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2,128,512 Patented Aug. 30, 1938 UNITED STATES PATENT OFFICE 2,128,512 FREE METHAANE-SULPHONIG ACIDS 0F PY RAZOLONEAMINES AND PROCESS OF PRE PARING VTHEM Max Bockmiihl and Leonhard Stein, Frankfort on-the-Main-Hochst, Germany, assignors to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York No Drawing. Application January 8, 1935, Serial No. 924. In Germany January 13, 1934 8 Claims. (Cl. 260-310) sulphonic acid, 1-cyclohexyl-2.3-dimethyl-4 Our present invention relates to free methane sulphonic acids of pyrazoloneamines and to a methylamino-5-pyrazolone- 4 -methanesu1phonic process of preparing them. I It is known that the omega-alkylsulphonic acids of aromatic amines are produced by caus ing an aldehyde and sulphurous acid to act upon an aromatic amine. The same acids have been acid, 1 - (4 - methylcyclohexyl) -2.3-dimethyl-4 methylamino-5-pyrazolone- 4 -methanesulphonic acid, 1-para-tolyl-2.3-dimethyl-4-methylamino 5~pyrazolone-4-methanesulphonic acid, l-phen yl-2-cyclohexyl-3-methyl-4-methylamino- 5 -py - produced by acidifying the alkali metal salts of razolone-4-methanesulphonic acid, 1-phenyl-2 omega-aminomethanesulphonic acids, obtained by condensing aromatic amines with aldehydes ?-pyrazolone-4-methanesulphonic acid, l-phen and alkali bisulphite. Though these acids are highly liable to decomposition they may be iso (4-methylcyclohexy1) -3-methyl-4~methylamino - lated by taking advantage of their insolubility methanesulphonic acid, 1-phenyl-2.3-dimethyl 4-phenylamino-5-pyrazolone-4-methanesulphon or sparing solubility in water. ic acid, 1-phenyl-2.3-dimethyl-4-para-to1yI-5-py The application of the above reactions to the amines of the py razolone-4-methanesulphonic acid, 1-pheny1-2.3 razolone series has, hitherto, been unsuccessful, dimethyl-4-cyclohexyl-5-pyrazolone-4-methane - since the omega-aminoalkylsulphonic acids of this series are extremely soluble in water and no method has become known for separating the free acids from aqueous solution; moreover, the sulphonic acid, 1-phenyl-2.3-dimethyl-4~(4 methyl-cyclohexyl) -5-pyrazolone-4-methanesul - phonic acid, 1-phenyl-2.3-dimethyl-4-cyclohex enyI-S-pyrazolone-4-methanesulphonic acid, 1 acids are readily decomposed, as may be recog cyclohexyl-2.3 - dimethyl - 4 - amino-5-pyrazolone nized by the odor of sulphurous acid shortly 4-methanesu1phonic acid. As organic solvents there may, for instance, be used lower alcohols and ketones, such as methyl alcohol, ethyl al after the acidi?cation of the solutions of their salts. Now we have found that the aminomethyl sulphonic acids of the pyrazolone series may be obtained in a solid form from the corresponding amine, formaldehyde and sulphurous acid or by acidifying the salts of the corresponding amino methanesulphonic acids, the operation being con ducted in the presence of organic solvents with complete or partial exclusion of-water. As meth anesulphonic acids of the pyrazoloneamines there may be used those having the amino group in 4-position, particularly those of the following general formula: 40 I R1 in which R1 stands for a six-membered aromatic 20 cohol, propyl alcohol, isopropyl alcohol, acetone, methylethyl ketone, furthermore acetic ester and ‘ benzene. If the aminomethylsulphonic acid is easily soluble in the organic solvent used for the preparation, a second organic solvent such as ether or the like may be used at any stage of the process. , v The process may, for instance, be carried out by dissolving the amine in question in alcohol, introducing the molecular proportion of sulphur ous acid and then adding the molecular propor tion of formaldehyde. After addition of a few crystals the new acids then crystallize in most cases. If not, the precipitation may be induced by the addition of ether or another solvent. For the execution of the process it is immaterial in 40 which sequence the different reactants are added. It is, therefore, possible to cause the aminesul phites ?rst prepared to react with the formalde- . hyde or to cause the amines to react simultane 45 or hydroaromatic hydrocarbon radical, R2 for ously with the formaldehyde and sulphurous methyl or a six-membered hydroaromatic hydro carbon radical and R3 for hydrogen, alkyl or a siX-membered aromatic or hydroaromatic hydro acid. The Schiff’s bases or the methylene-bis compounds of the amines which may be produced from the amines by reaction with the formalde carbon radical, for instance, 1-phenyl-2.3-di hyde may be transformed with sulphurous acid methyl-‘l-methylamino-5-pyrazolone-4-methane 10 yl-2.3-dimethyl - 4 - ethylamino-5-pyrazolone-4 - into the corresponding methylsulohonic acids; 59 2,128,512 2 in the latter case a further molecular proportion of formaldehyde is added in order to completely transform the amine into the methylsulphonic acid. With a like success it is also possible to start from the known alkali metal salts of the amino methylsulphonic acids of pyrazolone-amines, cc. of acetone and 64 grams of sulphurous acid are introduced into the solution, while cooling. On addition of '75 cc. of