NZ208009A

NZ208009A - Preparation of hydrochlorides

Info

Publication number: NZ208009A
Application number: NZ208009A
Authority: NZ
Inventors: M Szarvas; E Horvath; L Cseke; J Balint; F Fabian; L Kun
Original assignee: Biogal Gyogyszergyar
Priority date: 1983-05-02
Filing date: 1984-05-01
Publication date: 1987-07-31
Also published as: KR840009296A; DE3469513D1; FI86844C; FI841544A0; DK216384D0; KR870002001B1; AU2761184A; AU564839B2; FI841544A; JPH0517893B2; CA1208626A; FI86844B; EP0125542A1; JPS606623A; EP0125542B1; DK216384A; HU190896B; ATE32704T1; HUT34145A

Abstract

1. Process for the preparation of hydrochlorides of polar, water-soluble compounds having a protonatable nitrogen atom in a solvent, characterised in that the following steps are carried out : a) treatment of the polar, water-soluble compound having a protonatable nitrogen atom, or a salt thereof, with a reaction product, containing hydrogen chloride, of a sulphonyl compound of the formula (I) Q-SO2 -Cl, in which Q represents a hydroxy group, a C1 -C4 -alkyl group, an aryl group or a C1 -C4 -alkylaryl group, and an alcohol selected from the group comprising aliphatic alcohols, cycloaliphatic alcohols, aliphatic diols or triols, aromatic alcohols or mixtures thereof, in a solvent or solvent mixture in which the reaction product has been prepared by dissolving the compound of the formula (I) in an excess of the alcohol in an amount of from 0.1 to 10 mol/l, and in which the solubility of the hydrochloride salt so prepared is at least 0.1% by weight in the solvent or solvent mixture, and b) recovering the hydrochloride salt.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £08009 2 080 0 9 Priofity Datff(s): . Complete -p-.ti.-'a!. F . i. :5r8i^-Clvc:: ..CO.l^./0.0 3 t JUL 1987* Puck :•■ r• P- • P.O. '*!» r, ■! r* l'!'" N.Z. PATENT OFFICE _ -1 MAY 1984 p. re,".1 ■ j Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "PROCESS FOR THE PREPARATION OF HYDROCHLORIDES" 5,WE BIOGAL GYOGYSZERGYAR, of 4042 Debrecen, Pallagi ut 13, Hungary, a Hungarian -company, hereby declare the invention, for vhich ?•/we pray that a patent may be granted to ae/us, and the method by vhich it is to be performed, to be particularly described in and by the following statement (followed by page 1M -1- !a> PROCESS FOR THE PREPARATION OP HYDROCHLORIDES 2 080 09 This invention relates to a new process for the preparation of hydrochlorides, i.e. of acid addition salts formed with hydrochloric acid, particularly of compounds containing a protonatable nitrogen atom. 5 The hydrochlorides of compounds containing a protonatable nitrogen atom are polar, water-soluble compounds widely used in many areas of the practice, e.g. in the therapy, in the nanifacture of plastics, 10 in plant protection, in dyes, as analytical reagents, etc. The extended employment of the hydrochlorides is well characterized by the fact that about ten per cent of the drugs listed in Merck's Index (Ninth Ed., Ed. by .-J. '.Vindholz, Merck, Rahway, J.3.A., 1976), 15 that is, about 300 compounds are therapeutically used in the form of the hydrochlorides. The starting materials for the preparation of hydrochlorides are generally substances containing a protonatable nitrogen atom and being of a basic or 20 amphoteric character, although compounds containing a nitrogen atom of acidic character, e.g. urea, can also form hydrochlorides. In general, the hydrochlorides of these compounds are prepared by treating a compound with hydrochloric 25 acid in water or in a mixture of water and an organic A 315S-741/TO - 2 - 2^8.) 