DEC0009364MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: May 13, 1954. Advertised on August 23, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION-

CLASS 12q GROUP 602 INTERNAT. CLASS C 07c

C 9364 IVb / 12 q

Dr. Max Matter, Worb, Bern (Switzerland)

has been named as the inventor

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36

Process for the production of a polyglycol ester of p-amino-benzoic acid which can be used as a local anesthetic

The invention relates to the preparation of the ester of p-n-butylaminobenzoic acid with Nona-15 ethylene glycol monomethyl ether of the formula

CH ₃ -CH ₂ -CH ₂ -CH ₂ -NH-C

' ■.

and its salts.

The new ester shows valuable pharmacological Properties. So it has a pronounced local anesthetic effect, in particular it works selectively on the stretch receptors of the lungs. It is said to be used as a remedy, preferably as a cough suppressant be used. With regard to this use, the new connection has significant advantages, compared to known, comparable esters.

^) - CO- (O-CH ₂ -

-CHa) ₉ -OCH ₃

The new ester is made as follows: So you can p-n-butylaminobenzoic acid, if necessary in the form of their reactive derivatives, directly or gradually in their esters with non-ethylene glycol monomethyl ether convict. ■

A direct method is e.g. B. in that one p-n-butylaminobenzoic acid, optionally in the form their reactive derivatives, with non-ethylene glycol monomethyl ether, possibly in the form of his

609 580/494

C9364IVb / 12q

reactive derivatives. One can proceed in such a way that one p-n-butylaminobenzoic acid with non-ethylene glycol monomethyl ether, advantageously using the usual esterification catalysts, implements or that you z. B. more volatile in the form of their anhydride, halides or esters Alcohols, such as methanol, with non-ethylene glycol monomethyl ether, advantageously in the presence of basic ones Condensation agents, such as pyridine, metal alcoholates, possibly those of the non-ethylene

CH, - CH ₉ - CH ₉ - CH ₉ - NH-?

glycol monomethyl ether itself. But you can also use their metal salts with reactive esters of Nonaäthylenglykolmonomethyläthers, especially those with strong inorganic or organic Acids, such as hydrohalic acids or organic sulfonic acids, ζ. B. the ethane or Toluenesulfonic acid, implement.

A stepwise process is that one has an alcohol of the formula

--CO - (O - CH ₂ - CH _{2) m} - OH

preferably in the form of its metal salts or reactive esters, with an alcohol of the formula

'H- (O-CH ₂ -

preferably in the form of its reactive esters or metal salts, etherified, where m and φ are integers from ι to 8 which meet the condition m - \ - φ = g .

CH ₃ -CH ₂ -CH ₂ -CH ₂ -NH-

etherified with methanol. So you can use this alcohol, optionally in the form of a reactive ester or metal salt, with methanol, optionally in the form of its metal salt or reactive ester, implement.

Another embodiment of the process consists in that in compounds of the formula

._CO- (O-CH ₂ -CH ₂ ) ₉ -O-CH ₃

_{where R 1} denotes a radical which can be converted into the n-butylamino _{group, R 1} converts into this group.

So you can z. B. convert a free amino group into the n-butylamino group, e.g. B. through implementation with reactive esters of n-butanol. But you can also connect with a free Reductively alkylate amino group or nitro group in the presence of n-butyraldehyde.

The reactions are in the presence or absence of diluents and / or condensing agents or catalysts with ordinary or carried out at elevated temperature in open or closed vessels under pressure.

Depending on the procedure, the new ester is obtained as a base or as a salt. From the salts can in a manner known per se, the free base can be prepared, from which by reaction with Acids that are suitable for the preparation of therapeutically useful salts that win the salts leave.

