Claims
- 1. A process for the preparation of acetoacetamide-N-sulfonic acid or a salt thereof, which comprises reacting in an inert organic solvent a salt of sulfamic acid, selected from the group consisting of ammonium, primary, secondary, tertiary and quaternary ammonium salts of sulfamic acid, which is partially soluble therein, with at least the equimolar amount of diketene as an acetoacetylating agent resulting in the formation of a salt of the acetoacetamide-N-sulfonic acid or, after subsequently liberating the free acid by addition of a strong acid resulting in acetoacetamide-N-sulfonic acid.
- 2. A process as in claim 1, wherein the ammonium salts of acetoacetamide-N-sulfonic acid are of the formula
- H.sub.3 C--CO--CH.sub.2 --CO--NH--SO.sub.3.sup.- M.sup.+
- and wherein
- M.sup.+ is N.sup.+ R.sup.1 R.sup.2 R.sup.3 R.sup.4 and wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4, independently of one another, are H or C.sub.1 -C.sub.8 -alkyl, C.sub.6 -C.sub.10 -cycloalkyl-aryl or -aralkyl.
- 3. A process as in claim 2, for the preparation of a salt of acetoacetamide-N-sulfonic acid wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4, independently of one another, are H, methyl, ethyl, propyl, isopropyl, n-, iso-, tert- or 2-butyl or phenyl.
- 4. A process as claimed in claim 1, wherein the acetoacetylating agent is used in an excess of up to 30 mol-%.
- 5. A process as claimed in claim 4, wherein the acetoacetylating agent is used in an excess of up to 10 mol-%.
- 6. A process as claimed in claim 1 wherein the inert organic solvent used is one solvent or a mixture of solvents selected from the group consisting of halogenated aliphatic hydrocarbons, aliphatic ketones, aliphatic or alicyclic ethers, lower aliphatic carboxylic acids, lower aliphatic nitriles, N-alkyl-substituted amides of carbonic acid and of lower aliphatic carboxylic acids, aliphatic sulfoxides and aliphatic alicyclic sulfones.
- 7. A process as claimed in claim 6, wherein the inert organic solvent used is at least one inert organic solvent selected from the group consisting of halogenated aliphatic hydrocarbons having up to 4 carbon atoms, aliphatic ketones having 3 to 6 carbon atoms, alicyclic ethers having 4 to 5 carbon atoms, aliphatic carboxylic acids having 2 to 6 carbon atoms, acetonitrile, N-alkyl-substituted amides of carbonic acid and of aliphatic carboxylic acids, wherein the amides have a total of up to 5 carbon atoms, dimethyl sulfoxide and sulfolane.
- 8. A process as claimed in claim 1 wherein the inert organic solvent used is a solvent or a mixture of solvents selected from the group consisting of methylene chloride, 1,2-dichloroethane, acetone, glacial acetic acid, and dimethylformamide.
- 9. A process as claimed in claim 1, wherein the inert organic solvent used is methylene chloride.
- 10. A process as claimed in claim 1, wherein the reaction is carried out in the presence of a tertiary amine or tertiary phosphine catalyst.
- 11. A process as claimed in claim 10, wherein the amine or phosphine catalyst has up to 20 carbon atoms per N or P atom.
- 12. A process as claimed in claim 10, wherein the amine or phosphine catalyst has up to 10 carbon atoms per N or P atom.
- 13. A process as claimed in claim 10, wherein the catalyst used is an amine catalyst.
- 14. A process as claimed in claim 13, wherein the amine catalyst has up to 20 carbon atoms per N atom.
- 15. A process as claimed in claim 13, wherein the amine catalyst has up to 10 carbon atoms.
- 16. A process as claimed in claim 13, wherein the catalyst is triethylamine.
- 17. A process as claimed in claim 10, wherein the amount of catalyst present is up to 0.1 mol per mol of sulfamate.
- 18. A process as claimed in claim 13, wherein the salt of sulfamic acid which is used and which is at least partially soluble in the inert organic solvent is a salt of sulfamic acid and a tertiary amine which is identical to the tertiary amine which is the amine catalyst.
