Title of Invention	PROCESS FOR PREPARING 1,2-DIAMINO COMPOUNDS
Abstract	The invention provides a mufti-step process for preparing 1,2-diamino compounds of formula wherein R<1>, R<1>, R<2'> RTand R<3> have the meaning given in the specification and pharmaceuticallycceptable addition salts thereof, from 1,2-epoxides of formula wherein R<1>, R<1>, R<2> and R<2'> have the meaning given in the specification.

Full Text

Azide free process for preparing Neuraminidase Inhibitors R6 The present invention concerns a new multi-step process for preparing 1,2-diamino compounds from 1,2-epoxides, in particular for preparing 1,2-diamino compounds useful as inhibitors of viral or bacterial neuraminidases, as well as specific intermediates useful in that multi-step process. PCT Patent Publication No. 96/26933 describes a large class of compounds useful as inhibitors of viral or bacterial neuraminidases and their preparation. These compounds comprise a six-membered partially unsaturated carbocyclic or heterocyclic ring system, which can be substituted by several different substituents. PCT Patent Publication No. 98/07685 discloses various methods for preparing compounds of the above class which are cyclohexene carboxylate derivatives. A particularly interesting compound is (3R,4R,5S)-5-amino-4-acetylamino-3-(l-ethyl-propoxy)-cyclohex-l-ene-carboxylic acid ethyl ester (C.U. Kim et aL, J. Am.Chem. Soc, 1997, 119, 681-690). A method of preparation of that 1,2-diamino compound in 10 steps starting from shikimic acid, or in 12 steps starting from quinic acid, is described by J.C. Rohloffe* aL, J. Org. Chem.,1998, 63,4545-4550. The 10 step method involves a final 4-step reaction sequence from the 1,2-epoxide (lS,5R,6R)-5-(l-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester via three potentially highly toxic and explosive azide intermediates. Dedicated know-how and expensive equipment are required to perform such a process. In a technical process, it is preferable to avoid use of azide reagents and azide intermediates. U.S. Patent No. 6,437,171 discloses an improved method for preparing 1,2-diamino compounds from 1,2-epoxides by using allylamine-magnesium bromide etherate to open the epoxide and allylamine-Brensted acid to open the aziridine. Although this new method addresses the azide handling problem, it has a low overall yield from epoxide to final drug substance. The problem to be solved by the present invention, therefore, is to find an aside-free process for preparing 1,2-diamino compounds from 1,2-epoxides that has higher overall yield. That problem has been solved by the invention, as described below, and as defined in the appended claims. The invention provides a process for preparing 1,2-diamino compounds of formula and pharmaceutical^ acceptable addition salts thereof wherein, R1, Rr, R2 and R2', independently of each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, aryl-lowef alkyl, aryl-lower alkenyl, or aryl-lower alkynyl, or R1 and R2, R1 and R2, R1' and R2 or Rr and R2' taken together with the two carbon atoms to which they are bound, are a carbocyclic or heterocyclic ring system, or R1 and R1' or R2 and R2' taken together with the carbon atom to which they are bound, are a carbocyclic or heterocyclic ring system, with the proviso that at least one of R1, Rr, R2 and R2' is not H, and R3 is a substituent of an amino group which process is characterized in that it comprises the steps of: a) reacting a 1,2-epoxide of formula wherein R1,R1',R2 and R2' are as above with an amine of formula R5NH2 wherein R5 is a substituent of an amino group, but not H, to form a 2-aminoalcohol of formula wherein R1, R1', R2, R2' and R5 are as above; b) converting the 2-aminoalcohol of formula (HI) to the aziridine of formula wherein R1, R1', R2, R2' and R5 are as above; c) reacting the aziridine of formula (IV) with an amine of formula R NHR , wherein R7 and R8, independently from each other, are H or a substituent of an amino group, with the proviso that not both R7 and R8 are H to obtain a 1,2-diamino compound of formula wherein R1, R1', R2, R2', R5, R7and R8 are as above; d) acylating the secondary amino group in position 1 of the 1,2-diamino compound of formula (V) to form an acylated 1,2-diamino compound of formula wherein R1, R1', R2, R2', R3, R5, R7 and Rs are as above; e) removing R5 from the acylated 1,2-diamino compound (VI) to produce an acylated 1,2-diamino compound of formula wherein R1, R1', R2, R2\ R3, R7and R8 are as above; and, f) deprotecting the amino group in position 2 of the 1,2-diamino compound of formula (VII) to produce the 1,2-diamino compound of formula (I). If desired, the resulting 1,2-diamino compound of formula (I) can be further transformed into a pharmaceutically acceptable addition salt. The term "alkyl" means a straight chain or branched saturated alkyl group with 1-20, preferably 1-12, C-atoms, which can caR1'y one or more substituents. The term "alkenyl" means a straight chain or branched alkenyl group with 2-20, preferably 2-12, C-atoms, which can caR1'y one or more substituents. The term "alkynyl" means a straight chain or branched alkynyl group with 2-20, preferably 2-12, C-atoms, which can caR1'y one or more substituents. The term "cycloalkyl" signifies a saturated, cyclic hydrocarbon group with 3-12, preferably 5-7, C-atoms, which can caR1'y one or more substituents. The term "aryl" denotes a mono-nuclear or di-nuclear aromatic group which can caR1'y one or more substituents, for example, phenyl, substituted phenyl, naphthyl, or substituted naphthyl. / The term "heterocyclyl" means a saturated or unsaturated monocyclic or bicyclic group with 1 or 2 nitrogen, sulfur and/or oxygen atoms, for example, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, isobenzofuranyl, furanyl, tetrahydrofuranyl, thiofuranyl, dihydrothiofuranyl, benzo[b]dihydrofuranyl, tetrahydrothiofuranyl, thioxanyl, dioxanyl, ditfiianyl, chromanyl, isochromanyl, dithiolanyl, pyridyl, pyperidyl, imidazolidinyl, pyR1'olidinyl, quinolyl or isoquinolyl, which can caR1'y one or more substituents. The term "carbocyclic ring system" means a cyclic alkyl group with 3-12, preferably 5-7, C-atoms, which can include one or two carbon-carbon double bonds, and which can caR1'y one or more substituents, for example, cyclopentene, substituted cyclopentene, cyclohexene, substituted cyclohexene, cycloheptene, or substituted cycloheptene. The term "heterocyclic ring system" means a monocyclic or bicyclic group with 1 or 2 nitrogen, sulfur and/or oxygen atoms, which can include one or two double bonds and caR1'y one or more substituents, as exemplified above under the term "heterocyclyl", for example tetrahydropyran, dihydropyran, substituted dihydropyran, tetrahydrofuran, isobenzotetrahydrofuran, thioxan, 1,4-dioxane, dithian, dithiolan, piperidine, or piperazine. Suitable substituents on the above groups are those which are inert in the reactions involved. Examples of suitable substituents on such alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyWower alkenyl, heterocyclyl-lower alkynyl, aryl, or aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, are lower alkyl, lower alkoxy, lower alkyl carboxylate, carboxylic acid, carboxamide, N-(mono/di-lower alkyl)-carboxamide. Examples of suitable substituents on such a carbocyclic or heterocyclic ring system are alkyl of 1 to 12 C-atoms, alkenyl of 2 to 12 C-atoms, alkynyl of 2 to 12 C-atoms, alkoxy of 1 to 12 C-atoms, alkyl of 1 to 12 C-atoms-carboxylate, carboxylic acid, carboxamide, N-(mono/di-alkyl of 1 to 12 C-atoms)-carboxamide. PrefeR1'ed substituents are lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, carboxylic acid, lower alkyl carboxylate, carboxamide, N-(mono/di-lower alkyl)-carboxamide. The term "lower" here denotes a group with 1-6, preferably 1-4, C-atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl, pentyl and its isomers and hexyl and its isomers. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, rec-butoxy, tert-butoxy and 1-ethyl-propoxy. Examples of lower alkyl carboxylates are methyl carboxylate, ethyl carboxylate, propyl carboxylate, isopropyl carboxylate and butyl carboxylate. Examples of lower alkanoyl groups are acetyl, propionyl and butyryl. In accordance with the present invention, the term "substituent of an amino group" refers to any substituents conventionally used to hinder the reactivity of an amino group, as described in Green, T., "Protective Groups in Organic Synthesis", Chapter 7, John Wiley and Sons, Inc., 1991, 315-385, herein incorporated by reference. Such prefeR1'ed substituents are acyl, alkyl, alkenyl, alkynyl, aryl-lower alkyl, silyl methyl wherein silyl is trisubstituted with lower alkyl, lower alkenyl, lower alkynyl and/or aryl. Advantageously, the reactivity of the amino group can also be hindered by protonation, e.g., with Lewis acids, including H4". The term "acyl" means alkanoyl, preferably lower alkanoyl, alkoxy-carbonyl, preferably lower alkoxy-carbonyl, aryloxy-carbonyl or aroyl such as benzoyl. In a prefeR1'ed embodiment the invention comprises a process for preparing 4,5-diamino-shikimic acid derivatives of formula and pharmaceutically acceptable addition salts thereof wherein R is an optionally substituted alkyl group, R is an alkyl group and R is a substituent of an amino group from a cyclohexene oxide of formula wherein R11 and R12 are as above. The term alkyl in R11 has the meaning of a straight chain or branched alkyl group of 1 to 20 C-atoms, preferably of 1 to 12 C-atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, terf-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers and dodecyl and its isomers. This alkyl group can be substituted with one or more substituents as defined in, e.g., WO 98/07685. Suitable substituents are alkyl having 1 to 20 C-atoms (as defined above), alkenyl having 2 to 20 C-atoms, cycloalkyl having 3 to 6 C-atoms, hydroxy, alkoxy having 1 to 20 C-atoms, alkoxycarbonyl having 1 to 20 C-atoms, F, CI, Br, and L The prefeR1'ed meaning for R11 is 1-ethylpropyL R12 here is a straight chain or branched alkyl group of 1 to 12 C-atoms, preferably of 1 to 6 C-atoms, as exemplified above. The prefeR1'ed meaning for R12 is ethyl. In the compound of formula (VIE), the substituent of an amino group is as defined above. Suitable substituents of amino groups are also described in, e.g., the WO 98/07685. PrefeR1'ed substituents of an amino group for R are alkanoyl groups, more preferably lower-alkanoyl with 1 to 6 C-atoms such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). PrefeR1'ed alkanoyl group and therefore prefeR1'ed meaning for R is acetyl. The prefeR1'ed 1,2-diamino compound of formula (I) or 4,5-diamino-shikimic acid derivative of formula (VIE) therefore is the (3R,4R,5S)-5-amino-4-acetylamino-3-(l-ethyl-propoxy)-cyclohex-l-ene-carboxylic acid ethyl ester or the (3R,4R,5S)-5-amino-4-acetylamino-3-(l-ethyl-propoxy)-cydohex-l-ene-carboxylic acid ethyl ester phosphate (1:1). The prefeR1'ed 1,2-epoxide of formula (II) or cyclohexene oxide of formula (IX) therefore is the (lS,5R,6R)-5-(l-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester. Step (a) Step (a) comprises reacting a 1,2-epoxide of formula (II) with an amine of formula R5NH2 to form the respective 2-aminoalcohol of formula (IE). The amine of formula R5NH2 in step (a) is a primary amine which shows reactivity for opening the 1,2-epoxide ring. R5 in the amine of formula R5NH2 preferably is a straight chain or branched alkyl of 1 to 6 C-atoms. The straight chain or branched alkyl of 1 to 6 C-atoms preferably is tert-butyl or an analog thereof such as te/t-butyl or any branched alkyls with a tertiary carbon atom that is attached to the nitrogen. Suitable examples are, e.g., 2-methylbutyl and 2-methylpentyl. PrefeR1'ed amines of formula R5NH2 with the meaning of a straight chain or branched alkyl of 1 to 6 C-atoms group therefore include feR1'-butylamine, 2-methylbutylamine, or 2-methylpentylamine, and more preferably tert-butylamine. The prefeR1'ed amine of formula R5NH2 is terf-butylamine. The amine of formula RSNH2 is generally used in a molar amount of 1.0 to 3.0 equivalents, preferably of 1.5 to 2.5 equivalents, based on one equivalent of the 1,2-epoxide of formula (II). Step (a) can be performed without a catalyst under normal or elevated pressure, however, the reaction time of step (a) can be significantly reduced in the presence of a catalyst. Suitably the catalyst is a metal catalyst or a magnesium halide. Convenient metal catalysts known to catalyze ring opening reactions of 1,2-epoxides with amines are lanthanide compounds such as lanthanide trifluoromethanesulfonates like Yb(OTf)3, Gd(OTf)3 and Nd(OTf)3 (M. Chini et al, Tetrahedron Lett., 1994, 35,433-436), samarium iodides (P. Van de Weghe, Tetrahedron Lett., 1995,36,1649-1652) or other metal catalysts such as amide cuprate reagents (Y. Yamamoto, J. Chem. Soc., Chem, Commun., 1993,1201-1203) andTi(0-i-Pr)4 (M. Caron etal, J- Org. Chem., 1985, 50,1557 and M. Muller, etal, J. Org. Chem., 1998, 68, 9753). The ring opening with metal catalysts is caR1'ied out in the presence of an inert solvent such as tetrahydrofuran at temperatures between 20°C and 150°C. In accordance with the present invention, the magnesium halides are the prefeR1'ed catalysts for the ring opening of 1,2-epoxides with amines. The term "magnesium halide derivative" here denotes anhydrous or hydrated magnesium chloride, magnesium bromide or magnesium iodide, or an etherate, in particular a dimethyl etherate, a diethyl etherate, a dipropyl etherate, or a diisopropyl etherate thereof. Anhydrous magnesium chloride is the prefeR1'ed catalyst. The magnesium halide is suitably used in a molar amount of 50-120 mol %, preferably of 100 mol %. Suitable solvents for the magnesium halide catalysis are protic solvents such as ethanol or methanol, or preferably an aprotic solvent such as tetrahydrofuran, dioxane, teR1'-butyl methyl ether, diisopropylether, isopropylacetate, ethylacetate, methylacetate, acetonitrile, benzene, toluene, pyridine, methylene chloride, dimethylformamide, N-methylformamide and dimethylsulfoxide or mixtures thereof. The aprotic solvent is preferably selected from tetrahydrofuran, diisopropylether, tert-butyl methyl ether, acetonitrile, toluene or a mixture thereof, and more preferably is toluene or MTBE-acetonitrile. Magnesium halide catalysis is advantageously caR1'ied out at temperatures between 0°C and 200°C, preferably