19 solvent, mainly an alcohol; this is described for oxytetracyclin (OTC) hydrochloride in the British patent specifications Hos. 718,020 and 713,032. An other possibility for the preparation of hydrochlorides 5 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 suspension. Furthermore, it is possible to prepare a hydrochloride by means of an organic solvent, mainly of 10 an alcohol, containing previously dissolved gaseous hydrogen chloride. The above-mentioned OTC hydrochloride is prepared in this way for example according to the Belgian patent specification No. 633,381 or the Hungarian patent specification No. 143,911 (copies of both are available on Patent Office file). In the case of this latter method the solubility relations of the starting and/or target products are influenced by niethanolic calcium chloride solution (J. Am. Chem. Soc. 7_3, 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 therefore cannot simply be isolated by precipitation or crystallization following a double decomposition reaction. " " - 3 - 208009 The formation of hydrochloride can also proceed in aprotic solvents or even in the absence of any solvent when the proton arising from the dissociation of the hydrogen chloride is bound by the lone electron pair of 5 the nitrogen atom of the anhydrobase ("The Chemistry of the Amino Group", Ed. by 3. Patai, Interscience, London, 1363). Several hydrochlorides are known to crystallize with hydrate water. The crystal lattice of e.g. OTC 10 hydrochloride is built up involving three molecules of water when the amount of water is sufficient fc.f. Hungarian patent specification .Yo. 143,911). The solubility of these hydrochlorides in organic solvents, e.g. in alcohols, i3 significantly higr.er under anhydrous 15 conditions than in the presence of water. This feature is utilised e.g. for the preparation of OTC hydrochloride in such a way that the starting material, being used for the formation of the hydrochloride, is treated with a methanolic solution of gaseous hydrogen chloride under 20 anhydrous conditions, the solid contaminations are removed from the thus formed hydrochloride solution by filtration and then aqueous concentrated hydrochloric acid ia added to give pure, crystalline OTC hydrochloride in a known manner fc.f. Belgian patent specifi-25 cation itfo. 638,381). '<Vhen working with aqueous solutions, the hydro- 2 080 0 - 4 - chlorides are recovered mostly by concentrating or evaporating the solutions for avoiding the losses. Thus, sensitive organic hydrochlorides will contain chemical contaminations as a consequence of decomposition. The 5 lyophilization of the solutions is a power-consuming operation requiring an expensive equipment. A high 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 10 acid; however, the preparation and use of dry, gaseous hydrogen chloride cannot be considered as a sufficient accomplishment on an industrial scale. The accomplishment by double decomposition, i.e. the interaction with an other hydrochloride, is also 15 disadvantageous as an aqueous solvent as reaction medium should be used. The aim of this invention is to provide a new process for the preparation of hydrochlorides by means of which the hydrochlorides of particularly the compounds 20 containing a protonatable nitrogen atom can be prepared in high yields and in a very pure state, in a more simple and economical way as compared to the processes known at present. The present invention is based on the discovery 25 that from compounds of the formula Q - S02 - CI, 2<>8J09 - 5 - wherein Q atandg for a hydroxyl, alkyl or an aryl group, the latter being optionally substituted by a alkyl group, 5 hydrogen chloride is liberated by adding an alcohol, and this reaction is useful for the formation of hydrochlorides in a suitable selected solvent. Thus, the invention relates to a process for the preparation of hydrochlorides which comprises reacting 10 a compound, useful to form a hydrochloride (except a cycloalkylamine; and pyridine; diisopropylamine and diisopropyl-ethylamlne) 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 15 Q - S02 - CI, wherein Q stands for a hydroxyl, alkyl or an aryl group, the latter being optionally substituted 20 by a C^_^ alkyl group, in a solvent, in the presence of an alcohol and isolating in a known manner the hydrochloride obtained. The compound of the formula Q - SO,, - ci reacts with the alcohol to give hydrogen chloride" and a mono- 25 ester of the sulphuric acid intermediates, both remaining 4V '""T^dissolved in the excess of the alcohol used. By using -A £ 'Vi (f26MAYI987J i . -. . 