After cleavage of the two benzyl residues by hydrogenolysis in the presence of carbon with palladium, the new mixture of esters of formula is obtained:
 EMI29.2
 as a viscous, substantially colorless oil which is soluble in water at room temperature.

   In the above formula, n has an average value of about 12, and the sum n + y averages about 15.

 <Desc / Clms Page number 30>

 



   Example 12
In the presence of catalytic quantities of potassium ethoxide, alcoholysis is carried out, according to the method described in
 EMI30.1
 Example 5, 4.45 g of methyl 5- (n5-heptoxy-5-dlbônzylamlno-benzoate with 11 g of methyl ether, m '- (2-hydroxY-3-ethoxy-propyl) of Ilocta- ethylene glycol After partitioning between benzene and a saturated solution of sodium bicarbonate, after evaporation of the benzene layers, an ester-polyether is obtained which, by hydrogenation with palladium carbon at room temperature in glacial acetic acid, is obtained. turns into a new ester of formula
 EMI30.2
   which is soluble in water at room temperature and constitutes a practically colorless oil.



   The methyl ester used above as an intermediate product can be obtained as follows:
12 g of 3- (n) -heptoxy-5-nitro-benzoic acid (cf. Journal of the American Chemical Society 77 4061 [1955]) are dissolved in 100 cm 3 of ether and slowly added an equimolecular amount of a solution of diazomethane in ether. When the evolution of nitrogen has ceased, it is still left to stand for half an hour at room temperature,

 <Desc / Clms Page number 31>

 After evaporation of the ether, 13.1 g of a residue are obtained which can be crystallized from methanol by cooling to -15. The methyl 3- (n) -heptoxy-5-nitro-benzoate thus prepared melts at 250.

   11.7 g of it are hydrogenated in the presence of charcoal with palladium in a mixture of methanol and glacial acetic acid 1: 1 at room temperature and at atmospheric pressure, until the calculated quantity of hydrogen has been absorbed. . After removal of the catalysts by filtration, evaporated in vacuo. The residue is taken up in ether and this solution is washed with a binormal solution of sodium carbonate and with water. The ethereal solution, after having been dried over sodium sulphate, gives up by evaporation a residue which, after recrystallization in 80% methanol, melts at 67. To further purify it, it can be dissolved in benzene and filtered through a little aluminum oxide.



  After having removed the benzene by distillation, it is recrystallized once again from cyclohexane, after which the methyl 3- (n) -heptoxy-5-amino-benzoate with a melting point of 68 is obtained. -69 in the form of colorless flattened prisms. The yield is; 8; 4 g. The N-dibenzylated compound of this ester is obtained according to the method described in Example 3, the crude dibenzylated derivative is. first hydrolyzed to free carboxylic acid which melts, after recrystallization from methanol and gasoline, at 99-100. From this free carboxylic acid one obtains the methyl ester by reaction

 <Desc / Clms Page number 32>

 on diazomethane dissolved in ether. This methyl ester melts at 46-47.



   Example 13
According to the indications given in Example 2, alcoholysis is carried out for 2 hours, in the presence of 0.2 cm3 of a 25% solution of sodium methoxide in absolute methanol,
 EMI32.1
 3.5 g of methyl 3- (n) -heptoxy-5-dibenzylan! Ino-benzoate <3 (cf. Example 12) with 8 g of deca-ethylene glycol monomethyl ether. By isolating the reaction product in an analogous manner, 7 g of a viscous, almost imperceptible oil is obtained.
 EMI32.2
 colore, which consists of the 3- (n) '- heptoxy-5-di-' benzy.amino-ben2o ester: that of deoa-ethylene glycol monomethyl ether of the formula-;
 EMI32.3
 
Its purification and debenzylation can be carried out in a manner analogous to that indicated in Example 3.