between 25°C and 70°C. The respective 2-aminoalcohol of formula (ID) can be isolated after the reaction has been finished and if so desired purified by methods known to those skilled in the art. Step (b) Step (b) comprises converting the 2-aminoalcohol of formula (IE) to the aziridine of formula (TV). Because R5 is a straight chain or branched alkyl of 1 to 6 C-atoms as outlined above in step (a), mesylation-cyclization is the major step for the conversion in step (b). The mesylation-cyclization is caR1'ied out by using a sufonylating agent such as halogenides or the anhydrides of the following sulfonic acids: methane sulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid and trifluoromethanesulfonic acid. PrefeR1'ed sulfonylating agents are halogenides or anhydrides of methane sulfonic acid, such as, methanesulfonyl chloride. The sulfonylating agent is preferably added in an amount of 1.0 to 2.0 equivalents relating to one equivalent of the 2-aminoalcohol of formula (HI). The mesylation-eyclization is advantageously caR1'ied out in an aqueous aprotic solvent, such as, methylene chloride or toluene. The reaction temperature is preferably chosen in the range of 25°C and 70°C. Step (c) Step (c) comprises converting the aziridine of formula (TV) to a 1,2-diamino compound of formula (V) with an amine of formula R7NHR8, wherein R7 and R8, independently from each other, are H or a substituent of an amino group, with the proviso that not both R7 and R8 are H. The amine of formula R NHR of step (c) is a primary or secondary amine which shows reactivity for opening the aziridine ring. R7 or R8 in the amine of formula R7NHR8 preferably is a straight chain or branched alkenyl of 2 to 6 C-atoms, optionally substituted benzyl or heterocyclyl methyl. The straight chain or branched alkenyl of 2 to 6 C-atoms preferably is allyl or an analog thereof, such as, an allyl or allyl group which is substituted on the a-, P-or y-carbon by one lower alkyl, lower alkenyl, lower alkynyl or aryl group. Suitable examples are, e.g., 2-methylallyl, 3,3-dimethylallyl, 2-phenylallyl, and 3-methylallyl. PrefeR1'ed amines of formula R7NHR8 with the meaning of a straight chain or branched alkenyl of 1 to 6 C-atoms group therefore include allylamine, diallylamine or 2-methylallylamine, and more preferably, diallylamine. Optionally substituted benzyl preferably is benzyl or benzyl analogs which are either substituted on the a-carbon atom with one or two lower alkyl, lower alkenyl, lower alkynyl or aryl groups or substituted on the benzene ring with one or more lower alkyl, lower alkenyl, lower alkynyl, lower-alkoxy or nitro groups. Suitable examples are α- methylbenzj'l, α-phenylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methox3'benzyl, 4-nitrobenzyl or 3-methylbenzyl. PrefeR1'ed amines of formula R7NHRS with the meaning of an optionally substituted benzyl group include benzylamine, dibenzylamine, methylbenzylamine, 2-methoxybenzylamine. 3-methoxybenzylamine or 4-methoxybenzylamine, and more prefeR1'ed is benzylamine. Heterocyclyl methyl preferably is heterocyclyl methyl wherein either the methyl group is substituted with one or two lower alkyl, lower alkenyl, lower alkynyl or aryl groups or the heterocyclic ring is substituted with one or more lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy groups. Suitable examples are furfuryl or picolyl. The prefeR1'ed amine of formula R7NHR8 is diallylamine. The amine of formula R7NHR8 is generally used in a molar amount of 1.0 to 2.0 equivalents, preferably of 1.0 to 1.5 equivalents, based on one equivalent of the aziridine of formula (IV). Step (c) can be performed without a catalyst under normal or elevated pressure, however, the reaction time of step (c) can, in general, be significantly reduced in the presence of a catalyst. If either R7 or R8 is a benzyl group or a benzyl analog, the suitable catalysts can be ytterbium triflate (20 mol %) or lithium perchlorate (1 equivalent). If R7NHR8 is an aliphatic amine, the suitable catalysts can be sulfonic acid and its derivatives, such as methane sulfonic acid, benzene sulfonic acid and 10-Camphorsulfonic acid (CSA). The sulfonic acid catalyst is preferably added in an amount of 1.0 to 2.0 equivalents relating to one equivalent of the aziridine of formula (IV). Lewis acid catalysts (10-20 mol%) such as copper (II) chloride, copper (II) bromide, or copper (II) triflate, zinc chloride, zinc triflate, or boron trifluoride etherate are also suitable if excessive diallylamine is used. The prefeR1'ed catalysts are either 10-Camphorsulfonic acid and methanesulfonic acid. The ring opening with sulfonic acid is suitably carried out without solvent at temperatures between 100°C and 120°C. Step (d) Step (d) comprises the acylation of the secondary amino group in position 1 of the 1,2-diamino compound of formula (V) to form an acylated 1,2-di amino compound of formula (VI). Acylation can be effected under strong acidic conditions by treating the 1,2-diamino compound of formula (V) with acylating agents known to a person skilled in the art. The acylating agent can be an aliphatic or aromatic carboxylic acid, or an activated derivative thereof, such as an acyl halide, a carboxylic acid ester or a carboxylic acid anhydride. Suitable acylating agents are preferably acetylating agents such as acetylchloride, trifluoracteylchloride or acetic anhydride, A suitable aromatic acylating agent is benzoylchloride. The reaction can be caR1'ied out without catalysts, but the yield is low in the absence of catalysts. The catalysts can be selected from organic bases like pyridine and its derivatives such as N,N-dimethylaminopyridine (DMAP), sodium- or potassium-acetate or from inorganic bases, such as di- or tri-potassium phosphate or cacium oxide. Preferably, the acylation takes place under acidic conditions using a mixture of 0.5 to 2.0 equivalents of acetic anhydride using sodium acetate or pyridine as catalysts. The preferable catalyst is sodium acetate. An inert solvent such as tert-butyl methyl ether may be added, it is however also possible to run the reaction without addition of any solvent. The acetic anhydride is preferably added in an amount of 1.0 to 10.0 equivalents, preferably of 5 equivalents relating to one equivalent of the 1,2-diamino compound of formula (V). When the amount of acetic anhydride is between 1.5 to 5.0 equivalents, the rate of the reaction increases with the amount of acetic anhydride added. The temperature is chosen in the range of 70°C to 120°C, the prefeR1'ed temperature is between 100°C and 120°C. Step (e) Step (e) comprises removing the alkyl group from position 1 of the acylated 1,2-diamino compound (VI) to produce an acylated 1,2-diamino compound of formula (VTI). As the prefeR1'ed meaning of R5 is a tert-butyl group, the prefeR1'ed process of Step (e) is removal of the tert-butyl group from the acylated 1,2-diamino of formula (VI). The tert-butyl group of the acetamide of formula (VI) is cleaved by heating in acid, e.g., 2N HC1 at reflux for prolonged period of time. The prefeR1'ed method for cleavage of the terf-butyl group from the acetamide of formula (VI) is with trifluoroacetic acid (TFA) at 25°C or with hydrogen chloride in ethanol at