208009 - o — chloroaulphonic acid (Q = OH) together with an alkanol as alcohol component, an alkyl hydrogen sulphate will b: formed. Thia latter contains an acidic proton; however, as an acid it is weaker by one order than 5 hydrochloric acid. The alkyl metnanesulphonates, as well aa alkyl p-toluenesulphonates formed when using methaneaulphonyl chloride (Q = CH^) or p-toluenesulphonyl chloride (Q = £-CH^-CgH^), reapectively, together with an alkanol are not acidic in character. 3y choosing an 10 appropriate alcohol and sulphonyl chloride derivative aa well aa a aolver.t, it can in all casea be ensured that the hydrochloride will precipitate, while the .■nonosster formed will remain in the .solution. The sulphonyl chloride derivatives mentioned above 15 are preferred representatives of compounds of the formula Q - S02 - CI. Suitable alcohol components are e.g. aliphatic alcohols such as methanol, ethanol or protanol; aliphatic diola or triols such as ethylene glycol; alicyclic 20 alcohols such as cyclohexanol; aromatic alcohols such as benzyl alcohol; or the mixtures of these alcohols. Examples of the compounds suitable to form hydrochlorides are amines, e.g. aliphatic, aromatic, alicyclic, aralkyl-, heterocycloalkyl- or heteroaromatic amines; 25 triazene and its derivatives; hydroxylamine and its derivatives; hydrazine and its derivatives; carboxylic 2 08009 - 7 - acid imidates and amidines; carbazide; semicarbazide; guanidine; atninoacida; aminoaugars and their derivatives; five-mem'oered aromatic or partially or fully saturated cyclic compounds containing one or more nitrogen 5 atorafs) and optionally other heteroatom (s ), e.g. pyrrole, oxazole, isoxazole, thiazole, iaothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, and their derivatives; six-membered aromatic or partially or fully saturated cyclic compounds contain-o ing one or more nitrogen atom/"a) and optionally other he teroatom (a ). e.g. pyridine, pyridazine, pyri.midine , pyrazine, oxadiazine, thiadiazine, triazine, tetrazine and their derivatives; three- or :our-membered unaaturatec or saturated cyclic compounds containing 15 one or more nitrogen atonfa), e.g. azirir.e, ciazirine, azete, diasete, triazete and their derivatives; seven-to ten-membered, saturated or unsaturated heterocyclic compounds containing one or more nitrogen a torn fa) and optionally other heteroatomfa), e.g. azepine, oxazepine, 20 thiazepine, diazepine, oxadiazepine, thiaiiazepine, I, ' ' azocine, azonine, azecine, acridine and t:ieir derivatives alkaloida; steroids; basic or amphoteric dyes and their derivatives; basic or amphoteric antibiotics, e.g. Clindamycin, Streptomycin, Neomycin, Tobramycin; anti-25 biotica containing a 3-lactam ring, e.g. Pivampicillin, Cephalexin; tetracyclins, e.g. Oxytetracyclin or an 2 08009 Oxytetracyclin complex, Chlorotetracyclin, Tetracyclin, Doxicyclin; anthracyclins, e.g. Daunomycin, Adriamycin, Aclavinone; cyclopsptides , .. .g. Enduracidin; macrolidea, e.g. Erythromycin, Nystatin, Oleandomycin and their 5 derivatives, etc. The process 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 10 mixtures of these solvents containing optionally water. According to the present invention, the solubility of the hydrochloride to be prepared should be at least j.l per cent by weight in the inert solvent or solvent mixture used. The compound of the formula ; - - CI is 15 dissolved in the alcohol employed as reactant. The concentration of this latter solution amount3 in general to 0.1 to 10, preferably to 0.5 to 2 moles/litre. By using the process of the