- 19. A process as claimed in claim 1, wherein the reaction is carried out at a temperature between about -30 and +50.degree. C.
- 20. A process as claimed in claim 1, wherein the reaction is carried out at a temperature between about 0 and +25.degree. C.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 3410439 |
Mar 1984 |
DEX |
|
Acetoacetamide-N-sulfonyl fluoride
This application is a continuation of application Ser. No. 300,763, filed Jan. 23, 1989, abandoned, which is a cont. of Ser. No. 870,001, filed June 3, 1986, abandoned, which in turn is a div. of Ser. No. 714,177, filed Mar. 20, 1985, now Pat. No. 4,607,100.
6-Methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide is the compound of the formula ##STR1## As a consequence of the acidic hydrogen on the nitrogen atom, the compound is able to form salts (with bases). The non-toxic salts, such as, for example, the Na, the K and the Ca salt, can, because of their sweet taste, which is intense in some cases, be used as sweeteners in the foodstuffs sector, the K salt ("Acesulfame K" or just "Acesulfame") being of particular importance.
A number of different processes is known for the preparation of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and its non-toxic salts; see Angewandte Chemie 85, Issue 22 (1973) pages 965 to 73, corresponding to International Edition Vol. 12, No. 11 (1973), pages 869-76. Virtually all the processes start from chloro-or fluorosulfonyl isocyanate (XS0.sub.2 NCO with X=Cl or F). The chloro- or fluorosulfonyl isocyanate is then reacted with monomethylacetylene, acetone, acetoacetic acid, tert.-butyl acetoacetate or benzyl propenyl ether (usually in a multistage reaction) to give acetoacetamide-N-sulfonyl chloride or fluoride which, under the action of bases (such as, for example, methanolic KOH), is cyclized and provides the corresponding salts of 6-methyl-3,4-dihydro -1,2,3-oxathiazin-4-one 2,2-dioxide. Where desired, the free oxathiazinone can be obtained from the salts in a customary manner (with acids).
Another process for the preparation of the oxathiazinone intermediate acetoacetamide-N-sulfonyl fluoride starts from sulfamoyl fluoride H.sub.2 NSO.sub.2 F, which is the partial hydrolysis product of fluorosulfonyl isocyanate (German Offenlegungsschrift 2,453,063). The fluoride of sulfamic acid H.sub.2 NSO.sub.2 F is then reacted with an approximately equimolar amount of the acetoacetylating agent diketene, in an inert organic solvent, in the presence of an amine, at temperatures between about -30 and 100.degree. C.; the reaction takes place in accordance with the following equations (with triethylamine as the amine): ##STR2##
The acetoacetamide-N-sulfonyl fluoride is then cyclized in a customary manner using a base, for example using methanolic KOH, to the sweetener: ##STR3##
Although some of the known processes provide quite satisfactory yields of 6-methyl-3,4-dihydro-1,2,3-oxathiazin -4 one 2,2-dioxide and its non-toxic salts (up to about 85% of theory based on the starting sulfamoyl halide), they are still in need of improvement, particularly for industrial purposes, because of the necessity of using chloro- or fluorosulfonyl isocyanate, which are not very easy to obtain, as starting materials; this is because the preparation of the chloro- and fluorosulfonyl isocyanate requires considerable precautionary measures and safety arrangements by reason of the starting materials (HCN, Cl.sub.2, SO.sub.3 and HF), some of which are rather unpleasant to handle. The preparation of the chloro- and fluorosulfonyl isocyanate are based on the following reaction equations:
Replacement of the sulfamoyl fluoride in the process according to the abovementioned German Offenlegungsschrift 2,453,063 by, for example, the considerably more easily obtainable (for example from NH.sub.3 +SO.sub.3) sulfamic acid H.sub.2 NSO.sub.3 H or its salts hardly appeared promising because the reaction of Na sulfamate H.sub.2 NSO.sub.3 Na with diketene in an aqueous-alkaline solution does not provide any reaction product which can be isolated pure. Rather, it has been possible to obtain the 1:1 adduct, which is probably at least partially formed in this reaction, only in the form of the coupling product with 4-nitrophenyldiazonium chloride, as a pale yellow dyestuff; see Ber. 83 (1950), pages 51-558, in particular page 555, last paragraph before the description of the experiments, and page 558, last paragraph: ##STR4##
Moreover, the acetoacetamide-N-sulfonic acid has otherwise been postulated only, or also, as an intermediate in the decomposition of 6-methyl-3,4-dihydro-1,2,3-oxathiazin -4-one 2,2-dioxide during boiling in aqueous solution; see the literature cited in the introduction, Angew. Chemie (1973) loc. cit.: ##STR5## Thus, because the state of the art processes for the preparation of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and its non-toxic salts are, in particular, not entirely satisfactory for being carried out on an industrial scale, in particular as a result of the necessity to use starting materials which are not very straight-forward to obtain, the object was to improve the known processes appropriately or to develop a new improved process.