reflux. The TFA is preferably added in an amount of 1.0 to 10.0 equivalents, preferably of 5 equivalents, relating to one equivalent of the 1,2-diamino compound of formula (VI). The temperature for the reaction using TFA is in the range of 25°C to 50°C. The hydrogen chloride in ethanol is preferably added in an amount of 1.0 to 2.0 equivalents relating to one equivalent of the 1,2-diamino compound of formula (VI). The temperature for the reaction using hydrogen chloride in ethanol is in the range of 50°C to 70°C, preferably at 64°C. An inert solvent may be added, it is however also possible to run the reaction without addition of any solvent. Step (f) Step (f) comprises deprotecting the amino group in position 2 of the 1,2-diamino of formula (VII) and, if desired, further transforming the resulting 1,2-diamino compound of formula (I) into a pharmaceutically acceptable addition salt, Deprotecting the amino group, le.y removal of the substituent of the amino group in position 2 is dependent on the residue R7 and R8, Because the prefeR1'ed meanings for R7 and R8 are straight chain or branched alkenyl of 2 to 6 C-atoms as outlined above in step (c), removal of the alkenyl group takes place in the presence of a suitable metal catalyst, preferably a precious metal catalyst such as Pt, Pd or Rh, either applied on an inert support, such as charcoal or alumina, or in complexed form. Because the prefeR1'ed amine of R7NHR8 is diallylamine according to step (c), a prefeR1'ed catalyst is palladium acetate, and a more prefeR1'ed catalyst is tetrakis(triphenylphosphine) palladium in the presence of 1,3-dimethylbarbituric acid (NDMBA) which serves as an allyl-transfer acceptor. For example, the reaction is effectively caR1'ied out with 1 mol % of palladium acetate relating to the 1,2-diamino of formula (VH). Lower charges of the catalyst (0.1-0.5 mol %) also work, but reaction time is longer. The NDMBA is preferably added in an amount of 0.6 to 1.5 equivalents relating to one equivalent of the 1,2-diamino of formula (VII), The removal of the alkenyl group is advantageously caR1'ied out in an aqueous solvent. The solvent itself can be protic or aprotic. Suitable protic solvents are, e.g., alcohols such as methanol, ethanol and isopropanol. Suitable aprotic solvents are, e.g., acetonitrile, tetrahydrofurane (THF), toluene, and dioxane. The prefeR1'ed solvent is ethanol. The reaction temperature is preferably in the range of 20°C and 70°C. The 1,2-diamino compound of formula (I) can be isolated, e.g., by evaporation and crystallization, but it is preferably kept in, e.g., an ethanolic solution and then further transformed into a pharmaceutically acceptable addition salt following the methods described in J.C.Rohloff et al, J.Org.Chem., 1998,63,4545-4550; WO 98/07685). The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane sulfonic acid, p-toluenesulfonic acid, and the like. The salt formation is effected in accordance with methods which are known per se and which are familiar to one skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methansulfonates, p-toluenesulfonates and the like are examples of such salts. PrefeR1'ed pharmaceutically acceptable acid addition salt is the 1:1 salt with phosphoric acid which can be formed, preferably, in ethanolic solution at a temperature of-20°C to 50°C. wherein R5, R11 and R12 are as stated above, or an addition salt thereof. A prefeR1'ed representative of the compounds of formula (X) is ethyl (3R,4S,5R)-5-N-(l,l-Dimethylethyl)amino-3-(l-ethylpropoxy)-4-hydroxy-cyclohexene-l-carboxylate (with R11 = 1-ethyl-propyl, R12 = ethyl, and R5 = te??-butyl). An additional new intermediate is a compound of formula (XI): wherein R5, R11 and R12 are as stated above, or an addition salt thereof. A prefeR1'ed representative of compounds of formula (XI) is ethyl (3R,4S,5R)-4,5-(l,l-Dime1hylelhyl)imino-3-(^^ 1-ethyl-propyl, R12= ethyl, and R5= teR1'-butyl). Another new intermediate from the invention is a compound of formula (XII): wherein R3, R5, R7, R8, R11 and R12 are as stated above or an addition salt thereof. PrefeR1'ed representatives of compounds of formula (XH) are ethyl (3R,4R,5S)-5-N,N-Diallylamino-4-(1,1-dimethylethyl)amino-3-(I-ethylpropoxy)-I-cyclohexene-1- carboxylate (with Rn= 1-ethyl propyl, R12= ethyl, R5= tert-butyl, R3= H, R7= allyl, R8= allyl), ethyl (3R,4R,5S)-4-N-Acetyl(l,l-methylethyl)amino-5-N,N-diallylamino-3-(I- ethylpropoxy)-l-cyclohexene-l-carboxylate (with Rn= 1-ethyl propyl, R12= ethyl, R5= terf-butyl, R3= acetyl, R7= allyl, R8= allyl) and ethyl (3R,4R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate hydrochloride (with Rn= 1-ethyl propyl, R12= ethyl, R5= tert-butyl, R3= acetyl, R7= allyl, Rs= allyl). wherein R1, R1', R2 and R2', independently from each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, or aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, or R1 and R2, R1 and R2', R1' and R2 or R1' and R2' taken together with the two carbon atoms to which they are bound, are a carbocyclic or heterocyclic ring system, or R1 and R1' or R2 and R2' taken together with the carbon atom to which they are bound, are a carbocyclic or heterocyclic ring system, with the proviso that at least one of R1, R1', R2 and R2' is not H, and R5 is a substituent of an amino group but not H, comprising treating a 1,2-epoxide of formula wherein R1, Rl\ R2 and R2' are as above with an amine of formula R5NH2 wherein R5 is as described above, in the presence of a magnesium halide catalyst. This process coR1'esponds to the prefeR1'ed method of step a) as described herein. Accordingly, the respective description of step a) is incorporated herein by reference. PrefeR1'ed amines of formula R5NH2 accordingly are tert-butylamine, 2-methylbutylamine, and 2-methylpentylamine, and more preferably, tert-butylamine, and the prefeR1'ed magnesium halide catalyst is magnesium chloride. The invention further relates to a new process for the transformation of the acylated 1,2-diamino compound of formula (VI) wherein R1, R1', R2, R2', R3, R5, R7 and Rs are as above, into an acylated 1,2-diamino compound of formula (VTI) wherein R1, R1', R2, R2', R3, R7 and R8 are as above. This process coR1'esponds to step e) as described herein before. Accordingly, the vhole description of step e) is incorporated herein by reference. Also, the same references as given under step e) apply here. As stated above, this process comprises removing the alkyl group from the hrogen at position 1 of the acylated 1,2-diamino of formula VI. The invention is further illustrated by the following examples. Example 1 Preparation of (3R,4R,5S)-5-amino-4-acetylamino-3-(l-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester from (lS,5R,6R)-5-(l-ethyl-propoxy)-7-oxa-bicyc!o[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester. a) Preparation of ethyl (3R,4S,5R)-5-N-(l,l-Dimethylethyl)amino-3-(l-ethylpropoxy)-4-hydroxy-cyclohexene-l-carboxylate In a 500 ml 3-necked round bottom flask equipped with a condenser with dry nitrogen adapter, an overhead paddle stiR1'er and a septum with teflon thermocouple, 21.1 mL (14.67 g, 200.6 mmol, 1.7 equivalents) of teR1'-butylamine are added to a suspension of 21.32 g (82.6 mmol, 70 mol%) of magnesium bromide