formaldehyde of 40 per cent strength and of a few crystals, the meth anesulphonic acid obtained according to example 1 crystallizes in an almost quantitative yield. The acid obtained melts with decomposition at made from the corresponding amines with the aid of formaldehyde and alkalibisulphite (cf. Ger ' 131° C. to- 132D C. The methanesulphonic acid obtainable accord man patent speci?cation 421.505) and to acidify the said alkali metal salts under the above stated ing to Examples 1 and 2 may be transformed into ' conditions. When causing pyrazoloneamines to‘ the corresponding sodium salt by means of caus react with formaldehyde and sulphurous acid it tic soda solution. The magnesium and calcium is advantageous to work with solvents miscible. ‘salts may be obtained in a similar way. (3) 147 grams of 1-phenyl-2.3-dimethyl—4 with water. When causing methanesulphonic acid salts to react with acids it is also possible to >benzylamino-S-pyrazolone are dissolved in 1000 work in the presence of a solvent which is not cc. of absolute alcohol and 38 cc. of formaldehyde of 40 per cent strength are added, while cooling. It is important for the process of this invention v32 grams of sulphurous acid are introduced, while that no substantial amount of water be present.v further cooling. After some time the l-phenyl When causing pyrazolone amines to react with 2.3-dlmethyl-4 - benzylamino - 5 — pyrazo-lone - 4 formaldehyde and sulphurous acid the presence methanesulphonic acid crystallizes in a yield of 90 of water cannot be entirelyavoide'd, ‘since the per cent. The point of decomposition is at 133° C. (4) 35 grams of the sodium salt of 1-phenyl formaldehyde must be added in the form of an aqueous solution, The amount of water inthe ;2.3edimethyl-4-methylamino - 5 - pyrazolone - 4 25 total volume of the reaction mixture should, " methanesulphonic acid are dispersed in 200 cc. of however, not exceed 5 per cent. When causing alcohol and the solution is mixed with 100 grams the salts of methanesulphonic acids to react with of an alcoholic hydrochloric acid of 3.6 per cent strength. When the reaction is complete the mineral acids it is possible to work in the com whole is ?ltered. After a short time the meth— plete absence of water. The process of our present invention involves anesulphonic acid described in Examples 1 and 2 30 various advantages. It is practically dif?cult to crystallizes out. Decomposition point 131° C. to miscible with water. 7 produce in a pure form the monoalkylamino-py razolones as they are utilized for the manufacture 123° C. (5) 45 grams of 1-cyclohexyl-2.3-dimethyl-4 of pharmaceutical products, since the secondary methylamino-5-pyrazolone (‘obtainable according 35 bases are frequently contaminated with tertiary to the co-pending application Serial No. 709,232, ?led January 31, 1934, in the name of Max Bock and primary bases. The present invention offers the possibility of directly obtaining from a crude mixture of amines the methylsulpho-nic acids of the desired. secondary bases. By condensing, for 40 instance, the crude product of 4-methylamino-1 phenyl - 2.3 - dimethylpyrazolone containing ' be miihl and Walter Krohs) are dissolved in 250 cc. of absolute alcohol, 15 cc. of formaldehyde of 40 per cent strength are added and 13 grams of sul phurous acid are introduced into the solution, 40 while cooling. On addition of ether the l-cyclo sides the secondary amine quantities of primary and tertiary amine, with formaldehyde and sul lone-4-methanesulphonic acid crystallizes. Point phuric acid in an alcoholic solution, the omega methanesulphonic acid of 4-methylaminopyrazo lone which is comparatively more, sparingly solu ble precipitates very soon, whereas the homolo gous compound and the tertiary base remain dissolved. Since the omega-aminoethanesul 50 phonic acids may easily be transformed with the aid of an alkali into their salts, chemically pure salts of the omega-methanesulphonic acid of sec hexyl-2.3-dimethyl-4 - methylamino -‘ 5 - pyrazo of decomposition 153° C. to 154° C. Yield 90 per HR El cent. (6) 223 grams of 4.4'-methylene-bis-l-phenyl 2.3-dimethyl-4-methylamino-5-pyrazolone of the following formula: ondary pyrazolone-amines may easily be ob tained by starting from a mixture of amines of 55 the 4-amino—pyrazolones. Furthermore the aminomethanesulphonic acids according to our present invention are intended to be used for the manufacture of new phar 60 maceuti cal products. The following examples illustrate the inven tion: (1) 219 grams of 1-phenyl-2.3-dimethyl-4 methylamino-5-pyrazolone are dissolved in 1000 cc. of absolute alcohol and after addition of 75 65 cc. of formaldehyde of 40 per cent strength 64 grams of sulphurous acid are introduced, while cooling. By continued cooling, the l-phenyl-2.3 dimethyl-4-methylamino-5—pyrazolone~4 - meth anesulphonic acid crystallizes after some time. 70 The well crystallized acid is ?ltered by suction and subsequently washed with a small quantity of alcohol. The yield is almost quantitative; the point of decomposition is at 131° C. to 132° C. (2) 219 grams of 1-phenyl-2.3-dimethyl-4 75 