CA1208626A - Process for the preparation of hydrochlorides - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF HYDROCHLIRIDES

A b s t r a c t The invention relates to a process for the preparation of hydrochlorides, i.e. of acid addition salts formed with hydrochloric acid, particularly of compounds containing a protonatable nitrogen atom According to the process of the invention a compound useful to form a hydrochloride and being suitably in the form of a derivative containing protonatable nitrogen atom or in the form of a salt is reacted with a sulphonyl compound of the formula Q - SO2 - Cl, wherein Q stands for a hydroxyl, C1-4 alkyl or an aryl group, the latter being optionally substituted by a C1-4 alkyl group, in a solvent, in the presence of an alcohol, whereupon the hydrochloride obtained is recovered in a known manner.

Description

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PROCESS FOR THE PREPARAT ION OF HY~ROC.~LORIDES

This invention rela-te~ to a new proce~s for the preparation of hydrochlorides, i.e. of acid addition salts ~ormed with hydrochlorlc acid, particularly of compounds containin~ a protonatable nitroaen atom.
The hydrochloride~ o~ compounds containi~g a protonatable nitrogen atom are polar, water-soluble compound3 widely used in many areas o~ the practice, e.g. in the therapy, in the manifacture of plastics, in plant protection, in dyes, as analytical reagents, etc. The extended employment of the hydrochlcrides i9 well characterized b~ the ~act that about ten per cent of the drugs li~ted in ~Ierck's Index (Ninth Ed " Edo by M. Windholz, hIerck, Rahway, U.S.~., 1976), that is, about 900 compounds are therapeutically used in the form o~ the hydrochlorides.
The starting materials ~or the pre~aration of hydrochlorides are generally substance3 containin~ a protonatable nitrogen atom and being of 2 basic or amphoteric character, although compounds containing a nitrogen atom of acidic cha~acter, e~g. urea, can also form hydrochloride3.
In general, the hydrochlorides of these compound3 are prepared by treating a compound with hydrochlorîc acid in water or in a mixture o~ water and an organic , solvent, ~ainly an alcohol; this i~ described for o~ytetracyclin (OTC) hydrochloride in the British patent specifications Nos. 718,020 and 718,032. An other possibility for the preparation of hydrochlorides is to dissolve or suspend the starting compound in an organic solvent, e.g. in an alcohol, and to introduce gaseous hydrogen chloride into the solution or suspen~ion. Furthermore, it i9 possible to prepare a hydrochloride by means of an organic solvent, mainly of an alcohol, containing previously dissolved gaseous hydrogen chloride. The above-mentioned OTC hydrochloride i9 prepared in this way for examp-le according to the Belgian patent specification No. 638~381 or the Hu~garian patent sDecification No. 143,911. In case of this latter method the solubility relations of the starting and/or target product~ are influenced by methanolic calci~lm chloride solution (J. Am. Chem. Soc. 739 4212 /1951/;
US patent specifications Nos. 2,658,078 and 2,915,555).
In principle, the hydrochlorides can also be prepared by the interaction, i.e~ double decomposition reaction with an other organic or inorganic hydrochloride salt;
however, these processes are not frequently used in the practice as the hydrochlorides are the most soluble salts and there~ore cannot simply be isolated by precipitation or crystallization following a double decomposition reaction.