etherate in 70 mL dry toluene at 25°C (cool H2O bath), the resulting colorless sluR1'y is stiR1'ed for 60 min. In a 100 mL 1-necked round bottomed flask capped with a septum, a solution of 30,00 g (118.00 mmol) of (lS,5R,6S)-5-(l-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester in 60 mL dry toluene is prepared, which is then added via 18 gauge stainless steel cannula to the magnesium bromide-amine complex suspension at 20-25°C. The resulting suspension is heated at 50°C (silicon oil bath) for 23 h. After cooling the suspension to 25°C, 57 mL of 2.5 M ammonium chloride solution are added and the resulting suspension is stiR1'ed at 25°C for 30 min. Solids are removed by suction filtration and the layers separated. The organic layer is concentrated in vacuo (rotary evaporator at 35°C and 25 mm Hg then vacuum pump at 25°C and 1 mm Hg for 17 h) to yield as crude product 37.73 g (Theoretical 38.63 g) of ethyl (3R,4S,5R)-5-N-(l,l-Dimethylethyl)amino-3-(l-ethylpropoxy)-4-hydroxy-cyclohexene-l-carboxylate as an orange oil with trace solids. An analytical sample is prepared by radial chromatography on silica gel. 1HNMR (CDCI3) 5 6.84-6.82 (m, 1H), 4.23 (t, 1H, J = 4.0 Hz), 4.20 (q, 2H, J = 7.0 Hz), 3.6-3.0 (broad, 1H, NH or OH), 3.55 (p, 1H, J = 6.0 Hz), 3.37 (dd, 1H, J = 4.0 Hz, J = 9.5 Hz), 3.12-3.08 (m, 1H, J = 5.0 Hz), 2.91 (dd, 1H, J = 5.5 Hz, J = 17 Hz), 1.97-1.91 (m, 1H, J = 8.0 Hz, J = 17 Hz), 1.59-1.54 (m, 4H), 1.29 (t, 3H, J = 7.0 Hz), 1.13 (s, 9H), 0.95 (t, 3H, J = 7.5 Hz), 0.91 (t, 3H, J = 7.5 Hz). l3C NMR (CDC13) 5166.9, 135.7,131.7, 82.8,72.6, 71.3, 61.0, 51.3, 4S.9, 34.3, 30.5, 26.8,26.7,14.5,10.4,9.5. ffi. (neat) 3600-3300,2970,2940,2880,1720,1660, 1470,1400, 1370,1240,1110, 1080,1060,670 cm"1. HRFABMS found m/z 328.2481 (M + H+), calcd for C18H34NO4, 328.2488. (b) Preparation of ethyl (3R,4S,5R)-4,5-(l,l-Dimethylethyl)imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate In a 500 ml 3-necked round bottom flask equipped with a condenser with dry nitrogen adapter, an overhead paddle stiR1'er and a septum with teflon thermocouple, 9.36 mL of methanesulfonyl chloride (13.86 g, 121.0 mmol, 1.05 equivalents) are added to a solution of 37.73 g crude tert-butylamino alcohol obtained according to (a) in 150 mL dry toluene at 20-25°C (cool H2O bath) over 6 min. The resulting solution is stiR1'ed at 25°C for 60 min. 32.1 mL of triethylamine (23.31 g, 230.4 mmol, 2.0 equivalents) are then added, dropwise, at 20-30°C (cool H2O bath) over 12 min. The resulting suspension is stiR1'ed at 25°C for 67 min and then heated at 70°C (silicon oil bath) for 3 h. After the suspension is cooled down to 25°C, a solution of 16.7 g (120,8 mmol) of anhydrous potassium carbonate in 60 mL H2O are added. The suspension is stiR1'ed for 15 min before the layers are separated. The organic layer is concentrated in vacuo (rotary evaporator at 35°C and 25 mm Hg then vacuum pump at 25°C and 1 mm Hg for 17 h) to yield 35.66 g (Theoretical 35.65 g) of crude ethyl (3R,4S,5R)-4,5-(l,l-Dimethylethyl)imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate in the form of an orange oil with trace solids. An analytical sample is prepared by radial chromatography on silica gel. 1H NMR (CDCI3) δ 6.80-6.78 (m, 1H), 4.17 (dq, 2H, J = 7.5 Hz, J = 1.5 Hz), 4.15-4.14 (m 1H), 3.39 (p, 1H, J = 6.0 Hz), 2.62-2.52 (m, 2H), 2.13-2.11 (m, 1H), 2.00 (d, 1H, J = 6.0 Hz), 1.61-1.51 (m, 4H), 1.26 (t, 3H, J = 7.5 Hz), 1.00 (s, 9H), 0.98 (t, 3H, J = 7.5 Hz), 0.92(t,3H,J = 7.5Hz). C NMR (CDCI3) δ 167.3,134.4,128.6, 82.4, 70.9, 60.7, 53.3, 33.2, 29.9, 27.0,26.9, 26.8,25.0,14.5,10.2, 9.9. IR (neat) 3575,2970,2930,2875,1720,1650,1460, 1370,1250,1230,1215,1080, 1070,1050,670 cm'1. HRFABMS found m/z 310.2378 (M + H+), calcd for C18H32NO3, 310.2382. (c) Preparation of ethyl (3R,4R,5S)-5-N,N-DiaIlylamino-4-(l,l-dimethylethyl)amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate In a 500 mL 1-necked, round-bottomed flask equipped with a condenser, a dry nitrogen adapter and a magnetic stir bar, 29.45 g of 10-Camphorsulfonic acid (126.8 mmol, 1.1 equivalents) are added to a mixture of 35.66 g of the ethyl (3R,4S,5R)-4,5-(1 ,l-Dimethylemyl)imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate as obtained from (b) and 17.1 mL (13.44 g, 138.3 mmol, 1.2 equivalents) of diallylamine. The resulting suspension is heated at 120°C (silicon oil bath) for 4 h. The suspension is cooled to 25°C and a solution of 5.27 g (132 mmol) of sodium hydroxide in 70 mL H20 is added. The suspension is stiR1'ed for 15 min before the layers are separated. The organic layer is concentrated in vacuo (rotary evaporator at 35°C and 25 mm Hg then vacuum pump at 25 °C and 1 mm Hg for 18 h) to yield 44.00 g (Theoretical 46.86 g) of ethyl (3R)4R,5S)-5-N,N-Diallylamino-4-(l,l-dimethylethyl) amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate as a brown oil with trace solids. An analytical sample is prepared by radial chromatography on silica gel. !H NMR (CDC13) δ 6.87 (t, IH, J = 2.5 Hz), 5.79 (m, 2H), 5.17 (d, 2H, J = 17.5 Hz), 5.11 (d, 2H, J = 10.5 Hz), 4.22 (q, 2H, J = 7.0 Hz), 3.94-3.92 (m, IH), 3.41-3.36 (m, IH), 3.31-3.27 (dm, 2H, J = 14 Hz), 2.92 (dd, 2H, J = 14 Hz, J = 8.0 Hz), 2.81 (dd, IH, J = 10.5 Hz, J = 6.5 Hz), 2.69 (dt, IH, J = 10.5 Hz, J = 4.5 Hz), 2.56 (dd, IH, J = 17.0 Hz, J = 4.5 Hz), 2.19 (dt, IH, J = 17.0 Hz, J = 3 Hz), 1.82-1.74 (m, IH), 1.64-1.56 (m, IH), 1.51-1.38 (m, 2H), 1.31 (t, 3H, J = 7.0 Hz), 1.15 (s, 9H), 0.91 (t, 3H, J = 7.5 Hz), 0.87 (t, 3H, J = 7.5 Hz). 13C NMR (CDCI3) 5 167.1,137.9,136.9, 130.3,117.7, 80.1,78.8, 60.9, 58.5, 55.3, 52.6, 50.7,31.1,26.7,25.3,22.5,14.5,10.5,9.87. IR (neat) 3590, 3640-3000, 2980, 2930, 2875, 2820, 1720,1665, 1640, 1230, 675 cm'1. HRFABMS found m/z 407.3280 (M + H*), calcd for C24H43N2O3, 407.3274. (d) Preparation of ethyl (3R54R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate In a 500 mL 1-necked, round-bottomed flask equipped with a condenser, a dry nitrogen adapter and a magnetic stir bar, 20.4 mL of acetic anhydride (22.09 g, 216.4 mmol, 2.0 equivalents) are added to a mixture of 44.00 g of the ethyl (3R,4R,5S)-5-N,N-Diallylamino-4-(l,l-dimethylethyl) amino-3-(l~ethylpropoxy)-l-cyclohexene-l- carboxylate as prepared in (c) and 44 mL dry pyridine at 20-25°C (cool H20 bath). The resulting clear brown solutionis heated at 100°C (silicon oil bath) for 22 h. The solution is cooled to 25°C and 40 mL of pyridine are recovered in vacuo (rotary evaporator at 35°C and 15 mm Hg). The residual oil is taken up in 150 mL of toluene. A solution of 14.00 g (350 mmol) of sodium hydroxide in 45 mL H2O is prepared and 50 mL of this NaOH solution are added to the mixture. The suspension is then stiR1'ed for 15 min before the layers are separated. The organic layer is concentrated in vacuo (rotary evaporator at 35°C and 25 mm Hg then vacuum pump at 25°C and 1 mm Hg for 19 h) to yield 49.52 g of opaque brown oil with solids. The brown oil (49.52 g) is taken up in 250 mL hexanes and 12.5 g of activated carbon, for example Darco G60™ , was added. After stiR1'ing for 15 min, the suspension is suction filtered through a pad of 10.0 g silica-alumina 135. The filter cake is rinsed with 50 mL fresh hexanes. The combined mother liquors are concentrated in vacuo (rotary evaporator at 30°C and SO mm Hg then vacuum pump at 25°C and 1 mm Hg for 25 h) to yield 42.56 g (Theoretical 48.12 g) of ethyl (3R,4R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate as an orange syrup. An analytical sample is prepared by radial chromatography on silica gel. The hydrochloride salt is prepared then recrystallized from ethyl acetate to afford colorless needles, m.p. 131-133°C (dec with gas evolution). For the free base: !H NMR (CDCI3) δ 6.87 (m, 1H), 5.81-5.73 (m, 2H), 5.12 (d, 2H, J = 17 Hz), 5.07 (d, 2H, J = 10.5 Hz), 5.02-4.85 (br), 4.22 (dt, 2H, J = 7 Hz), 3.85-3.75 (br), 3.58-3.46 (br), 3.28 (br), 3.24 (br d, 2H, J = 14 Hz), 2.88 (dd, 2H, J = 14 Hz, J = 8 Hz), 2.46-2.38 (m, 2H), 2.28-2.18 (br, 3H), 1.88 (br), 1.63-1.54 and 1.44-1.34 (m, m, 4H), 1.51 (s, 9H), 1.31 (t, 3H, J = 7 Hz), 0.93 (t, 3H, J = 7.5 Hz), 0.81 (t, 3H, J = 7.5Hz). 