present invention hydrochlorides can be obtained in high yields, in a very 20 pure state, in a simple way which is easy to perform on an industrial scale. The process of our invention will further be illustrated by the following Examples without, however, any limitation thereto. - J - 2 08009 Example 1 After stirring a mixture of 150 nil. of methanol and 50 g. of an OTC-calcium ailicate-complex (containing 25 g* of OTC) at room temperature for half an hour, 5 15 g. of anhydrous calcium chloride in 100 ml. of methanol were added during 30 minutes. The mixture was stirred for 30 minutes, and a solution of chlorosulphonic acid in methanol with a concentration of 1.5 moleg/litre was added until a pH value of 3.5 '^as reached ^34 ml. of 10 this solution was needed under the control of a pH meter operating with 3 glass electrode). 1 g. of activated carbon was added, then the mixture was stirred for 30 minutes, filtered and washed ,vith 50 ml. of a calcium chloride solution (containing 3*75 g of anhydrous calcium 15 chloride) in methanol. To the combined filtrationa 17 ml. of concentrated hydrochloric acid were added while stirring and cooling, within 15 minutes, so a pH value of 0.40 was reached, whilst at a ?H value of 1.5 0.2 g. of pure OTC hydrochloride was added for inoculation to 20 cause an immediate crystallization. The mixture was stirred additionally for 30 minutes, filtered and the recovered needles were suspended in 25 ml. of methanol containing 2.5 ml. of concentrated hydrochloric acid, filtered, washed twice with 10 ml. of methanol, 25 re-suspended in 25 nil. of cold methanol, filtered, washed again twice with 10 ml. of methanol, filtered and dried m 208009 - 10 - by air heated to a temperature of 50 °C. In this way 23.4 g. of crystalline OTC hydrochloride were obtained in the form of yellow nec*\sa containing 90 % of OTC hydrochloride and 1 % of water. This means a yield of 5 78 # based on the starting complex. Example 2 A mixture containing 20 g. of dry OTC hydrochloride (needle-shaped crystals containing lS.o g. of OTC hydrochloride), 37 ml. of 0.1 nolar hydrochloric acid and 10 56 ml. of methanol was treated with 1 g. of activated carbon and filtered after stirring for a few minutes. To the filtrate 103 ml. of a methanolic solution containing chloroaulphonic acid in a concentration of 1.63 moles/litre were added while stirring and cooling at 5 to 10 °C, 15 whilst pure OTC hydrochloride crystallized out. The mixture was stirred at the same temperature for 30 minutes, the product was filtered, suspended in 20 ml. of a cold, dilute methanolic hydrochloric acid solution, filtered and washed with 10 ml. of methanol, re-suspended in 20 ml. 20 of cold methanol, filtered and washed again with 10 ml. of methanol and finally dried by air heated to 50 °C. In this way 16.7b g. (82 %) of yellow, crystalline OTC hydrochloride were obtained containing 91 % of OTC hydrochloride and 8 % of water. 25 Example 3 A solution containing 20 g. of crude OTC base 208009 - li - dihydrate ^containing 17 g. of OTC base), 37 ml. of 2 molar hydrochloric acid and 5° ml. of methanol wag treated according to Example 2 to give 15.13 g. (31 of yellow, crystalline OTC hydrochloride containing 91 of OTC 5 hydrochloride and 3 % of water. Example 4 A solution containing 10 g. of betaine (carboxy-methyl trimethylammoniun chloride) in 3 ml. of water wag filtered and 60 ml. of an ethanolic solution containing 10 chloroaulphonic acid in a concentration of l.p moles/litre were added under stirring at room temperature. The fixture containing a crystalline precipitate •.