The ~ormation of hydrochloride can also oroceed in aprotic solvents or even in the ab3ence of any solvent when the proton ariging from the di~sociation of the hydrogen chloride i9 bound by the lone electron pair of the nitrogen atom of the anhydrobase ("The Chemistry of the Amino Group", Ed. by S. Patai, Inter~cience, London, 1~68), Several hydrochlorides are known to crystallize Nith hydrate water. The crystal lattice of e.g. OTC
hydrochloride is built up involving three molecules of water ~hen the amount of water i3 suf~icient ¢c~f.
Hungarian patent 3pecification No. 143,911). The ~olubility of these hydrochlorides in org~nic solvents, e,g. in alcohols, is ~ignificantly hig:~.er under anhydrous conditions t'nan in the presence of water. ~his ~eature is utilized e.g. for the preparation o~ OTC hydrochloride in such a way that the starting material, being used for the formation of the hydroc'nloride, i~ treated with a methanolic solution of` gaseous hydroaen chloride under anhydrous conditions, the solid contaminations are removed from the thus formed hydrochloride solution by filtration and then aqueous concentrated hydrochloric acid is added to give pure9 cry~talline OTC hydro-chloride in a known manner (c.f. Belgian patent speci~i-cation No. 638,881).
When workina with aqueou3 solutions, the hydro-~Z~8626 chlorides are recovered mostly by cor.centrating or evaporating the solutions for avoiding the losses. Thus, sensitive organic hydrochloride~ will contain chemical contaminations as a consequence of decomposition. The lyophiliæation of the solutions i9 a power-consuming operation requiring an expensive equipmentO A hig`n yield can be reached by introducing dry hydrogen chloride gas into a solvent or by using a solvent containing dry hydrogen chloride gas, e,g. ethanolic hydrochloric acid; however, the preparation and use of dryg gaseous hydrogen chlorlde cannot be considered as a sufficient accomplishment on an industrial scaleO
The accomplis~ment by double decomposition~ i.e.
the interaction with an other hydrochloride, is also disadvantageou3 as an aqueou~ solvent as reaction medium should be used~
The aim of this invention i9 to provide a new process for the preparation of hydroc'nlorides by means of which the hydrochlorides of particularly the compounds containing a protonatable nitrooen atom can be prepared in high yields and in a very pure state, in a more simple and econo~ical way as compared to the processes known at present.
The present invention is based on the discovery that ~rom compound~ of the ~ormula Q ~ S2 ~ Cl~

36~6 wherein Q stands for a hydroxyl, C1 4 alXyl or an aryl group, the latter being optionally substituted by a Cl 4 alkyl group, 5 hydro~en chloride is liberated by adding an alcohol, and this reaction is useful for the formation of hydrochlorides in a suitable 3elected solvent.
Thus, the invention relates to a process for the preparation of hydrochlorides which compri~es reacting a compound, useful to form a hydrochloride and being suitably in the form of a derivative containing a protonatable nitrogen atom or in the form of a salt, with a sulphonyl compound of the formula Q ~ S2 ~ Cl, wherein Q stand~ for a hydro~yl, Cl 4 alkyl or an aryl group, the latter being optionally substituted by a Cl 4 alkyl ~roup, in a solvent 9 in the presence of an alcohol and isolating in a known manner the hydrochloride obtained~
The compound of the formula Q - S02 - Cl reacts with the alcohol to give hydrogen chlorlde and a mono-ester of the sulphuric acid intermediates, both remainino dissolved in the excess of the alcohol used. By u3ing chlorosulphonic acid (Q = OH~ together ~ith an alkanol as alcohol component, an alkyl hydrogen sulphate be formed. This latter ~ontains an acidic proton;
however, as an acid it is weaker by one order th~n hydrochloric acid. The alkyl methanegulphonates, as well as alkyl p-toluenesulphonates formed when using methane3ulphonyl chloride (Q = CH3) o~ _-toluenesulphon chloride (Q - p-CH3 C6H4~, respectively, together with an alkanol are not acidic in character. By choosing an appropriate alcohol and sulphonyl chloride derivative as well as a solvent, it can in all cases be ensured that the hydrochloride ~ill precipitate, while the monoester ~ormed ~ill remain in the solutionO
The sulphonyl chloride derivatives mentioned above are pre~erred repregentatives of compound3 of the formula ~ S2 ~ C1.
Suitable alcohol components are e.g. alipnatic alcohols such as methanol9 ethanol or pro~anol; aliphatic diols or triols such as ethylene ~lycol;~alicyclic alcohols such as cyclohexanol; aromatic alcohols such as benzyl alcohol; or -the mixtures of these alcohols~
~ xamples of the compounds suitable to ~orm hydro-chlorides are amines, e.g. aliphatic, aroma-tic, alicyclic, aralkyl-, heterocycloalkyl- or heteroaromatic amines;
triazene and its derivatives; hydroxylamine and its derivatives; hydrazine and its derlvatives; carboxylic ~2~8 acld imidates and amidines; carbazide; semicarbazide;
~uanidine; aminoacids; amino3uOars and their derivatives;
five-membered aromatic or partially or fully 3aturated cyclic compounds containing one or more nitrogen atom(s) and optionally other heteroatom(3), e.g.
pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, tri~zole, tetrazole, and their derivatives; si~-membered aro~atic or partially or fully ~atu~ated cyclic compounds contain-l~ ing one or more nitrogen atom(s) and optionally ot~rheteroatom(3). e.g. pyridine, pyridazine, pyrimidi~e, pyrazine, oxadiazine, t~iadiazine, triazine, tetrazine and their derivatives; t~ree or four-membered unsaturated or ~aturated cyclic compo~lnds containing one or more nitrogen atom(s~, e.g. azirine, diazirlne, azete, diazete, triazete and their derivaLive3; seven-to ten-membered, saturated or unsaturated heterocyclic compound3 containing one or more nitrogen atom(s~ and optionally other heteroatom(s), e.g. azepine, oxazepine, thiazeDine, diazepine, oxadiazepine, thiadiazepine, azocine, azonine, azecine, acridine and their derivatives;
alkaloids; steroids; basic or amphoteric dyes and their derivatives; basic or amphoteric antibiotics, e.g.
Clindamycin, Streptomycin, ~eomycin, Tobramycin; anti-biotic~ containing a 3-lactam ring, e~g. Pivampicillin, Cephalexin; tetracycl in9, e.g. 0xytetracyclin or an ~2~386;;~6 Oxytetracyclin complex, Chlorotetracyclin, Tetrac~clin, Doxicyclin; ~nthracyclins, e.g. Daunomycin, ~driamycin, Aclavinone; cyclopeptides, e.g. Enduracidin; ma~ olides, e.g. Erythromycin, Nystatin, Oleandomycin and their derivatives, etc.
The proce3s of the invention is carried out in a solvent or a solvent mixture. An excess of the alcohol used may serve as solvent; however~ suitable solvents are other alcohols, esters, ketones or ethers as well as mixt~res of the3e solvents containing optionally water.
AccordinJ to the present invention, the solubility of the hydrochloride to be prepared should oe at least ~.1 per cent by weight in the inert ~olvent or solvent mixture used. The compound of ~he formula Q - S02 - Cl is dissolved in the alcohol employed as reactant. The concentrati3n of this latter 301ution amounts in general to 0.1 to 1~, preferably to 0.5 to 2 moles/litre.
By u~ing the process OL the present invention hydrochlorides can be obtained in high yields 9 in a very ?ure state, in a simple way which is easy to perform on an industrial scale.
The process of our invention will ~urther be illu3trated by the following Examples ~itaout~ however, any limitation thereto.