It is noteworthy that the new ester has considerable solubility in water. Such a solution has the characteristic of becoming cloudy when heated at a certain temperature, which is dependent on the concentration. This, ₀ solution specific to a io ° / temperature value is called the cloud point and is a physical constant. He is 45 ^0. the

CH, - CH ₉ - CH ₉ - CH ₉ - NH- <

V- CO - (0-CH ₂

-CH ₂ ) ,, - OH

CH ₂ ) ^ - OCH ₃ ,

Another method consists in making an alcohol of the formula

Turbidity is reversible; the solution clears again on cooling.

The compounds mentioned as starting materials are known or can be according to known ones Establish methods.

The invention is described in the following example. Between part by weight and part by volume exists the same relationship as between granim and cubic centimeter. The temperatures are in Degrees Celsius.

example

4.42 parts by weight of ethyl pn-butylaminobenzoate with 17.2 parts by weight of Nonaäthylenglykolmonomethyläther, which ^{boils at 0.01 mm Hg at 190 0} , placed in a closed reaction vessel, which has an adjustable inlet for. Solvent and is connected to a connection for distilling off in vacuo. For complete drying is heated and during 1 hour at 100 to 105 ⁰ introduced at a vacuum of 12 mm Hg absolute xylene under the surface of the mixture. This creates a constant flow of xylene vapor through the entire apparatus, which carries away the last traces of moisture and other volatile impurities. The xylene is condensed in a condenser. The mixture is cooled to 20 to 30 ^° and 0.06 part by weight of sodium methylate, dissolved in 0.6 part by weight of methanol, is added. Then, again in vacuo at 100 to 105 ⁰ J, xylene is passed through, all of the methanol and the ethanol formed during the transesterification evaporating. The transesterification is allowed to proceed under these conditions until a sample of the reaction mass is clearly soluble in cold water, which is the case after approximately 2 to 3 hours. There is now an almost quantitative yield of the ester of p-butylaminobenzoic acid with non-ethylene glycol monomethyl ether of the following formula:

-CO - (O _{-CH 2} - CH ₂ J _{9 -OCH 3}

580/494

C 9364 IYbIUq

arose, which still contains excess Nonaäthylenglykolmonomethylather. For purification, is dissolved in benzene and mshrmals washed with 5 ° / _o sodium carbonate solution. It is advisable to shake out all washing solutions with fresh benzene. The new ester remains with this distribution between benzene and sodium carbonate solution in the benzene, the excess Nonaäthylenglykolmonomethyläther and little brown impurities are removed from the

ίο added dilute sodium carbonate solution. By evaporating the dried and nitrated benzene solution, the new ester is obtained in the form of a colorless to very pale yellow oil, which is easily soluble in most organic solvents, with the exception of aliphatic hydrocarbons. The new ester is precipitated by heating to about 45 ° from a io ° / ₀ aqueous solution; however, it easily goes back into solution on cooling. It is ideally suited for therapeutic anesthesia. Aqueous solutions are stable and can be sterilized.

The non-ethylene glycol monomethyl ether mentioned as the starting material can be prepared as follows: 23 parts by weight of sodium are at 90 to 100 ° in

250 parts by volume of ethylene glycol dissolved. Then left at 100 to 100 ° bath temperature in the course of 6 hours with thorough stirring, 433 parts by weight of octaethylene glycol monomethyl ether benzenesulfonate drop in and leave for 17 hours without

Stir in an oil bath from 100 to 100 °.