13C NMR (CDCI3) δ172.5,166.8,140.5,137.2,130.7,117.1,79.5, 73.2,62.2, 60,9, 56.0,53.2, 32.2, 31.8, 27.2,26.6,25.4,23.6,14.5,10.0,9.9. ffi. (neat) 3570, 3090,2975,2940, 2880,2820,1720,1625,1475,1450,1370,1240, 1120,1060,675 cm-1. HRFABMS found m/z 449.3368 (M + H+), calcd for C26H45N2O4,449.3379. For the hydrochloride salt: 1HNMR (CDCI3)δ 6.97 (br, 1H), 6.61-6.51 (m, 1H), 6.35-6.25 (m, 1H), 5.53-5.39 (m, 4H), 5.01-4.98 (br d, 1H), 4.77-4.70 (m, 1H), 4.26 (q, 2H, J = 7 Hz), 4.24-4.18 (br, 1H), 4.06-3.99 (br, 1H), 3.88 (brt, 1H), 3.51-3.44 (m, 1H), 3.41-3.33 (m, 1H), 3.33-3.27 (m, 1H), 2.80-2.73 (br d, 1H), 2.66-2.58 (m, 1H), 2.62 (m, 1H), 2.54 (s, 3H), 1.68 (s, 9H), 1.68-1.54 (m, 2H), 1.46-1.34 (m, 2H), 1.34 (t, 3H, J = 7 Hz), 0.96 (t, 3H, J = 7.5 Hz), 0.82 (t, 3H, J = 7.5 Hz). 13C NMR (CDCI3) δ 175.9,165.5,140.0,128.3,127.4,127.0,125.1,124.0,79.7,71.0, 61.4,59.3, 58.9, 58.2, 55.4, 53.0,32.5,28.1, 26.6,25.1,24.2,14.3,10.1,10.0. (e) Preparation of ethyl (3R,4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate In a 500 mL 1-necked, round-bottomed flask equipped with a dry nitrogen adapter and a magnetic stir bar, 210 mL of precooled (0-5°C) trifluoroacetic acid (311 g) is added to 42.56 g of the ethyl (3R,4R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate as obtained from (d), and the solution is stiR1'ed at 25°C for 5.5 h. Trifluoroacetic acid (~ 145 mL) is then distilled in vacuo (rotary evaporator at 30°C and 90 to 30 mm'Hg). 150 mL of toluene-hexanes (1:1, v:v) is added and the solution was again concentrated in vacuo (rotary evaporator at 30°C and 80 to 30 mm Hg). The residual oil (80 g) is diluted with 150 mL of 1:1 (v:v) toluene-hexanes before 150 mL of saturated sodium carbonate solution are added. The suspension is stiR1'ed for 15 min, then 150 mL water are added, and the layers separated. The aqueous layer is extracted with 50 mL of 1:1 (v:v) toluene-hexanes. The combined organic layers are extracted twice with 3.0 M HC1 (first time 30 mL and second time 15 mL). The combined aqueous layers are diluted with 100 mL toluene and a solution, prepared by dissolving 5.67 g (142 mmol) of sodium hydroxide in 17 mL of H2O, is added at 20-25°C (ice-water bath) (aqueous = pH 13-14), The layers are separated and the aqueous layer is extracted with 50 mL toluene three times. The combined toluene extracts are dried (MgSO4), filtered, and concentrated in vacuo (rotary evaporator at 35°C and 25 mm Hg) to yield 38.73 g of brown syrup. The syrup is triturated five times with hexanes (first time 200 mL then 100 mL for four times) at 25°C. The supernatant is decanted after each time. The final suspension is suction filtered and the solid dried in vacuo (vacuum pump at 25°C and 1 mm Hg for 17 h) to yield 26.76 g (Theoretical 37.24 g, 5-step yield 72%) of ethyl (3R,4R,5S)-4-N-Acetylamino-5-N»N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate with some slightly tacky beige solid. An analytical sample was prepared by recrystallization from heptane-ethyl acetate, m.p. 101.8-102.3°C. 1HNMR (CDCI3)δ 6.73 (m, IH), 5.76-5.68 (m, 2H), 5.35 (d, IH), 5.16 (d, 2H, J = 16.5 Hz), 5.07 (d, 2H, J = 10 Hz), 4.21 (q, 2H, J = 7 Hz), 4.08 (dm, IH, J = 9 Hz), 3.91 (dt, IH, J = 11.5 Hz, J = 9 Hz), 3.32 (p, IH, J = 5.5 Hz), 3.28 (dm, 2H, J = 14.5 Hz), 3.05 (dt, IH, J = 11.5 Hz, J = 5 Hz), 2.92 (dd, 2H, J = 14.5 Hz, J = 7.5 Hz), 2.58 (dd, IH, J = 17 Hz, J = 5 Hz), 2.17 (ddt, IH, J = 17 Hz, J = 10.5 Hz, J = 3.5 Hz), 2.00 (s, 3H), 1.54-1.47 (m, 4H), 1.30 (t, 3H, J = 7 Hz), 0.91 (t, 3H, J = 7 Hz), 0.87 (t, 3H, J = 7 Hz). 13C NMR (CDCI3) δ 170.4,166.9,138.5, 137.3,129.9,116.9, 82.4,77.7, 61.1, 56.5, 53.5, 52.5, 26.3, 25.8, 23.9, 23.7, 14.5, 9.8, 9.5. IR (KBr) 3270, 3110,2980-2960,2930,2880,2810,1720,1650,1580,1470,1450, 1380, 1270,1235,1120, 1075,1055,925 cm"1. HRFABMS found m/z 393.2756 (M + H+), calcd for C22H37N204,393.2753. Anal, Calcd for C22H36N2Q4: C, 67.32; H, 9.24; N, 7.14. Found: C, 67.00; H, 9.42; N, 7.03. (f) Preparation of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate A 50 mL airlessware flask (N2-vacuum line on sidearm) equipped with a septum and a magnetic stir bar is charged with 1.874 g of 153-Dimethylbarbituric Acid (NDMBA) (12.00 mmol). The flask is sealed and the atmosphere is changed to dry nitrogen (10 nitrogen-vacuum cycles). The flask is transfeR1'ed to a glove bag and 50.0 mg (0.0433 mmol) of tetrakis (triphenylphosphine) palladium is charged. A solution of 3.925 g (10.00 mmol) of the ethyl (3Rs4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-3-(l-ethyIpropoxy)-l-cyclohexene-l-carboxylate prepared as in (e) in 5 mL of dry TKF is prepared in a 15 mL 1-necked flask capped with a septum (10 nitrogen-vacuum cycles prior to adding THF). This solution is then transfeR1'ed to the reaction flask using a 20-gauge stainless steel cannula. The transfer is completed using 2 mL of fresh dry THF. The resulting yellow suspension is heated at 50°C for 133 min. The suspension is cooled to 25°C and 10 mL toluene and 8 mL 1.5 M HC1 are added. The layers are separated (aqueous pH = 1). The aqueous layer is washed with 10 mL of toluene three times. A solution of 0.52 g (13 mmol) NaOH in 1.5 mL H20 is slowly added to the aqueous layer (aqueous pH =12). 5 mL of brine are then added. The resulting suspension is extracted with 10 mL of isopropyl acetate three times. The combined extracts are concentrated in vacuo (rotary evaporator at 30-3 5°C and 60 mm Hg, hexanes trituration, then vacuum pump at 25°C and 1 mm Hg for 16 h) to yield 2.770 g (Theoretical 3.124 g , 88.7% yield) of ethyl (3R,4R,5S)-4-N«Acetylamino-5-amino~3-(l~ethylpropoxy)-l-cyclohexene-l-carboxylate as a colorless solid. Example 2 Preparation of (3R,4R,5S)-5-amino-4-acetylamino-3-(l-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester from (lS,5R,6R)-5-(l-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester. Steps (a), (b) and (c) are performed as described supra^ in Example L (dl) Preparation of ethyl (3R,4R,5S)-4-N-Acetyl(l)l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate In a 500 mL 1-necked, round-bottomed flask equipped with a Claisen adapter, an overhead (paddle) stiR1'er, and a water-cooled condenser with dry nitrogen adapter, 40.9 mL of acetic anhydride (44.2 g, 433 mmol, 4.83 equivalents) are added to a mixture of 45.55 g (36.49 g or 89.7 mmol at 80.1 wt%) of the ethyl (3R,4R,5S)-5-N,N-Diallylanuno-4-(14-dimethytethyl)amino-3-(I-ethylpropoxy)-I-cyclohexene-1-- carboxylate as obtained from (c) and 10.66 g (130 mmol, 1.45 equivalents) of anhydrous sodium acetate. The resulting suspension is heated at 120°C (silicon oil bath) for 4 h. The suspension was cooled to 25°C, diluted with 150 mL heptane, cooled to -5°C, then quenched by dropwise addition of a solution prepared by dissolving 31.0 g (776 mmol) of sodium hydroxide in 155 mL H20 (153.4 g) over 40 min at -5 to 0°C. The resulting suspension is warmed to 25°C then stiR1'ed for 30 min. The layers are separated, and the aqueous layer extracted with 25 mL of heptane. The combined organic layers are washed with 25 mL of H20 and then concentrated in vacuo (rotary evaporator at 30°C and 40-10 mm Hg) to yield 49.72 g of ethyl (3R,4R,5S)-4-N- AcetyI(M-dimeftylethyl)amino-5-N,N-diallymamino-3-(I-ethylproxy)-I-cyclohexene l-carboxylate (LC assay 81.6 wt%, Theoretical 40.26 g, 100.8% yield) as a brown syrup with trace solids. (d2) Preparation of ethyl (3R,4R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5- N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate hydrochloride In a 500 mL 3-necked flask with a teflon paddle, a glass stir shaft, a water-cooled glass bearing, a dry nitrogen adapter and a septum with teflon-coated thermocouple, a solution of the crude ethyl (3R,4R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (49,54 g, 40.0 g at 81.6 wt%, 89.2 mmol) in 85 mL anhydrous ethanol is prepared at 250-300 rpm. Another solution of dry hydrogen chloride (3.86 g HC1,106 mmol, 1.19 equiv) in 15 mL anhydrous ethanol is prepared separately at (3R,4R,5S)-4-N-Acetyl(U ethylpropoxy)-l~cyclohexene-l-carboxylate solution in the flask at 20°C over a few minutes. An additional 5 mL of ethanol are used to complete the transfer. The suspension is then cooled to 0-5°C. 105 mL of heptane are added dropwise over a few minutes and the suspension is cooled to -15°C and then stiR1'ed for 1 h at 150 rpm. The precipitate is suction filtered, first washed with 15 mL of 1:1 ethanol-heptane at -15°C, then washed with 35 mL heptane at -5°C, before a final wash with 35 mL heptane at 25°C. The washed precipitate is then dried in vacuo (vacuum pump at 25°C and ~ 1 mm Hg for 15 h) to yield 41.38 g of ethyl (3R,4R,5S)-4-N-Acetyl(l,l-dimethylethyl)amino-5-NJ>J-diallylamino-3-(l-ethylpropoxy)-l"Cyclohexene-l-carboxylate hydrochloride (LC assay 97-9 wt% hydrochloride salt, Theoretical 43.3 g, 93.6% yield) as fluffy near-colorless crystals. (e) Preparation of ethyl (3R>4R,5S)-4-N-Acetylainino-5-N?N-diallylamino-3-(l-ethylpropoxy) -1 -cyclohexene-1 -carboxylate A 500 mL 3-necked round-bottomed flask equipped with an overhead (paddle) stiR1'er, a condenser with dry nitrogen adapter and a septum with thermocouple, is charged with 41.28 g (40.45 g, 83.4 mmol at 98.0 wt%) of the ethyl (3R,4R,5S)-4-N^ Acetyl(l,l-dimethylethyl)amino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-1-carboxylate hydrochloride as obtained from (d2). 70 mL of anhydrous ethanol are added to the flask before a solution of 3.20 g (87.8 mmol, 1.05 equivalent) dry hydrogen chloride in 10 mL anhydrous ethanol is added at 25-30°C (teflon cannula). The suspension is heated at 62~63°C (pot) (70°C bath) for 3.5 h. 200 mL of toluene (metal can) are added at 45°C and the resulting solution distilled at atmospheric pressure under dry nitrogen until the pot temperature reaches 92°C. The solution is cooled to 0 to -5°C and 35 mL of H20 added. A solution prepared by dissolving 4.81 g (120 mmol) of sodium hydroxide in 9.85 mL of H20 is then added portionwise at 0 to -5°C until the pH of the aqueous layer is between 13 and 14 (10.79 g solution, 3.54 g NaOH, 97.1 mmol, 0.57 equiv required). The suspension is warmed to 20°C and the layers separated. The aqueous layer is then extracted with 25 mL of toluene. The combined organic layers are concentrated in vacuo (rotary evaporator at 30-33°C and 30-10 mm Hg) to yield 44.63 g of ethyl (3R,4R,5S)^-N-Acetylamino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-1-carboxylate (LC assay 68.7 wt%, Theoretical 32.73 g, 93.7% yield) as a yellow syrup with trace solids. (f) Preparation of ethyl (3R,4R,5S)-4-N-Ace1ylamino-5-amino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate 31.78 g (0.08096 mol) of crude ethyl (3R,4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-3"(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, as prepared from (e), are dissolved in 77 mL of EtOH and charged to a 500 mL 3-necked round-bottomed jacketed flask equipped with an overhead (paddle) stiR1'er, a nitrogen inlet and a septum with thermocouple. 56 mL of Ethanol are used to rinse the transfer vessel to the reactor. 15.17 g of Dimethylbarbituric acid (0.09715 mol) are charged to the reactor flask followed by 0.8493 g of triphenylphosphine (0.003238 mol). A nitrogen sweep is placed on the reactor for 5 min and palladium acetate (0.1817 g, 0.0008096 mol) and ethanol (58 mL) are added and the jacket temperature set to 36°C. The reaction mixture is stiR1'ed for 2 h with agitation (284 RPM) under an atmosphere of nitrogen. The reaction is sampled for LC analysis and is completed. The jacket temperature is set to 10°C for an overnight hold. (g) Preparation of ethyl (3R,4R>5S)-4-N-Acetylamino-5-amino-3-(l- ethylpropoxy)-l-cyclohexene-l-carbox)"late phosphate [1:1] A 500 mL 3-necked round-bottomed jacketed flask equipped with an overhead (paddle) stiR1'er, an addition funnel with nitrogen inlet and a septum with thermocouple, is charged with a solution of 9.40 g (0.08153 mol) of 85% phosphoric acid, followed by 120 mL of absolute EtOH. The solution is heated to 52°C. The crude ethyl (3R,4R55S)-4-N-Acetylamino-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate solution from (f) is wanned to 25°C , then approximately 2/3 of the solution is rapidly added to the crystallization vessel. The crystallization mixture is seeded with 102 mg of oseltamivir phosphate and crystallization occurs immediately. The sluR1'y is aged 30 minutes before the remainder of the aminoacetamide solution is added over 30 minutes. The sluR1'y is cooled to -18.8°C (-20°C jacket) over 15 h and aged 2 h. A 600 mL jacketed, fritted funnel with a N2 sweep (set point of -17°C) is used for the isolation. The sluR1'y is poured into the funnel and as soon as the solvent front reaches the top of the cake, the crystallization vessel is rinsed with acetone (50 mL) and poured on top of the cake. The wet cake is washed with acetone (4 x 50 mL) followed by heptane (3 x 50 mL). The product is dried in vacuo (45°C and -20 mm Hg with a N2 sweep for 18 h) to yield 29.86 g (89.9% yield) of ethyl (3R,4R,5S)"4-N-AcetylaminO"5-amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate phosphate [1:1] as a colorless solid. Example 3 Preparation of (3R,4R,5S)-5-amino-4-acetylamino-3-(l -ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester from (lS,5R,6R)-5-(l-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester. a) Preparation of ethyl (3R,4S,5R)-5-N-(l,l-Dimethylethyl)amino-3-(l-ethylpropoxy)-4-hydroxy-cyclohexene-l-carboxylate A magnesium chloride-amine complex is first prepared by adding 65 mL (45.2 g, 0.619 mol, 1.50 equiv) of