Method for production of (3r, 3as,6ar)-hexahydrofuro[2,3-b]furan-3-yl(1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1- benzyl-2-hydroxypropylurethane

FIELD: medicine.

SUBSTANCE: production of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylurethane is carried out with application of intermediate compound 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(isobutyl)benzenesulfonamide. (3R,3aS,6aR)- hexahydrofuro [2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylurethane is applicable, in particular as inhibitor of HIV protease.

EFFECT: simplified process due to exclusion of necessity to extract phenyl ethynyl.

14 cl, 9 ex

The technical field to which the invention relates

The present invention relates to a method for producing (3R,3S,6R)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate, as well as intermediate compounds for use in the specified way. In particular, the invention relates to methods of producing (3R,3S,6R)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate who carry out using the intermediate 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylacetophenone that can be applied in industrial scale.

The level of technology

The virus that causes acquired immunodeficiency syndrome (AIDS), known under various names, including T-lymphocytic virus III (HTLV-III)or lymphadenopathy associated virus (LAV)or AIDS virus (ARV), or human immunodeficiency virus (HIV). Up to the present time identified two different collections, i.e. HIV-1 and HIV-2. Hereinafter in the description of the acronym HIV will be used for General designation of such viruses.

One of the crucial stages in the life cycle of retroviruses is the processing of protein precursors retroviral protease. For example, during the replication cycle of the HIV virus Pro is wcty of transcription of the genes gag and gag-pol are broadcast as proteins, which then are processed encrypted virus protease with the formation of enzymes and structural proteins core of the virus. Often protein-gag precursors are processed in the crust proteins, and proteins-pol precursors are processed in viral enzymes such as reverse transcriptase and retroviral protease. The correct processing of protein precursors retroviral protease required for Assembly of infectious virions, which thus makes retroviral protease attractive target for antiviral therapy. In particular, the HIV protease is an attractive target for the treatment of HIV.

On the market and in development, there are several protease inhibitors. Hydroxyethanesulfonic HIV protease inhibitors, such as 4-aminobenzenesulfonamide described as having a favorable pharmacological and pharmacokinetic properties against HIV virus wild type and mutants. A typical representative of the 4-aminobenzenesulfonamide class of protease inhibitors is APV. The method of synthesis of APV described in WO 99/48885 (Glaxo Group Ltd.).

4-Aminobenzenesulfonamide also can be obtained according to procedures described in EP 715618, WO 99/67417, US 6248775 and in Bioorganic Chemistry and Letters, Vol.8, pp. 687-690, "Potent HIV protease inhibitors incorporating a high-affinity P₂

WO 03/057665 (Ajinomoto K.K.) relates to a method for obtaining crystals benzosulfimide derivatives. In particular, describes the crystallization of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-aminobenzenesulfonamide, which is an intermediate compound of interest to obtain (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate. Specified interest intermediate connection receive, as disclosed on the basis of (2S,3S)-3-benzyloxycarbonylamino-1,2-epoxy-4-phenylbutane, in which interaction type isobutylamine, with subsequent combination with p-nitrobenzenesulfonamide with the formation of (2R,3S)-N-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide, which restores with simultaneous removal of the protective group and receive the necessary intermediate connection. In particular, in the method as aminosidine group for the short film the howling molecules using benzyloxycarbonyl (Cbz or Z). It is noted that the simultaneous recovery of nitro and removing the protective group of Cbz (2R,3S)-N-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide leads to a strongly exothermic reaction. Exothermic reactions, if possible, should be avoided or minimized, as in this case, it is more difficult to adjust the temperature of the reactions, i.e. if the reaction temperature is too low, the reaction rate is small and takes a long time; if the reaction temperature is too high, the reaction rate is too high and there is insufficient mixing that promotes uneven reaction, rapid oxidation products formed, or may occur unwanted side reactions, resulting in a selectivity for the product decreases. On the other hand, it is also noted that the catalytic reaction is disclosed in WO 03/057665, does not include treatment in an acidic environment. In the absence of treatment with the acid catalyst used during recovery and removal of the protective group is Cbz, will be poisoned grey p-nitrobenzenesulfonamide. The poisoned catalyst will inevitably lead to unwanted side reaction products, reducing the selectivity of the product.

In order for the chemical method was acceptable for industrial scale is, he must be able to receive connections with acceptable yield and purity, and at the same time be easy and simple, and cost effective. Such a new way that is acceptable on an industrial scale, was found for the synthesis of compounds of formula (6).