This object has been achieved according to the invention by a modification of the process of German Offenlegungsschrift 2,453,063 (mainly replacement of the sulfamoyl fluoride in the known process by salts of sulfamic acid) followed by ring closure of the resulting acetoacetylation product using SO.sub.3.
Thus, the invention relates to a process for the preparation of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and its non-toxic salts by
The reaction equations on which the process is based are as follows (with diketene as the acetoacetylating agent): ##STR6##
The process starts from starting materials which are straightforward to obtain and of low cost and it is extremely straightforward to carry out. The yields are about 90 to 100% of theory in step a) (based on the starting sulfamate), about 70 to 95% of theory in step b) (based on the acetoacetamide-N-sulfonate) and about 100% of theory in step c) (based on the oxathiazinone in the acid form), so that the yields resulting for the overall process are between about 65 and 95% of theory. Thus, compared with the state of the art processes, the invention represents a considerable advance.
It is extremely surprising that the reaction between sulfamate and acetoacetylating agent to give acetoacetamide-N-sulfonate by step (a) takes place smoothly because, on the basis of literature reference Ber. 83 (1950) loc. cit., according to which the reaction between Na sulfamate and diketene in aqueous-alkaline solution is apparently only rather undefined, a good yield and a 1:1 reaction product, which could be isolated pure without difficulty, was hardly to be expected from sulfamic acid or its salts and acetoacetylating agents.
It is equally surprising that the ring closure of acetoacetamide-N-sulfonate or of the free sulfonic acid, using SO.sub.3 in step (b) of the process, takes place exceedingly well, because the elimination of water or bases (MOH) taking place with ring closure in this step either does not occur or, at any rate, virtually does not occur with other agents which eliminate water or bases, such as, for example, P.sub.2 O.sub.5, acetic anhydride, trifluoroacetic anhydride, thionyl chloride etc.
In detail, the process according to the invention is carried out as follows: Step (a)
It is possible to use as the acetoacetylating agent the compounds known for acetoacetylations such as, for example, acetoacetyl chloride and diketene; the preferred acetoacetylating agent is diketene.
The amount of acetoacetylating agent used should be at least approximately equimolar (related to the reactant sulfamate). It is preferable to use an excess of up to about 30 mol-%, in particular an excess of only up to about 10 mol-%. Excesses greater than about 30 mol-% are possible, but entail no advantage.
