Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~r~
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
A 3158-741/T0
,
-- 2 --
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.
8626
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
-- 5 --
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
-- 6 --
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
-- 7 --
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
-- 3 --
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
- 12 -
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
- 13 -
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
-- 14
~ 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
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