3.~ 2~i g Example 1 After stirring a mixture of 150 ml. of methanol and 50 ~. of an OTC-ca~cium silicate-com~le~ (containing 25 g- of OTC) at room temperature for half an hour, 15 g. of anhydrous calcium chloride in 100 ml. of methanol were added during 30 minutes. The mi~ture was stirred for 30 minutes, and a solution of chlorosulphonic acid in methanol with a concentration of 1.5 moles/litre was added until a pH ~alue of 3.5 was reached (34 ml. of this solution wa~ needed under the control of a pH
meter operatina with a gla3s electrode). 1 gO of activated carbon was added, then the mi~ture wa3 stirred for 30 minutes, filtered and washed with 50 ml. of a calcium chloride solution (containing 3.75 g of anhydrous calcium chloride) in methanol. To the combined filtration~ 17 .~1.
of concentrated hydrochloric acid were added while stirring and cooling, within 15 minutes, 90 a pH value o~ 0.~0 was reached, whil~t at a pH value of 105 0.2 g.
of pure OTC hydrochloride was added for inoculation to cause an immediate crystallization. The mixture wa9 stirred additionally for 30 minutes, filtered and the recovered needles were suspended in 25 ml. of methanol containing 2.5 ml. of concentrated h7drochloric acid 5 ; filtered 7 washed twice with 10 mlO of methanol, re-suspended in 25 ml. of cold methanol, filtered, washed a~ain twice with 10 ml. of methanol, filtered and dried 362~i -- 10 -- , by air heated to a temperatu-e of 50 C. In this way 23.4 g.of crystalline OTC hydrochloride were obtained in the form of yellow needles containing 90 c,~ -~ OTC
hydrochloride and 7 ~0 of wa-terO This means a yield of 78 ~ based on the starting complex.
E~ample 2 A mi~tuIe containing 20 g. of dry OTC hydrochloride (needle-shaped crystals containing 18.6 g, of OTC hydro-chloride), 37 ml.of 0.1 molar hydrochloric acid and 56 mlO of methanol was treated with 1 g. of activated carbon and ~iltered after stirring for a few minutes.
To the filtrate 108 ml. of a methanolic solution containing chlorosulphonic acid in a concentration of 1.~3 moles/litre were added ~hile stirring and cooling at 5 to 10 C, whilst pure OTC hydrochloride crystallized out. The mixture wa~ stirred at the same ~emperature ~or 30 minutes, the product was filtered, suspended in 20 ml. o~ a cold, dilute methanolic hydrochloric acid solution~ filtered and washed with 10 ml. of methanol, re-~u~pended in 20 mlO
of cold methanol, filtered and wa~hed again with 10 ml.
of methanol and finally dried by air heated to 50 C.
In thi~ way 16.76 g. (82 ~) of yellow, crystalline OTC
hydrochloride were obtained containin~ 91 ~ of OTC
hydrochloride and 8 % of water.
Example 3 A solution containing 20 ~, of crude OTC base z~