After cooling, the reaction mixture is distributed between 500 parts by volume of water and 1000 parts by volume of chloroform. The aqueous layer is extracted four times with 500 parts by volume of chloroform each time and the chloroform layers are washed one after the other with 500 parts by volume of water. The combined chloroform extracts are dried and evaporated. This gives 353 parts by weight of an oily, dark brown residue. This is mixed with 100 parts by volume of 25 ° / ₀ ammonia and allowed to stand overnight at room temperature, then heated for 2 hours at 90 ^0, and finally evaporated in a water pump vacuum on a water bath to dryness. In this way, 350 parts by weight of a residue are obtained. It is dissolved in 175 parts by volume of water and allowed to flow through a column of a mixture of 100 parts by volume of a sulfonic acid polystyrene cation exchanger and a quaternary ammonio-polystyrene anion exchanger, activated separately and then mixed. It is rewashed with 175 parts by volume of water and evaporated. 335 parts by weight of an oily residue are obtained in this way. It is washed again with water and 2 eluates of 175 parts by volume of water each are collected, which on evaporation (10 mm, 100 °) yield 9 or 0.20 parts by weight of oil as residues. Fractional distillation in a high vacuum of 0.01 mm gives at 190 ⁰ 300 parts by weight of nonethylene glycol monomethyl ether as a colorless oil in addition to a little forerunner and 38 parts by weight of distillation residue which solidifies to brown crystals.

The Octaäthylenglykolmonomethylätherbenzolsulfonat mentioned is obtained as follows: 383 parts by weight in 500 parts by volume of Octaäthylenglykolmonomethyläther are dissolved benzene and added over a period of ι hour at 20 to 30 ⁰ simultaneously with good agitation with 180 parts by volume of benzenesulfonyl chloride and 100 parts by weight of powdered sodium hydroxide. The mixture is stirred for a further 2 hours and then left to stand overnight without stirring. The Pu is significantly higher than 7. 600 parts by volume of water are stirred in, forming two layers. The aqueous layer is extracted once with 200 parts by volume of benzene. The two combined benzene solutions are mixed with 50 parts by volume of 25 ° / ₀ ammonia and shaken for 4 hours on the machine, then with 50 parts by volume 2 N sodium hydroxide solution again shaken for a short time. The aqueous layer is extracted again with 200 parts by volume of benzene and the two benzene layers are washed one after the other with 50 parts by volume of 2η sodium hydroxide solution and 50 parts by volume of water. 473 parts by weight of crude sulfoester are obtained from the combined and dried benzene extracts by evaporation in vacuo.

The aqueous extracts can be extracted once with 500 parts by volume of chloroform 30 parts by weight of octaethylene glycol monomethyl ether can be recovered.

The Octaäthylenglykolmonomethyläther in turn can be recovered as follows: 35 parts by weight of sodium are dissolved at 90 to ioo ⁰ in portions into 500 parts by volume of triethylene glycol. 522 parts by weight of pentaethylene glycol monomethyl ether benzene sulfonate are added dropwise over the course of 7 hours at 100 to 100 ° C. bath temperature with vigorous stirring and then left to ^{stand for 20 hours in an oil bath at 100 to 100 ° C.} (nitrogen atmosphere) without stirring.

After cooling, 300 parts by volume of water are added and the mixture is shaken well together with 1 liter of chloroform. The aqueous layer is extracted four times with 250 parts by volume of chloroform each time. The chloroform extracts are extracted twice in succession with 150 parts by volume of water each time. Are obtained from the chloroform extracts by drying and evaporation, 499 parts by weight of crude product which was ° / ₀ ammonia mixed well with 100 parts by volume of 25, allowed to stand overnight and then for 4 hours at ioo ° heated. It is evaporated in a vacuum in a water jet and 495.5 parts by weight of a residue are obtained. This is diluted with 250 parts by volume of water and allowed to flow through a column consisting of a mixture of 100 parts by volume of a sulfonic acid polystyrene cation exchanger and a quaternary ammonio-polystyrene anion exchanger. It is washed with 500 parts by volume of water and the eluate is evaporated at 10 mm and 100 °. A residue of 487 parts by weight is obtained.

484 parts by weight of the crude product prepared in this way result in 10 parts by weight of first runnings, 79 parts by weight of solidifying distillation residue and 400 parts by weight of octaethylene glycol monomethyl ether of bp _OiO1 165 ^{0 in} high vacuum distillation.