methylamino-5-pyrazolone are dissolved in 1000 and 37.5 cc. of formaldehyde of 40 per cent strength are dissolved in 1000 cc. of alcohol and 64 grams of sulphurous acid are introduced into the cooled solution. After a short time the 1 phenyl-2.3-dimethyl-4-methylamino - 5 - pyrazo 60 lone-4-methane-sulphonic acid described in Ex amples 1 and 2 crystallizes out. The yield is quantitative. Point of decomposition 131° C. to 132° C. (7) 22 grams of 1-cyclohexyl-2.3-dimethyl-4 amino-5-pyrazolone are dissolved in 100 cc. of ab solute alcohol and the solution is mixed with 7.8 cc. of a solution of formaldehyde of 40 per cent strength and 4 grams of sulphurous acid. On cooling, the free 1-cyclohexyl-2.3-dimethyl-4 amino-5-pyrazolone - 4 - methanesulphonic 70 acid crystallizes in a yield of 90 per cent strength. We claim: 1. The process which comprises causing formal dehyde and sulphurous acid to act upon l-phenyl 75 3 2,128,512 2.3 - dimethylamino~4-methylamino-5-pyrazolone 5. The processwhich comprises causing formal in the presence of ethyl alcohol and in the ab dehyde and sulphurous acid to act upon a com sence of a substantial amount of. water and isolat pound of the ‘following general formula: ing the free sulphonic acid. ' 2. In the process of’ preparing omega-methane sulphonic acids of 2.3-dialkyl-4-amino-pyrazo lones the steps which comprise conducting the step which directly leads to the formation of the free omego-methanesulphonic acid in the pres ence of an organic solvent in which said acids 10 are substantially insoluble, selected from the class I in which R1 stands for a radical of. the group con consisting of low molecular aliphatic alcohols, low sisting of six-membered aromatic and hydro~ molecular aliphatic ketones, acetic ester, benzene aromatic radicals and R3 for a member of the and ether in the absence of a substantial amount group consisting of hydrogen and six-membered 15 of water, and isolating the free sulphonic acid. aromatic and hydroaromatic hydrocarbon radi 15 3. In the process of preparing compounds of the cals, in the presence of an organic water-soluble following general formula: solvent in which said acids are substantially in soluble, selected from the class consisting of low molecular aliphatic alcohols, low molecular ali phatic ketones, acetic ester, benzene and ether, and in the absence of. a substantial amount of t. 25 in which R1 stands for a radical of the group consisting of. siX-membered aromatic and hydro aromatic hydrocarbon radicals, R2 for a member of the group consisting of methyl and a six water and isolating the free sulphonic acid. 6. A free omega-methanesulphonic acid of a 2.3-dialykl-4-amino-pyrazolone in a dry, solid, crystalline form, which is easily soluble in water and decomposes when melted. '7. A free omega-methane-sulphonic acid of the following general formula: membered hydroaromatic hydrocarbon radical and R3 for a member of the group consisting of 30 hydrogen, alkyl and six-membered aromatic and hydroaromatic hydrocarbon vradicals, the steps which comprise conducting the step which leads to the formation of the free omega-methanesul phonic acid in the presence of. an organic solvent in which said acids’ are substantially insoluble, selected from the class consisting, of low molecular aliphatic alcohols, low molecular aliphatic ke~ tones, acetic ester, benzene and ether, and in the 40 absence of a substantial amount of water and isolating the free sulphonic acid. 4-. In the process of preparing compounds of the following general formula: in which R1 stands for a radical of the group con 35 sisting of six-membered aromatic and hydro aromatic hydrocarbon radicals, R2 for a member of the group consisting of methyl and a six membered hydroaromatic hydrocarbon radical and R3 for a member of the group consisting of hydrogen, alkyl and six-membered aromatic and hydroaromatic hydrocarbon radicals, in a dry, ' solid, crystalline form, which is easily soluble in water and decomposes when melted. 45 8. A free omega-methanesulphonic acid of the 45 following general formula: l R: in which R1 stands for a radical of the group con sisting of six-membered aromatic and hydroaro N matic radicals and R3 for a member of the group consisting of hydrogen and six-membered aro 55 l .R‘ matic and hydroaromatic hydrocarbon radicals, the steps which comprise conducting the step in which R1 stands for a radical of the group con which leads to the formation of the free omega methanesulphonic acid in the presence of an or ganic solvent in which said acids are substantially aromatic radicals and R3 for a member of the insoluble, selected from the class consisting of. low 60 molecular aliphatic alcohols, low molecular ali phatic ketones, acetic ester, benzene and ether, and in the absence of a substantial amount of water and isolating the free sulphonic acid. ' sisting of six-membered aromatic and hydro group consisting of hydrogen and six-membered aromatic and hydroaromatic hydrocarbon radi cals, in a dry, solid, crystalline form, which is easily soluble in water and decomposes when 60 melted. - ' MAX BocKMiiHL. LEONHARD STEIN.