tert-butylamirte to a suspension of 35.7 g (0.375 mol, 0.90 equiv) of magnesium chloride in 200 mL dry toluene at 25°C. The resulting colorless sluiTy is stiR1'ed at 25°C for 6 h. A solution of 105.0 g (0.413 mol) of epoxide in 250 mL dry toluene is added via 18 gauge stainless steel cannula to the magnesium chloride-amine complex suspension at 20-25°C. The resulting suspension is heated at 50°C for 8 h. More tert-butylamine (52 mL, 36.2 g, 0.495 mol, 1.20 equiv) is added and the solution heated for an additional 12 h. resulting in a yellow solution. After cooling the yellow solution to 25°C, 200 mL of 10% w/w aqueous citric acid solution is added and the solution stiR1'ed at 25°C for 30 min. The layers are then separated. The organic layer is concentrated in vacuo (rotary evaporator at 40°C and 25 mm Hg then vacuum pump at 25°C and 1 mm Hg for 17 h) to afford 135.3 g of orange oil (LC assay 96.0 wt%, 96.1% yield). Steps (b), (c), (d), (e) and (f) are performed, as described supra, in Example 1. Claims 1. A process for preparing 1,2-diamino composunds of formula and pharmaceutically acceptable addition salts thereof wherein R1, R1, R2 and R2, independently from each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, cydoalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, or aryl-lower alkynyl, or R1 and R2, R1 and R2', Rr and R2 or R1' and R2' taken together with the two carbon atoms to which they are bound, are a carbocyclic or heterocyclic ring system, or R1 and R1 or R2 and R2' taken together with the carbon atom to which they are bound, are a carbocyclic or heterocyclic ring system, wherein at least one of R1, R1', R2 and R2' is not H, and R is a substituent of an amino group said process comprising the steps of: wherein R1, R1, R2 and R2' are as above with an amine of formula R5NH2 wherein R5 is a substituent of an amino group but not H, to form a 2-aminoalcohol of formula wherein R1, R1', R2, R2' and R5 are as above; b) converting the 2-aminoalcohol of formula (III) to the aziridine of formula wherein R1, R1', R2, R2' and R5 are as above; c) reacting the aziridine of formula (IV) with an amine of formula R7NHR8, wherein R7 and R8, independently from each other, are H or a substituent of an amino group, with the proviso that not both R7 and R8 are H, to obtain a 1,2-diamino compound of formula wherein R1, Rr, R2, R2', R5, R7and R8 are as above; d) acylating the secondary amino group in position 1 of the 1,2- diamino compound of formula (V) to form an acylated 1,2- diamino compound of formula wherein R1, R1', R2, R2', R3, R5, R7 and R8 are as above; e) removing R5 from the acylated 1,2-diamino compound (VI) to produce an acylated 1,2-diamino compound of formula wherein R1, R1, R2, R2', R3, R7 and R8 are as above; and f) deprotecting the amino group in position 2 of the 1,2-diamino compound of formula (VII) to produce the 1,2-diamino compound of formula (I). 2. The process of claim 1 wherein the 1, 2 epoxide is a cyclohexene oxide of formula wherein R11 and R12 are as above and the resulting 1,2 diamino compound is a 4,5-diamino-shikimic acid derivative of formula and pharmaceutically acceptable addition salts thereof, wherein R11 is an alkyl group or a substituted alkyl group, R12 is an alkyl group and R3 is a substituent of an amino group. 3. The process of claim 2, wherein the cyclohexene oxide of formula (IX) is (lS,5R,6R)-5-(l-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester and the resulting 4,5-diamino-shikimic acid derivative of formula (VHI) is selected from the group consisting of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, and ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate phosphate (1:1). 4. The process of claims 1 to 3, wherein R5 in the amine of formula R5NH2 is a straight chain or branched alkyl of 1 to 6 C-atoms. 5. The process of claim 4, wherein the amine of formula R5NH2 is text-butylamine. 6. The process of claim 1 to 5, wherein the reaction of step a) is conducted in the presence of a catalyst. 7. The process of claim 6, wherein the catalyst is a metal catalyst, a magnesium halide or a magnesium halide derivative. 8. The process of claims! to 7, wherein the cyclization in step (b) is performed in the presence of a sulfonylating agent. 9. The process of claims 1 to 8, wherein R7 and R8 in the amine of formula R NHR independently is, a strai t chain or branched alkenyl of 2 to 6 C-atoms, benzyl, substituted benzyl or heterocyclyl methyl. 10. The process of claim 9, wherein the amine of formula R7NHR8 is a primary or secondary amine. 11. The process of claims 9 to 10 wherein the amine of formula R7NHR8 is diallylamine. 12. The process of claim 1 to 11, wherein the ring opening in step c) is performed in the presence of a catalyst. 13. The process of claim 12, wherein the catalyst is sulfonic acid, a derivative of sulfonic acid or a Lewis acid. 14. The process of claims 1 to 13, wherein the reaction in step (d) is carried out in the presence of an acylating agent. 15. The process of claim 14, wherein the acylating agent is acetic anhydride. 16. The process of claims 1 to 15, wherein the reaction in step (d) is carried out in the presence of an organic or inorganic base as catalyst and at a temperature of 70°C to 120°C. 17. The process of claims 1 to 16, wherein the removal of the alkyl group R5 in step e) is carried out in the presence of an acid. 18. The process of claims 1 to 17, wherein deprotection in step f) takes place in the presence of a catalyst. 19. A compound of the formula wherein R11 is an alkyl group or substituted alkyl group and R5 and R12 are independently, an alkyl group and pharmaceutically acceptable addition salts thereof 20. The compound of claim 19, wherein the compound is ethyl (3R>4S,5R)-5-N-(l,l-Dimethylethyl)amino-3-(l-ethylpropoxy)-4-hydroxy-cyclohexene-l-carboxylate. 21. A compound of the formula wherein R11 is an alkyl group or substituted alkyl group and R5 and R12 are independently, an alkyl group and pharmaceutically acceptable addition salts thereof. 22. The compound of claim 21 wherein the compound is ethyl (3R,4S,5R)- 1,5-(l,l-Dimethylethyl)imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate. wherein R is an alkyl group, substituted alkyl group and R is an alkyl group, R is a substituent of an amino group, R is an alkyl group, and R7 and R8 are independently, H or a substituent of an amino group, wherein R7 and R8 are not both H, and pharmaceutically acceptable addition salts thereof. 24. The compound of claim 23, wherein the compound is ethyl (3R,4R,5S)-5~ N,N-Diallylamino-4-(l ,l-dimethylethyl)amino-3-(l -ethylpropoxy)- 1-cyclohexene-1- carboxylate. 25. The compound of claim 23, wherein the compound is ethyl (3R,4R,5S)-4- N-Acetyl(l,1-dimethylethyl)amino-5-N,N-diallylamino--3-(l--ethylpropoxy)--l- cyclohexene-1-carboxylate. 26. The compound of claim 23, wherein the compound is ethyl (3R,4R,5S)-4-N-Acetyl(l, l-dimethylethyl)-amino-S-NjN-diallylamino-3-(1-ethylpropoxy)-!-cyclohexene- 1-carboxylate hydrochloride. 27. The compound of claim 23 wherein the compound is ethyl (3R,4R,5S)-4-N-Acetylamino-5-N,N-diallylamino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate hydrochloride.

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