The pentaethylene glycol monomethyl ether benzene sulfonate used above can be made as follows

609 580/494

C 9364 IVbJ12q

530 parts by weight of benzenesulfonic acid ester of diethylene glycol monomethyl ether are allowed to flow over the course of 4 hours at 100 ° with stirring to a solution of 50 parts by weight of sodium in 800 parts by volume of triethylene glycol and the reaction mixture is kept at 100 ° ^C. overnight. After cooling, add 500 parts by volume of water and 100 parts by volume of chloroform and shake well. The chloroform layer is extracted twice more with 250 parts by volume of water each time and then evaporated. It leaves behind 220 parts by weight of crude pentaethylene glycol monomethyl ether. Extracting the three water layers five times with 500 parts by volume of chloroform each gives a further 250 parts by weight of crude pentaethylene glycol methyl ether. 400 parts by weight of the pure ether are obtained as a colorless oil from the crude product by distillation in a high vacuum at 0.01 mm and 100%.

50 parts by weight in 100 parts by volume of Pentaäthylenglykolmonomethyläther are dissolved benzene and added dropwise with 35 parts by volume of benzenesulfonyl chloride for ¹ Z ₂ hours under stirring and cooling at 20 to 30 ^0th At the same time, 15 parts by weight of powdered sodium hydroxide are introduced in equal portions. It is stirred for 2 ¹ I continued _{for 2} hours and then allowed to stand without stirring overnight. Then one filtered off under suction from the precipitated salts and the filtrate washed with 20 volumes of shaking 25 ° / ₀ aqueous ammonia for 4 hours. Any benzenesulfonyl chloride that may still be present is converted into the alkali-soluble sulfamide. With 50 volumes of io ° / ₀ is added sodium hydroxide solution and shake thoroughly. The aqueous layer was extracted once with 150 parts by volume of benzene and the two benzene extracts washed successively with 50 parts by volume io ° / ₀ sodium hydroxide solution and 50 parts by volume of water. Evaporation of the dried benzene solution gives 70 weight percentages

4.0 parts of solvent-free benzene sulfonic acid ester des Pentaethylene glycol monomethyl ether as an almost colorless oil.

Another method for preparing said Nonaäthylenglykolmonomethyläthers is performed as follows: Dissolve 41.5 parts by weight in 200 parts by volume of chloroform Nonaäthylenglykol, can simultaneously with good agitation at 15 to 30 ⁰ 15 parts by volume of benzenesulfonyl chloride, and 30 parts by volume I7 ° / _o aqueous sodium hydroxide solution in Drop in over the course of 1 hour and stir for a further 3 hours. After 30 hours, the chloroform layer is separated off and washed three times with 50 parts by volume of water each time. The aqueous layers are exhaustively extracted with chloroform. The chloroform extracts give 50 parts by weight of crude ester which, dissolved in 450 parts by volume of water, yields 18.5 parts by weight of enriched nonethylene glycol dibenzenesulfonic acid ester on extraction with carbon tetrachloride. By extracting the aqueous solution with benzene, 28 parts by weight of nonethylene glycol monobenzenesulfenic acid ester are obtained, which are dissolved in 30 parts by volume of methyl alcohol for 1 hour at 75 to 85 ° and with stirring to form a solution of 1.8 parts by weight of sodium in 70 parts by volume of methyl alcohol in a flask Let the reflux condenser flow with exclusion of moisture. The mixture is stirred for a further 2 hours and then left to stand in the bath at 70 to 80 ° for 20 hours. The reaction mixture is evaporated in a water jet vacuum, and the residue is stirred with 50 parts by volume of water and 200 parts by volume of chloroform. By exhaustive extraction of the aqueous layer with chloroform, 'in portions to 100 parts by volume and washing the extracts with 25 volume parts water 21.5 parts by weight of crude product is obtained, which, as described, with 25 ° / _o ammonia, and a mixture is treated in ion exchangers. This gives 21.3 parts by weight of evaporation residue, from which 19.4 parts by weight of colorless non-ethylene glycol monomethyl ether and 1.6 parts by weight of solidifying distillation residue are obtained by distillation in a high vacuum.