dihydrate fcontaining 17 g. of OTC ~a3e), 37 ml. of 2 molar hydrochloric acid and 56 ml. of methanol was treated according to Example 2 to give -5.13 g. (81 ,~) of yellow, crystalline OTC hydrochloride containing 91 ,~0 of OTC hydrochloride and 8 % of water.
Example 4 A solution containing 10 g. o~ betaine (carboxy-methyl trimethylammonium chloride) in 8 ml. of water ~a~
filtered and 60 ml. of an ethanolic solution containing chlorosulphonic acid in a concentration of 1.5 moles/litre were added under 3tirring at room temperature. The mixture containing a cry~talline precipitate .~ cooled to O ~, s-tirred at the same temperature ~or 1 nour, then the cry~tals were filtered, ~Nashed ~,vith n-?ropanol and dried to give 11.2 g. t36 ~0) of betaine hydrochloride as ,~hite cry3tal~,. m-pO 231 - 232 C.
Example 5 A solution containin~ 9.3 ml~ !10.3 g. ) o~ phenyl-hydrazine in 50 ml. of ethyl ether was treated under stirring with 27 ml. o~ an ethanolic solution containing methanesulphonAyl chloride in a concentration of 4 moles/litre.
The mixture containing a crystalline precipitate was stirred at room temperature for 30 minutes, then the product was filtered 7 washed with ethyl ether and dried to give 13.6 g. (94~o) o~ phenylhydrazine hydrochloride, m.p.: 245 - 246 C.

~Z~36~6 E~ample 6 A ~olution containing 9.7 g. of tobram~cin base in 40 ml of ~0 % methanol was filtered and the filtrate was treated with 40 ml. of a methanolic solution containing methanesulphonyl chloride in a concentratio~ of 0.5 moles/litre under ~tirring. A white precipitate was formed. ~he mixture was stirred for 15 minutes, the product was filtered, washed with metnanol and dried at 60 C under reduced pressure to give 13.1 g. of tobra-mycin hydrochloride containing 98 ~ of active ingredient.
An Rf value of 0.34 was found which is in a8reement with the Rf value of a standard sample fthin layer chromato-graphy was carried out on Merck 60F254 sllica gel layer, 20 x 20 cm; devel~ping ~ith a 2.5 mol~r sodium chloride 15 301ution in 30 ~ ethanol and detectin~ by a 0.5 ~0 aqueous sodium hypochlorite solutio~ and after drying9 3prayin3 with ethanol and after drying again; by a solution containing 1.1 ~ of cadmium iodide and 1.5 ~0 of starch /amylose/).
Example 7 To a mixture containing 15.3 g. of dopamine ; /2-(3,4-dihydroxyphenyl)ethylamine7 in 50 ml. of ethyI
ether 55 mlO of a methanolic solution containing p-toluenesulphonyl chloride in a concentration of 2 moles/litre were added portionwi~e under gtirring in a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, the precipitated crystals were Ir~c ~ ~r~