Suitable inert organic solvents are virtually all organic solvents which do not react in an undesired manner with the starting materials and final products or, where appropriate, the catalysts in the reaction, and which also have the ability to dissolve, at least partially, salts of sulfamic acid. Thus, the following organic solvents may be mentioned in this context as suitable and preferred:
halogenated aliphatic hydrocarbons, preferably those having up to 4 carbon atoms such as, for example, methylene chloride, chloroform, 1,2-dichlorethane, trichloroethylene, tetrachloroethylene, trichlorofluoroethylene etc.;
aliphatic ketones, preferably those having 3 to 6 carbon atoms such as, for example, acetone, methyl ethyl ketone etc.;
aliphatic ethers, preferably cyclic aliphatic ethers having 4 or 5 carbon atoms such as, for example, tetrahydrofuran, dioxane etc.;
lower aliphatic carboxylic acids, preferably those having 2 to 6 carbon atoms such as, for example, acetic acid, propionic acid etc.;
aliphatic nitriles, preferably acetonitrile;
N-alkyl-substituted amides of carbonic acid and lower aliphatic carboxylic acids, preferably amides having up to 5 carbon atoms such as, for example, tetramethylurea, dimethylformamide, dimethylacetamide, N-methylpyrrolidone etc.;
aliphatic sulfoxides, preferably dimethyl sulfoxide, and
aliphatic sulfones, preferably sulfolane ##STR7##
Particularly preferred solvents from the above list are methylene chloride, 1,2-dichloroethane, acetone, glacial acetic acid and dimethylformamide, especially methylene chloride.
The solvents can be used either alone or in a mixture.
The ratio of the amounts of the reaction starting materials to the solvent can vary within wide limits; in general, the weight ratio is about 1:(2-10). However, other ratios are also possible.
In principle, the amine and phosphine catalysts which can be used are all amines and phosphines whose use as catalysts for addition reactions of diketene is known. These are mainly tertiary amines and phosphines (still) having nucleophilic characteristics.
Those which are preferred in the present case are tertiary amines and phosphines in which each N or P atom has up to 20, in particular only up to 10, carbon atoms. The following tertiary amines may be mentioned as examples:
Trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, tricyclohexylamine, ethyldiisopropylamine, ethyldicyclohexylamine, N,N-dimethylaniline, N,N-diethylaniline, benzyldimethylamine, pyridine, substituted pyridines, such as picolines, lutidines, collidines or methyl ethyl pyridines, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, N,N'-dimethylpiperazine, 1,5-diazabicyclo-[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, also tetramethylhexamethylenediamine, tetramethylethylenediamine, tetramethylpropylenediamine, tetramethylbutylenediamine, as well as 1,2-dimorpholylethane, pentamethyldiethylenetriamine, pentaethyldiethylenetriamine, pentamethyldipropylenetriamine, tetramethyldiaminomethane, tetrapropyldiaminomethane, hexamethyltriethylenetetramine, hexamethyltripropylenetetramine, diisobutylenetriamine or triisopropylenetetramine.
A particularly preferred amine is triethylamine.
Examples of tertiary phosphines are methyldiphenylphosphine, triphenylphosphine, tributylphosphine etc.
The amount of catalyst is normally up to about 0.1 mole per mole of sulfamate. Larger amounts are possible, but entail hardly any advantages. In principle, reaction step (a) of the process according to the invention also takes place without catalyst; however, the catalyst acts to accelerate the reaction and is thus advantageous.
The sulfamic acid salts to be used for the process must be at least partially soluble in the inert organic solvent. This requirement is met by, preferably, lithium, NH.sub.4 and the primary, secondary, tertiary and quaternary ammonium salts of sulfamic acid. In turn, the ammonium salts which are preferred are those whose ammonium ion contains not more than about 20, in particular not more than about 10, carbon atoms. Examples of ammonium salts of sulfamic acid are the salts having the following ammonium ions: ##STR8##
A particularly preferred sulfamate is the triethylammonium salt.
The salts are usually obtained in a manner known per se by neutralization of sulfamic acid with LiOH, NH.sub.3 or the appropriate amines or quaternary ammonium hydroxide solutions, followed by removal of water. The base is preferably added in a stoichiometric excess (based on the sulfamic acid) of up to about 30 mol-%, in particular up to only about 15 mol-%. In addition, it is also preferred for the organic moiety in the ammonium ion to be identical to the organic moiety in the amine catalyst (for example use of triethylammonium sulfamate as the sulfamic acid salt and of triethylamine as the catalyst). In the case of salts with NH.sub.3 and primary and secondary amines, a stoichiometric amount of the amine component is preferably used, and the catalyst added is a weakly basic tert.-amine, such as, for example, pyridine.