The non-ethylene glycol mentioned as the starting material can be obtained in the following manner: 280 parts by volume of triethylene glycol are obtained. dissolved in 2000 parts by volume of benzene and mixed with vigorous stirring and cooling over the course of 1 hour at 30 to 35 ° at the same time with 800 parts by volume of benzene sulfochloride and 400 parts by weight of powdered sodium hydroxide. The mixture is stirred for a further 30 hours and then left to stand for 1 day. The crystallized salts and the excess sodium hydroxide are dissolved by stirring in 2500 parts by volume of water and the aqueous solution is extracted with 200 parts by volume of benzene. The combined benzene extracts were combined with 100 parts by volume of 25 ° / ₀ aqueous ammonia and shaken for 4 hours on the machine. Finally, shakes it again a short time with 200 parts by volume of io ° / ₀ aqueous sodium hydroxide solution. The aqueous portions are separated, the benzene solution is then washed with 100 parts by volume of water with 100 parts by volume io ° / ₀ sodium hydroxide solution and aqueous and all parts consecutively extracted with 200 parts by volume of benzene. Evaporation of the combined and dried benzene extracts gives 820 parts by weight of crude ester as a pale brownish oil which crystallizes from 10,000 parts by volume of methyl alcohol. This gives 665 parts by weight Triäthylenglykoldibenzolsulfonat mp 38-39 ^0th

215 parts by weight of the diester thus obtained in 25 parts by volume of anhydrous ether are added dropwise to a solution of 26 parts by weight of sodium in 400 parts by volume of triethylene glycol over a period of 4 hours at 100 to 100 ° with thorough stirring and with exclusion of moisture. The mixture is stirred for a further 6 hours and then left to stand without stirring at 100 to 10 hours. In the exhaustive extraction with ether in a continuously operating apparatus is obtained 460 parts by weight of an almost colorless oil which was 25 ° / is allowed to stand with 100 parts by volume of ₀ ammonia overnight. Then it is evaporated, taken up in 225 parts by volume of water and allowed to flow through a column of a mixture of a sulfonic acid polystyrene cation exchanger and a quaternary ammonio-polystyrene anion exchanger in order to add ionic components

580 / "+

C 9364 IYbIUq

remove. When evaporated in a water jet vacuum, the eluate gives 465 parts by weight of an almost colorless oil. By high vacuum distillation, in addition to 290 parts by weight of excess triethylene glycol 110 parts by weight of nonethylene glycol from

Bp. 0.01 ^τ 9 °° as ^a colorless oil and 50 parts by weight of a wax-like solidifying residue.

Furthermore, one can use the mentioned non-ethylene-

receive glycol monomethyl ether as follows: The mixture is allowed simultaneously in the course of 2 hours 200 parts by volume of 3O ° / ₀ sodium hydroxide solution and 200 parts by volume of benzenesulfonyl chloride under stirring at 20 ° chloroform dropwise into a solution of 400 parts by volume of triethylene glycol in 3000 parts by volume. The mixture is stirred overnight and then left to stand for 1 day. The precipitated salts are dissolved by stirring in 200 parts by volume of water and the chloroform layer is separated off, which is freed from about 100 parts by weight of unreacted triethylene glycol by extraction with water. The chloroform layer is evaporated and the 380 parts by weight of the oily residue is extracted exhaustively with water. The aqueous extract containing the monoester is exhaustively extracted with benzene. The benzene extract is evaporated and so gives 320 parts by weight of monobenzenesulfonic acid ester of triethylene glycol as an almost colorless oil. 165 parts by weight of triethylene glycol monomethyl ether and 220 parts by weight of 25% sodium methylate solution in methyl alcohol are mixed in a stirred flask with a reflux condenser, with the exclusion of moisture, and a further 200 parts by volume of benzene are added. The benzene is evaporated together with the methyl alcohol in a water jet vacuum and again