   The crude product which is then obtained is allowed to flow, in solution in ether, through a column of 50 g of aluminum oxide. The eluates leave by evaporation a viscous colorless oil which is constituted

 <Desc / Clms Page number 33>

 by the 3- (n) -heptoxy-5-amino-benzoic ester of the mono-methyl ether of deca-ethylene glycol, of the formula
 EMI33.1
 This compound is readily soluble in water and in many common organic solvents, and it separates from a 10% aqueous solution, when heated above 54, as a milky haze.



   The monomethyl ether of deca-ethylene glycol which is used in this example can, like the monomethyl ether of undeca-ethylene glycol described in Example 6, be obtained from the benzene-sulfonic ester of the ether. monomethyl of nona-ethylene glycol with ethyleneglyool.



  Following the procedure described in Example 6, 56 g of the novel polyether, boiling at 218-220 under a pressure of about 0.01 mm of mercury, are obtained in the form of a colorless oil which, when it is subjected to a thorough cooling, solidifies into a hygroscopic mass of a snow white which melts at 18-18.5 in the absence of humidity.



   If methyl 3- (n) -heptoxy-5-dibenzylamino-benzoate is alcoholized with mono-methyl ether of octa-ethylene glycol instead of the alcoholysis with mono-methyl ether of decaethylene glycol used above, we then finally obtain the 3- (n) -heptoxy-5-amino-benzoic ester of mono-methyl ether of octaethylene glycol which has properties similar to those of the ester described above. -above*


    

Claims (1)

Claims. I. A process for preparing new esters, characterized by the fact that esters of the formula are prepared in a manner known per se: EMI34.1 in which R and R 'represent an alkyl, ring-alkyl, alkoxyalkyl, a saturated oxacycloalkyl-alkyl-radical comprising from 1 to 7 carbon atoms, and R may also be hydrogen, R "represents 1 'hydrogen or an alkyl or alkoxyalkyl residue having at most 4 carbon atoms, R "' is put for hydrogen or a methyl or ethyl residue, and n indicates, as an integer with a value of 7 to 15, the number of identical or different remainders put in parentheses in the formula, with this condition that in at least n / 2 remainders of formula: EMI34.2 R 'represents hydrogen. The present process can be further characterized by the following points: <Desc / Clms Page number 35> 1) We convert benzoic acids of formula; EMI35.1 where appropriate, in the form of their reactive derivatives, in their esters with polyglycols of formula: EMI35.2 R to R "'and n having the meaning given under I. 2) Benzoic acids of the formula Indicated under 1) are reacted, where appropriate in the form of their reactive derivatives, with polyglycols of formula: EMI35.3 in which R ", R" 'and n have the meaning given under I., where appropriate in the form of their reactive derivatives. 3) Benzoic acids of the formula indicated under 1), or their reactive functional derivatives, are reacted with polyglycols of the formula indicated under 2), if necessary in the presence of condensing agents. 4) Benzoic acids of the formula given under 1) are reacted in the form of their metal salts with reactive esters of polyglycols of the formula given under 2). <Desc / Clms Page number 36> EMI36.1 5) In a compound due faithi; iulo. EMI36.2 in which R 'to R "' and n have the meaning given under I., and X represents a residue convertible into a group R-NH, R having the meaning given under I., X is transformed into a group R-NH. 6) The operation is carried out as indicated above, R and R ′ representing alcoholic residues comprising from 1 to 7 carbon atoms, and R possibly also representing hydrogen. II. As new industrial products: 7) The compounds obtained by carrying out the process defined above. 8) Esters corresponding to the formula: EMI36.3 EMI36.4 in which R and Rt represent an alkyl, cycloalkyl, alkoxyalkyl, a saturated oxacycloalkylalkyl residue having from 1 to 7 carbon atoms, and R may additionally be hydrogen, R "represents hydrogen or EMI36.5 an alkyl or alkoxyalkyl residue comprising at most 4 carbon atoms, R "'stands for hydrogen or a <Desc / Clms Page number 37> methyl or ethyl residue, and n Indicates, as an integer with a value from 7 to 15, the number of Identical or different residues put in parentheses in the formula, admitting this condition that in at least n / 2 remainders of formula : EMI37.1 R "represents hydrogen. 9) The ester of formula: EMI37.2