In general, the reaction temperature is selected to be in a range between about -30 and +50.degree. C., preferably between about 0 and 25.degree. C.
The reaction is normally carried out under atmospheric pressure. The reaction time can vary within wide limits; in general, it is between about 0.5 and 12 hours. The reaction can be carried out either by initial introduction of the sulfamic acid salt and metering in of diketene, or by initial introduction of diketene and metering in of the sulfamic acid salt, or by initial introduction of diketene and sulfamic acid and metering in of the base or, for example, by metering into the reaction chamber both reactants simultaneously, it being possible for the inert organic solvent either also to be initially introduced or to be metered in together with the reactants.
After the reaction is complete, for the isolation of the reaction product the solvent is removed by distillation and the residue (mainly acetoacetamide-N-sulfonate) is recrystallised from a suitable solvent such as, for example, acetone, methyl acetate or ethanol. The yields are about 90 to 100% of theory.
The Li and ammonium acetoacetamide-N-sulfonates are new compounds. They have the formula ##STR9## in which M.sup..sym. =Li.sup..sym. or
The total number of carbon atoms in the ammonium ion in the ammonium salts is preferably not more than about 20, in particular not more than about 10. The free acetoacetamide-N-sulfonic acid can, if desired, be obtained from the acetoacetamide-N-sulfonate by customary processes.
The acetoacetamide-N-sulfonate (or, where appropriate, the free acid) obtained in step (a) is then cyclized in step (b) using at least an approximately equimolar amount of SO.sub.3, where appropriate in an inert inorganic or organic solvent. The SO.sub.3 is generally used in an up to about 20-fold, preferably about 3- to 10-fold, in particular about 4- to 7-fold, molar excess based on the acetoacetamide-N-sulfonate (or the free acid). It can be added to the reaction mixture either in the solid or the liquid form or by condensing in SO.sub. 3 vapor. Normally however, a solution of SO.sub. 3 in concentrated sulfuric acid, liquid SO.sub.2 or an inert organic solvent is used. It is also possible to use compounds which eliminate SO.sub.3. Although, in principle, it is possible to carry out the reaction without solvent, nevertheless it is preferable to carry it out in an inert inorganic or organic solvent. Suitable inert inorganic or organic solvents are those liquids which do not react in an undesired manner with SO.sub.3 or the starting materials or final products of the reaction. Thus, because of the considerable reactivity of, in particular, SO.sub.3, only relatively few solvents are suitable for this purpose. Preferred solvents are:
It is possible to use the organic solvents either alone or in a mixture.
Particularly preferred solvents are liquid SO.sub.2 and methylene chloride.
The amount of inert solvent used is not critical. When a solvent is used, it is merely necessary to ensure adequate solution of the reactants; the upper limit of the amount of solvent is determined by economic considerations.
In a preferred embodiment of the process according to the invention the same solvent is used in both step (a) and step (b); this is preferably a halogenated aliphatic hydrocarbon, in particular methylene chloride. This is because, in this case, the solution obtained in step (a) can, without isolation of the acetoacetamide-N-sulfonate, be used immediately for step (b).
The reaction temperature in step (b) is normally between about -70 and +175.degree. C., preferably between about -40 and +10.degree. C.
Step (b) resembles step (a) in that it is normally carried out only under atmospheric pressure.
The reaction time can be up to about 10 hours.
The reaction can be carried out in such a manner that the acetoacetamide-N-sulfonate (or the free acid) is, where appropriate in solution, introduced and SO.sub.3, where appropriate in the dissolved form, is metered in, or both reactants are simultaneously transferred into the reaction chamber, or SO.sub.3 is initially introduced and the acetoacetamide-N-sulfonate (or the free acid) is added.