In particular, the present invention relates to a convenient method for obtaining compounds of formula (6) and intermediates for its reception, its salts accession, polymorphic and/or pseudopolymorphic forms on an industrial scale. More specifically, the present invention relates to an acceptable method of synthesis of compounds of formula (6), which also has the advantage of improved and cost-effective crystallization (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-aminobenzenesulfonamide with an acceptable degree of purity and yield. Even more specifically, the present invention relates to a separate method of carrying out reactions of the recovery and removal of the protective group includes treatment with an acid, which ultimately leads to a more regulated, selective and cost-effective method.

In one embodiment of the present invention relates to an improved method of crystallization with the regulation of pH and concentration in a certain interval, while in WO 03/057665 in connection with kr is stylizacji mentioned only the heating of the solution in the polar solvent, to improve the output, or the heat of solution (30-80^about(C) in order to dissolve the crystals present in the solution in a polar solvent, in order to improve cleaning.

The present invention also has the advantage of using commercially available starting substances, such as tert-butyl ester 1-oxiranyl-2-phenylethylamines acid. In addition, the precursor compounds of the formula (6), i.e., (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-aminobenzenesulfonamide or the compound of formula (5), can be obtained by the procedure in the same reactor, which leads to efficient use and exclusion stages of purification of intermediate compounds. The reagents used in the specified way, are safe and available in large quantities. In addition, each stage of this method is carried out in controlled conditions and get the desired connection with the optimal output. In addition, each stage of this method spend stereoselective that allows to synthesize pure stereoisomeric forms of the required connections.

Other objectives and advantages of the present invention will become apparent from the following further detailed description in conjunction with the accompanying examples.

In EP 0754669 (Kaneka Corporation) describes how to obtain alpha halogenated, alpha halogene is rinow and epoxides; in EP 1029856 (Kaneka Corporation) discloses a method of obtaining a (2R,3S)-3-amino-1,2-oxirane; and EP 1067125 also Kaneka Corporation, relates to a method for threo-1,2-epoxy-3-amino-4-phenylbutane. In EP 774453 (Ajinomoto Co., Inc.) describes how to obtain 3-amino-2-oxo-1-kalogeropoulou derivatives. In WO 01/12599 (Samchully Pharm Co. Ltd.) describes the new acylhydrazone derivatives and methods for their preparation. In WO 01/46120 (Aerojet Fine Chemicals LLC) disclosed an improved method of obtaining hydrochloride 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonamide and other derivatives of 2-hydroxy-1,3-diamines. In WO 96/28418 (G.D. Searle & Co., Inc.) disclosed califoniastateuniversitychico.sjroem.cn inhibitors of retroviral proteases. In WO 94/04492 (G.D. Searle & Co., Inc.) reveals hydroxyethanesulfonic alpha - and beta-amino acids useful as inhibitors of retroviral proteases. In WO 97/21685 (Abbott) disclosed receipt of the peptide analogues as inhibitors of retroviral proteases. In WO 94/05639 (Vertex Pharmaceuticals) describes sulfonamidnuyu inhibitors aspirinplease HIV-1.

Detailed description of the invention

The present invention relates to a method for obtaining compounds of formula (6)

its salts accession, polymorphic and/or pseudopolymorphic forms

including

(i) the introduction of isobutylamine in with the Association of the formula (1)

where

PG is aminosidine group;

R₁represents hydrogen or C_1-6-alkyl;

(ii) the introduction of p-nitrophenylacetylene group in the compound obtained in stage (i);

(iii) the restoration of the nitro compound obtained in stage (ii);

(iv) removing the protective group from the compound obtained in stage (iii); and

(v) reaction of a combination of compounds obtained in stage (iv), (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ilen derived with the formation of the compounds of formula (6).

In one embodiment of the present invention relates to a method for obtaining compounds of formula (6), characterized in that the method comprises the introduction phase of isobutylamine in the compound of formula (1')

with the formation of the compounds of formula (2')

the introduction of p-nitrophenylacetylene group in the compound of the formula (2') with the formation of the compounds of formula (3')

nitrogroup reduction of compounds of formula (3') with the formation of the compounds of formula (4')

removal of the protective group from compounds of formula (4') with the formation of the compounds of formula (5)

combinations of the compounds of formula (5) with (3R,3aS,6aR)-hexahydrofuro[2,3-b]fu is an-3-ilen derived with the formation of the compounds of formula (6).

