The present invention relates to a process for the preparation of alkyl-ureas, starting from O,S-dimethyl dithiocarbonate.
Alkyl-ureas are a family of well-known compounds. They are important intermediates in the production of isocyanates, drugs, phytomedicines and are used in colouring agents"" chemistry, as plasticizers and stabilisers (see Ulmann""s Encyclopaedia of Industrial Chemistry, Fifth Edition, 1996, Vol. A27, 355).
There are various processes for preparing monoalkyl-ureas. Among these, the main, long-known processes are the following reactions: i) the reaction of ammonia with a suitable carbamoyle chloride, obtainable by phosgenation of a suitable amine; ii) the reaction of a salt of a suitable amine with a cyanate of an alkaline metal; iii) the reaction of a suitable isocyanate with ammonia; iv) the reaction of a suitable amine with nitro-urea; v) the reaction of transamidation of urea with a suitable amine (see Houben-Weyl, Georg Thieme Verlag, Stuttgart 1952, Vol. VIII, 153). The starting materials used in the first four processes are fairly expensive, highly toxic and/or difficult to obtain. The fifth process does not exhibit the same disadvantages of the first four processes. The transamidation of urea with amines is carried out under pressure in an aqueous or anhydrous medium, as described in DE-C-8 555 551 and in U.S. Pat. No. 3,937,727, or, more easily, in a solvent at atmospheric pressure (see U.S. Pat. No. 4,310,692). The transamidation reaction uses, as a starting material, urea, which is an innocuous, non-toxic and inexpensive compound. However, the yields of the reaction products are fairly limited (they normally reach about 80%) and, at the same time, as results from their physical properties (melting point), their purity is low.
Similarly, the main processes for synthesising di- and tri-alkyl-ureas may be related to the above-described processes for monoalkyl-substituted ureas, i.e.: (i) the reaction of a suitable amine with a suitable carbamoyle chloride, obtainable by phosgenation of a suitable amine; (ii) the reaction of a suitable isocyanate with a suitable amine; (iii) the transamidation reaction of the ureas with suitable amines. The disadvantages of all these processes are the same as those mentioned above, i.e.: as regards the synthetic processes (i) and (ii), the toxicity, difficulty to obtain and/or very high costs of the raw materials; as regards process (iii), the yield and purity problems; on this subject, see for example U.S. Pat. No. 6,281,170, wherein the preparation of N,N,Nxe2x80x2-trialkyl-ureas starting from N,Nxe2x80x2-dimethyl-urea, with a yield of only 61% is disclosed.
Symmetric and asymmetric N,Nxe2x80x2-dialkyl-ureas have been recently prepared also starting from S,S-dimethyl dithiocarbonate (see Man-kiti Leung et al, J. Org. Chem., 1996, 61, 4175). O,S dimethyl dithiocarbonate is an industrially accessible compound (I. Degani, R. Fochi, V. Regondi, Synthesis, 1980, 375 and I. Degani, R. Fochi, V. Regondi, Synthesis, 1980, 149); however, the processes described for its conversion into symmetric and asymmetric N,Nxe2x80x2-dialkyl-ureas are not suitable for industrial exploitation, due to the long reaction times, the usually poor yield and, referring in particular to asymmetric ureas, due to the sophisticated operation conditions and the fairly high cost of the reagents.
Concerning symmetric dialkyl-ureas only, it is also possible to synthesise them from carbon dioxide and a suitable monoalkyl-amine at high temperatures and pressures, but with no more than a 75% conversion, which implies the need to recover and purify the gaseous effluents before being able to recycle them in the reaction, as described by U.S. Pat. No. 4,178,309.
The object of the present invention is a process for preparing mono-, di- and trisubstituted ureas that may solve the disadvantages of the known processes, i.e. a process which may provide high yields of the said ureas, in fair conditions and at a low cost. Such an object is brilliantly solved by the present invention, which relates to a process for preparing alkyl-ureas starting from O,S-dimethyl dithiocarbonate, represented by the following formula (1): 
characterised in that is provides the following steps:
A) causing the O,S-dimethyl dithiocarbonate (1) to react with a primary amine of general formula R1NH2 in order to obtain an O-methyl thiocarbamate of formula (2), wherein R1 is an alkylic, cyclo-alkylic or aryl-alkylic radical 
B) isomerising the O-methyl thiocarbamate of formula (2) in order to obtain a S-methyl thiocarbamate of formula (3) 
C) causing the S-methyl thiocarbamate of formula (3) to react with a compound of general formula Rxe2x80x2Rxe2x80x3NH, wherein Rxe2x80x2 and Rxe2x80x3 may be equal or different one in respect of the other and may be H, R2 and R3, wherein R2 and R3 are alkylic, cyclo-alkylic or aryl-alkylic radicals and may be equal to or different from R1, in order to obtain one of the alkyl-ureas (4), (5) or (6) 
The present invention relates to the preparation of monoalkyl-ureas (4), N,Nxe2x80x2-dialkyl-ureas (5) and trialkyl-ureas (6) starting from O,S-dimethyl dithiocarbonate (1), through the intermediate formation of O-methyl thiocarbamates (2) and S-methyl thiocarbamates (3), wherein R1, R2 and R3 represent alkylic, cyclo-alkylic or aryl-alkylic radicals which may be equal or different one in respect of the other and wherein R2 and R3 may also be H.