~ 2 filtered, washed ~ith ether and dried to give 17.3 ~, t91 ~ ~ of dopamine hydrochloride, m.p,: 240 - 241 C, Example 8 30 ml. of an ethanolic solution containing p-toluenesulphonyl chloride in a concentration of 2 moles/litre ~,vere added portions~ise at room -temperature to a mixture containing 15.2 ~. of morphine base in 30 ml, of 80 ~0 ethancl. ~he mi~ture was ~tirred for 2 hours, then at 5 C ~or 30 minutes, The crystalline product was filtered, washed with 2-propanol a~d dried to ~ive 1302 g. (97 ~) of morphine hydrochloride, m.p.:
198 - 200 C~ / ~ 725 -113.5 (c = 2.2 ~ a3 calculated for the anhydrous base, in aqueou3 solution).
Examples 9 to 31 The compound3 listed in the following Table were prepared 3imilarly as described in Examples 4 to 8, The reactants used, 301vents, reaction conditions9 yields and meltin~ points are indicated by u3ing the following abbreviations and symbols:
No. number of the Example A tar~et product B type o~ the starting material C medium ~or the salt ~ormation D Q - S02 Cl ~see below, too 3 E alcohol compone~t ~or the reaction with Q ~ S2 ~ Cl ~8ÇiZ6 ~ yield of the hydrochloride, ~
G meltin~ point of the hydrochlorid~, C
H specific rotation of the hydrochloride, /~7D
MeOH = methanol l-ProH = n-propanol l-BuOH = n-butanol EtOH = ethanol

2-PrOH = 2-propanol risopropanol) AcOEt - ethyl acetate Me2CO = acetone Et20 = ethyl ether CS = chlorosulphonic acid MsCl = methanesulphonyl chloride TsCl _ ~-toluenesulphonyl chloride 862~

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Claims (11)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a hydrochloride of a compound which comprises reacting the compound with a sulphonyl compound of the formula Q - SO2 - Cl wherein Q stands for a hydroxyl, C1-4 alkyl or an aryl group, the latter being optionally substituted by a C1-4 alkyl group, in a solvent, in the presence of an alcohol and recovering the hydrochloride obtained.

2. A process as claimed in claim 1 wherein the said com-pound which will form the hydrochloride is a compound containing one or more protonatable nitrogen atoms, or a salt thereof.

3. A process as claimed in claim 1 wherein the said com-pound which will form a hydrochloride is an amine, hydroxylamine, hydrozine, aminoacid, aminosugar, three- to twelve-membered heterocyclic compound, antibiotic or a derivative thereof.

4. A process as claimed in claim 1 wherein the said com-pound which will form a hydrochloride is an aminocyclitol anti-biotic, .beta.-lactam antibiotic, tetracyclin, antracyclin, cyclo-peptide or macrolide.

5. A process as claimed in claim 1, 2 or 3 wherein an excess of the alcohol is used as solvent.

6. A process as claimed in claim 1, 2 or 3 wherein a mix-ture of the employed said alcohol with an ether, ketone, ester other alcohol or water is used as solvent.

7. A process as claimed in claim 1, 2 or 3 wherein the compound of the formula Q - SO2 - Cl is chlorosulphonic acid, methanesulphonyl chloride or p-toluenesulphonyl chloride.

8. A process as claimed in claim 1, 2 or 3 wherein the alcohol is an aliphatic, alicyclic or aromatic or polyvalent alcohol or a mixture thereof.

9. A process as claimed in claim 1, 2 or 3 wherein the alcohol is an aliphatic alcohol containing 1 to 4 carbon atoms.

10. A process as claimed in claim 1, 2 or 3 which com-prises preparing a solution containing the compound of the for-mula Q - SO2 - Cl in a concentration of 0.1 to 10 moles/litre in the alcohol and reacting this solution with the said compound which will form a hydrochloride.

11. A process as claimed in claim 1, 2 or 3 which com-prises preparing a solution containing the compound of the for-mula Q - SO2 - Cl in a concentration of 0.5 to 2 moles/litre, in the alcohol and reacting this solution with the said compound which will form a hydrochloride.