•jag cooled to 0 °C, 3tirred at the same temperature for 1 hour, then the crystals were filtered, washed with n-propanol ana dried 15 to give 11.2 g. (36 %) of betaine hydrochloride as white crystals, m.p.: 231 - 232 °C. Example 5 A solution containing 9.3 ml. '10.3 g.) of phenyl-hydrazine in 50 ml. of ethyl ether was treated under 20 stirring with 27 ml. of an ethanolic solution containing metnanesulphonyl 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, waahed with ethyl ether and dried 25 to give 13.6 g. (34%) of phenylhydrazine hydrochloride, m.p.: 245 - 246 °C. - 12 - 2 08 0 0 9 Example 6 A solution containing 9.7 g. of tobramycin base in 40 ml of 30 -% methanol was filtered and the filtrate was treated with 40 ml. of a methanolic solution containing 5 methanesulphonyl chloride in a concentration of 3.5 moles/litre under stirring. A white precipitate was formed. The mixture was stirred for 15 minutes, the product was filtered, washed with methanol and dried at 60 °C under reduced pressure to give 13.1 g. of tobra-10 mycin hydrochloride containing 93 o of active ingredient. An R* value of 0.34 was found which i3 in agreement with the R^. value of a standard sample (thin layer chromatography was carried out on Merck 60?oc;, silica gel layer, 20 x 20 cm; developing with a 2.5 molar sodium chloride 15 solution in 30 % ethanol and detecting by a 0.5 7o aqueous sodium hypochlorite solution ana after drying, spraying with ethanol ana after drying again, by a solution containing 1.1 fo of cadmium iodide and 1.5 % of starch /amylose/). 20 Example 7 To a mixture containing 15.3 g. of dopamine /2-(3,4-dihydroxyphenyl)ethylamine7 in 50 ml. of ethyl ether 55 ml. of a methanolic solution containing p-toluenesulphonyl chloride in a concentration of 2 moles/litre were added portionwise under stirring in a 25 nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, the precipitated crystals were 2 080 0 9 - 13 - filtered, washed with ether and dried to give 17.3 g. (91 fo) of dopamine hydrochloride, m.p.: 240 - 241 °C. Example 3 30 ml. of an ethanolic solution containing 5 p-toluenesulphonyl chloride in a concentration of 2 molea/litre were added portionawise at room temperature to a mixture containing 15-2 g. of morphine base in 30 ml of 30 % ethanol. The mixture was stirred for 2 hours, then at 5 °C for 30 minutes. The crystalline product 10 was filtered, washed with 2-propanol and dried to give 13.2 g. (97 %>) of morphine hydrochloride, m.p.: 153 - 200 °C, iVl5 -113.5° (c = 2.2 * as calculated for the anhydrous base, in aqueous solution). Examples 9 to 31 15 The compounds listed in the following Table vie re prepared similarly aa described in Examples 4 to 3. The reactants used, solvents, reaction conditions, yields and melting points are indicated by using the following abbreviations and symbols: 20 No. number of the Example A target product B type of the starting material C medium for the salt formation D Q - 302 - CI (see below, too) 25 E alcohol component for the reaction with Q - S02 - CI - 14 - >208009 F G H MeOH = 1-ProH 1-BuOH EtOH = 2-PrOH AcOEt iIe2CO Ht^O C3 Ms CI TsCl yield of the hydrochloride, % melting point of the hydrochloride, °C specific rotation of the hydrochloride, /*7D5 methanol = n-propanol = n-butanol ethanol = 2-propanol fisopropanol) = ethyl acetate = acetone = ethyl ether = chlorosulphonic acid = methanesulphonyl chloride = o-toluenesulphonyl chloride Table - 15 - No. A B C 9 Pro pranolo1.HC1 Aliphatic amine 1-PrOH 10 Chlorguanide.HCl Guanidine derivative 90 % EtOH 11 Penicillamine.HCl Aminoacid AcOEt 12 Procaine.HCl Aromatic amine 1-PrOH 13 Ketamine.HCl Cycloal-kyl amine EtOH 14 Amantadine.HCl Cycloal-kyl amine EtOH+ Et20 15 Clindamycin.HCl .H20 Aminocyc-litol antibiotic EtOH+ AcOEt 16 Streptomycin. . 3HC1 Aminocyc-litol antibiotic EtOH 17 Pivampicillin.HCl -Lactam antibiotic 1-PrOH 18 Noformycin.2HCl Aminoacid antibiotic MeOH 19 Spectinomycin. Antibiotic EtOH+ 2HC1 H20 J D F H CS 1-PrOH 93 163-164 CS CS CS EtOH EtOH 96 243-244 2-PrOH 91 177-178 -63° (c = 5, NaOH) 88 153-156 CS EtOH 85 262-263 CS EtOH 94 360 MsCI EtOH 94 141-143 144° (water) MaCI EtOH 88 -84 CS CS 1-PrOH 85 154-156 200° (c=l, water) MeOH TsCl EtOH 92 262-264 8.8° (MeOH) 91 -20 K) O o o o </div>