CHo-CH ₂ -CH ₂ -CH ₂ -NH-

fetches the evaporation three more times after adding 200 parts by volume of fresh, anhydrous benzene each time. The evaporation residue is dissolved in 250 parts by volume of benzene and can in the course of 2 hours with good stirring at 90 ⁰ bath temperature a solution of 295 parts by weight of the Monobenzolsulfonsäureester Triäthylenglykols in 300 parts by volume of dry benzene dropwise. The mixture is stirred for a few hours and then left to stand in the 80 ° bath overnight. The precipitated sodium benzenesulfonate is filtered off with suction and the filtrate is evaporated. The residue is taken up in 150 parts by volume of water and the solution is allowed to run through a mixture of 100 parts by volume of a sulfonic acid polystyrene cation exchanger and a quaternary ammonio-polystyrene anion exchanger for complete deionization. The evaporation residue of the eluate was fractionally distilled under high vacuum and yields at 0.005 ^mm and 130 ⁰ 240 parts by weight Hexaäthylenglykolmonomethyläther, be implemented as a sodium compound in benzene with 295 parts by weight Triäthylenglykolmonobenzolsulfonat to 340 parts by weight Nonaäthylenglykolmonomethyläther of the 300 parts by weight according to the above description. The two reaction steps can also be carried out in succession in the same flask without working up the hexaethylene glycol monomethyl ether.

Claims (6)

PATENT CLAIMS: i. Process for the production of a local anesthetic p-amino-benzoic acid polyglycol esters of the formula I which can be used - (0 - CH ₂ - CH ₂ ) ₉ - OCH ₃ , (I) characterized in that p-n-butylaminobenzoic acid, optionally in the form of their reactive derivatives, with non-ethylene glycol monomethyl ether, optionally in the form of its reactive derivatives, esterified. 2. The method according to claim i, characterized in that that the esterification is carried out in the presence of condensing agents. 3. The method according to claim 1, characterized in that p-n-butylaminobenzoic acid in Esterified form of their metal salts with reactive esters of nonethylene glycol monomethyl ether. 4. Process for the production of a p-amino-benzoic acid polyglycol ester which can be used as a local anesthetic of the formula (I), characterized in that an ester of the general formula (II) CH3 -NH- < CO- (O- CH ₂ - CH _{2) ra} - OH (Π) optionally in the form of a metal salt or reactive ester, with an alcohol general formula (III) H- (O-CH ₂ -CH ₂ ) ^ - OCH ₃ (III)
optionally in the form of a reactive ester or metal salt, etherified, where m and p are integers from 1 to 8 which meet the condition m -f- f = 9. 5. Method of making a local anesthetic usable p-amino-benzoic acid polyglycol ester of the formula (I), characterized in that that the ester of the formula (IV) CH ₃ - CH ₂ - CH ₂ - CH ₂ - NH- < optionally in the form of a metal salt or reactive ester, with methanol, given -> - CO - (O - CH ₂ - CH ₂ ) ₉ OH (IV) if in the form of a reactive ester or metal salt, etherified. 609 580 / 494- C 9364 IVbIUq 6. A process for the preparation of a p-amino-benzoic acid polyglycol ester of the formula (I) which can be used as a local anesthetic, characterized in that in a compound of the formula (V) i ₅ H ₂ N- -CO - (O-CH ₂ - CH ₃ ) ₉ - OCH ₃ (V) the amino group by reaction with reactive ones Esters of butanol are converted into the n-butylamino group or a compound of formula (V) or (VI) -CO- (O-CH ₂ -CH ₂ -OCH ₃ (VI) reductively alkylated in the presence of butyraldehyde. Considered publications: German Patent Specifications No. 211801, 218 389, 947; 25th British Patent No. 698 636. © 609 580/494 8.56