It is preferable initially to introduce part of the SO.sub.3 , where appropriate in solution, and then to meter in, either continuously or in portions, acetoacetamide-N-sulfonate (or the free acid) and SO.sub.3 , where appropriate in the dissolved form.
Working-up is carried out in a customary manner. In the preferred case where methylene chloride is used as the reaction medium, working-up can be carried out as follows, for example: to the solution containing SO.sub.3 are added about 10 times the molar amount (based on SO.sub.3) of ice or water. This brings about phase separation: the 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide which has formed is present mainly in the organic phase. The fractions still present in the aqueous sulfuric acid can be obtained by extraction with an organic solvent such as, for example, methylene chloride or an organic ester.
Otherwise, after the addition of water, the reaction solvent is removed by distillation, and the 6-methyl -3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide which remains in the sulfuric acid of reaction is extracted with a more suitable solvent. Suitable solvents are those which are sufficiently stable towards sulfuric acid and which have a satisfactory dissolving capacity; in addition, the reaction product should have in the solvent system a partition coefficient which is favorable for the isolation. Not only halogenated hydrocarbons but also esters of carbonic acid such as, for example dimethyl carbonate, diethyl carbonate and ethylene carbonate, or esters of organic monocarboxylic acids such as, for example, isopropyl formate and isobutyl formate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and neopentyl acetate, or esters of dicarboxylic acids or amides which are immiscible with water, such as, for example, tetrabutylurea, are suitable. Isopropyl acetate and isobutyl acetate are particularly preferred.
The combined organic phases are dried with, for example, Na.sub.2 SO.sub.4, and are evaporated. Any sulfuric acid which has been carried over in the extraction can be removed by appropriate addition of aqueous alkali to the organic phase. For this purpose, dilute aqueous alkali is added to the organic phase until the pH reached in the aqueous phase is that shown by pure 6-methyl-3,4-dihydro -1,2,3-oxathiazin-4-one 2,2-dioxide at the same concentration in the same two-phase system of extracting agent and water. When it is intended to obtain the free compound, this undergoes additional purification in a customary manner (preferably by recrystallization). The yield is between about 70 and 95% of theory based on acetoacetamide-N-sulfonate (or the free acid).
If, however, it is intended to obtain a non-toxic salt of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide, neutralization step (c) is also carried out.
For this purpose, the oxathiazinone compound produced in the acid form in step (b) is neutralized with an appropriate base in a customary manner. With this in view, for example the organic phases which have been combined, dried and evaporated at the end of step (b) are neutralized in suitable organic solvents such as, for example, alcohols, ketones, esters or ethers, or in water, using an appropriate base, preferably using a potassium base such as, for example, KOH, KHCO.sub.3, K.sub.2 CO.sub.3, K alcoholates etc. Alternatively, the oxathiazinone compound is neutralized and extracted directly from the purified organic extraction phase (step b) using an aqueous potassium base. The oxathiazinone salt then precipitates out, where appropriate after evaporation of the solution, in the crystalline form, and it can also be recrystallized for purification.
The yield in the neutralization step is virtually 100%.
Both the overall process according to the invention, consisting of process steps (a), (b) and (c), and the individual process steps (a) and (b) are new and considerably advantageous.
Non-Patent Literature Citations (5)
| Entry |
| Petersen, Chem. Ber., 83, 551-558 (1950). |
| Briody & Satchell J.C.S. S. 3778 (1965). |
| Fieser et al., "Reagents for Organic Synthesis", vol. 2, Wiley-Interscience, New York, 1969, p. 267. |
| Roberts et al., "Principles of Organic Chemistry", W. A. Benjamin Inc., New York, 1965, p. 493. |
| Methoden Der Organischen Chemie (Houben-Weyl) (1968) p. 253. |
Divisions (1)
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Number |
Date |
Country |
| Parent |
714177 |
Mar 1985 |
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Continuations (2)
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Number |
Date |
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| Parent |
300763 |
Jan 1989 |
|
| Parent |
870001 |
Jun 1986 |
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Patent Grant
5011982