Claims

<div class="application article clearfix printTableText" id="claims"> I - 1G Table (continued) No. A B 20 Doxicyclin.HG1 Tetracyclin antibiotic 21 Tetracyclin.HCl Tetracyclin antibiotic 22 Doxorubicin.HCl Anthracyclin anti biotic 23 Oleandomycin.HCl Macrolide antibiotic 24 Tonaylamine.HCl Heteroaryl amine 25 Metidylazine.HCl Pyrrole derivative 26 Tetramisole.HCl Imidazole derivative 27 Phenglutarimide.HCl Pyridine derivative 28 Opipramol.HCl Pyrazine and azepine derivative 29 Nalorphine.HCl Alkaloid 30 Hydrocortamate.HCl Steroid 31 Cyproheptadine.HCl Pyridine derivative C D E P G H EtOH CS EtOH 92 199-202 -110° 1-BuOH TaCl 1-BuOH 9b 213-214 -257. 5° Me^CO Ma CI MeOH 32 204-205 248° fc-0.15, MeOH) AcOEt MaCl EtOH 90 133-135 -54° (MeOH) EtOH+ EL^O Ma CI EtOH 95 174-176 2-PrOH TaCl 2-PrOH 9 3 187-189 EtOH TaCl EtOH 84 264-266 MeOH+ AcOEt CS MeOH 81 176-177 EtOH CS EtOH 94 227-229 EtOH Co EtOH 94 270 AcOEt CS EtOH 92 222 EtOH CS EtOH 88 252-254 as -© 00 o o \0 2n8 j.u&

1. A process for the preparatio^i of a hydrochloride,

which comprises reacting a compound useful to form a

5 • hydrochloride (except a cycloalkylamine;/^3^ridine; diisopropylamine and diisopropylethylamine) in the form of a derivative containing protonatable nitrogen atom(a) or in the form of a salt, with a sulphonyl compound of the formula

Q - S02 - CI,

10 wherein

Q stands for a hydroxyl, alkyl or an aryl group,

the latter being optionally substituted by a alkyl group,

in a solvent, in the presence of an alcohol and recovering 15 the substantially pure hydrochloride.

2. A process as claimed in claim 1, which comprises and pyridine? diisopropylamine and diisopropylethylamine) using a compound (except a cycloalkylamine;/selected from the group consisting of an amine, hydroxy lainine, hydrazine, amino acid, an aminosugar , three- to xwelve-zDemberea heterocyclic compound, and/

antibiotic or a derivative thereof

20 as a starting material for the preparation of a hydrochloride.

3« A process as claimed in claim 1 or 2, which comprises using an antibiotic of the aminocyclitol type, P-lactam antibiotic, tetracyclin, an.t±uracyclin , cyclopeptide or a xnacrolide bs a starting material for the preparation of a

25 hydrochloride •

4* process as claimed 1c any of claims 1 "to 3»

-*•- '03009

U

which comprises using an excees of the alcohol as solvent.

5. A process *9 claimed in any of clai.us 1 to 3,

which comprises using a mixture of the employed elcohol with an ether, ketone , ester , other alcohol and/or nith

5 *£-ter as the solvent.

6. A process as claimed in any of claims 1 to 5,

*hich comprises using chlorosulphonic acio, methanesulphonyl chloride or c-toluenesulphonyl chloride as e compound of the formula Q - SOp - CI.

7. A process as claimed in any of claims 1 to 6,

*nicr. comprises using an aliphatic alcohol preferal:iv containing ] to i carbon eto.rjs, an alicyclic or aromatic or polyvalent alcohol or a mixture thereof 29 alcohol compo^nt.

9. A process as claimed in any of claims 1 to 7, 15 which comprises preparing a solution containing the compound of the formula Q - S0? - CI in & concentration of 0.1 to 10 moles/litre, in the alcohol and reacting this solution with a compound useful for the formation of a hydrochloride.

9. A process as claimed in claim 8 wherein the compound of the formula q-S02~c1 *s *n a concentration of 0.5 to 2 moles/ litre in the alcohol.

10. A hydrochloride whenever prepared by the process as claimed in any of claims 1 to 9.

11. A process as claimed in claim 1 substantially as herein particularly described with reference to any one of the Examples.

12. A hydrochloride whenever prepared by the process as/ claimed in claim 1 substantially as herein particularly /,

I 2MAf?J9S7/geBcr^be^ with reference to any one of the Examples. \ f „7

BALDWIN. SON/A''CAREY

U 1 i

^O

!'.

attorneys for the vsvLicants

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