The first step provides causing the O,S-dimethyl dithiocarbonate (1) to react with a primary amine R1NH2, wherein an alkylic, cyclo-alkylic or aryl-alkylic radical is bound to the nitrogen atom, which reaction results in yields between 99% and 99.9% of O-methyl thiocarbamate (2), wherein R1 represents the same radicals of the primary amine; the molar ratio R1NH2/(1) lies between 1.1 and 1.2; the reaction temperature is between 20xc2x0 C. and 30xc2x0 C.; the reaction time is between 2 and 3 hours. The O-methyl thiocarbamate (2) thus obtained is highly pure and may be employed directly in the following step. During the formation of the O-methyl thiocarbamate (2), a mole of methanthiol is produced, which is a product of a certain industrial value and is recovered under the form of sodium salt in aqueous solution, with a 94-98% yield.
The second step consists in isomerising the O-methyl thiocarbamate (2) into S-methyl thiocarbamate (3), wherein R1 represents the same radicals of the primary amine and of the corresponding O-methyl thiocarbamate (2). The isomerisation reaction is made at a temperature between 40xc2x0 C. and 60xc2x0 C., in an organic solvent, preferably toluene, in amounts between 0.05 and 4.50 parts in weight per part in weight of (2), using, as initiator, a quantity of dimethyl sulphate between 4% and 8% of the weight of the reagent; the reaction time is between 0.5 and 4 hours; the reaction yields are between 94% and 98%. Dimethyl sulphate may be replaced by a protic organic acid, preferably by methansulphonic acid, used as catalyst. When the reaction is carried out using a protic organic acid, the reaction temperature is about 100xc2x0 C.; the reaction time is between 2 and 3.5 hours; yields are around 98%. The S-methyl thiocarbamate (3) thus obtained is extremely pure and may be employed directly in the following step.
The third step provides causing the S-methyl thiocarbamate (3), wherein Rxe2x80x3 represents the same radicals of the primary amine R1NH2 and of the corresponding O-methyl thiocarbamate (2), to react with a compound of general formula Rxe2x80x2Rxe2x80x3NH, wherein Rxe2x80x2 and Rxe2x80x3 may be equal or different one in respect of the other and they may be H or an alkylic, cyclo-alkylic or aryl-alkylic group. In case a monoalkyl-urea of formula (4) is to be obtained, Rxe2x80x2=Rxe2x80x3=H and the compound reacting with the S-methyl thiocarbamate is aqueous ammonia. The reaction is carried out at a temperature between 60xc2x0 C. and 70xc2x0 C.; the reaction time is between 3 and 6 hours; the reaction yields are between 93% and 96%. The alkyl-urea (4) thus obtained is extremely pure and does not require further purification steps in order to be employed for the intended purposes. During the formation of the monosubstituted urea (4), a mole of methanthiol is produced, which product hasxe2x80x94as mentioned beforexe2x80x94a good industrial value and which is therefore recovered under the form of sodium salt in aqueous solution, with a 95% yield.
Alternatively, if a dialkyl-urea of formula (5) is to be obtained, Rxe2x80x2=H, Rxe2x80x3=R2 (which may also correspond to R1) and the compound with which the O-methyl thiocarbamate (3) is made to react is a primary amine R2NH2. The reaction is carried out at a temperature between 30xc2x0 C. and 60xc2x0 C.; the reaction time is between 4 and 8 hours; the reaction yields are between 93% and 96%. The dialkyl-urea (5) thus obtained is extremely pure and may be employed directly for the intended purposes. Also during the formation of the N,Nxe2x80x2-disubstituted urea (5), a mole of methanthiol is produced, which is recovered under the form of sodium salt in aqueous solution, with a 95% yield.
Furthermore, if a trialkyl-urea of formula (6) is to be obtained, Rxe2x80x2=R2, Rxe2x80x3=R3 and the S-methyl thiocarbamate (3) is to react with a secondary amine R2R3NH. The reaction is carried out at a temperature between 60xc2x0 C. and 70xc2x0 C.; the reaction time is between 1 and 2 hours; the reaction yields are between 93% and 96%. The trialkyl-urea (6) thus obtained is extremely pure and may be employed without any further purification for the intended purposes. During the formation of the N,N,Nxe2x80x2-trisubstituted urea (6), a mole of methanthiol is produced, which is recovered under the form of sodium salt in aqueous solution, with a 95% yield.
The process constituted by the steps A-C as described above, which employs, as a, starting compound, the O,S-dimethyl dithiocarbonate, an easily accessible, safe and inexpensive compound, provides, in mild and easily obtainable conditions and with usually very high yields, mono-, di- and trialkyl-substituted ureas, respectively of formulae (4), (5) and (6), wherein the substituents R1, R2 and R3, which may be equal or different one in respect of the other, are highly pure and, in most cases, immediately usable alkylic, cyclo-alkylic or aryl-alkylic radicals. The present process also has the important advantage of producing sodium methanthiolate, by completely exploiting the O,S-dimethyl dithiocarbonate (1) used as a starting compound.
The present invention will now be described more in detail, with reference to some examples, which are only provided for purposes of illustration and are not intended to be limiting.