Thus, the present invention includes methods for obtaining the compounds of formula (6), its salts accession, polymorphic and/or pseudopolymorphic forms through an intermediate compound of formula (5)

Preferably the compound of formula (5) is crystallized as the free base. On the other hand, the compound of formula (5) is crystallized in the form of salts with strong acids such as hydrochloric acid, Hydrobromic acid, methanesulfonate acid, sulfuric acid, oxalic acid, citric acid, etc. Crystallization of the compounds of formula (5) improves the degree of its purity and output - both factors favorable for obtaining compounds of formula (6). On the other hand, the compound of formula (5) can crystallize in the form of polymorphic and/or pseudopolymorphic form.

Preferably the compound of formula (6) crystallized in the form of pseudopolymorphic form, preferably in the form of an alcoholate, preferably in the form of ethanolate.

The compound of formula (1)

The compound of formula (1) represents

where

PG is aminosidine group;

R₁represents hydrogen or C_1-6-alkyl.

The term "aminosidine group", as used herein, refers to one or more selectively removed to cover the pines in the amino group, usually used to block or protect the functional amino group against undesirable side reactions during synthetic procedures and includes all the usual aminosidine group. Examples aminosidine of the urethane groups are blocking groups such as tert-butoxycarbonyl ("BOC"), 2-(4-biphenyl)propyl(2)oxycarbonyl ("Rooted"), 2 phenylpropyl(2)oxycarbonyl ("ROS"), 2-(4-xenil)isoproterenol, isopropoxycarbonyl, 1,1-diphenylether(1)oxycarbonyl, 1,1-diphenylpropyl(1)oxycarbonyl, 2-(3,5-acid)propyl(2)oxycarbonyl ("Ddz"), 2-(p-5-toluyl)propyl(2)oxycarbonyl, 1-methylcyclopentadienyl, cyclohexyloxycarbonyl, 1-methylcyclohexanecarboxylic, 2-methylcyclohexanecarboxylic, etoxycarbonyl, 2-(4-toluensulfonyl)etoxycarbonyl, 2-(methylsulphonyl)etoxycarbonyl, 2-(triphenylphosphino)etoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc"), 2-(trimethylsilyl)etoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-relaxerror, 5-benzisothiazolinone, 4-acetoxybenzoic, 2,2,2-trichlorocyanuric, tribromoethanol, 2-ethinyl(2)propoxycarbonyl, cyclopropanecarbonyl isobornylacitate, 1-piperidinylcarbonyl, benzyloxycarbonyl ("Z" or "Cbz"), 4-phenylbenzoxazole, 2-methylbenzyloxycarbonyl, α-2,4,5,-tetramethylethylenediamine ("Tmz"), 4-way shall dibenzalacetone, 4-forantimicrobial, 4-chlorobenzenesulfonyl, 3-chlorobenzylidene, 2-chlorobenzenesulfonyl, dichlorobenzenesulfonyl, 4-bromobenzyloxycarbonyl, ortho-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-cyanobenzeneboronic, 4-(decyloxy)benzyloxycarbonyl etc., benzoylmethylecgonine group, ditionally ("Dts") group, 2-(nitro)phenylsulfinyl group ("Nps"), diphenylphosphinomethyl group and similar groups. The species used aminosidine groups, as a rule, are not the determining factor up until derivativesa amino group is stable in the conditions of subsequent reactions and can be removed at the appropriate point without destroying the rest of the connection.

Other examples aminosidine groups are phenylacetyl, formyl (For), trityl (Trt), acetyl, TRIFLUOROACETYL (TFA), trichloroacetyl, dichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, benzoyl, tert-aryloxyalkyl, tert-butoxycarbonyl, 3,4-dimethoxyphenylacetone, 4-(phenylazo)benzyloxycarbonyl, 2-furfurylalcohol, diphenylcarbinol, 1,1-dimethylpropanolamine, phthalyl or phthalimido, succinyl, alanyl, leucyl and 8-hinolincarbonova, benzyl, diphenylmethyl, 2-nitrophenylthio, 2,4-dinitrophenyl, methanesulfonyl, para-toluensulfonyl, N N-dimethylaminomethylene, benzylidene, 2-guy who oxybenzone, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethyl, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 2-acetylcyclohexanone, 3,3-dimethyl-5-oxocyclohexyl, diphenylphosphoryl, dibenzoyltartaric, 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl, trimethylsilyl, triethylsilyl, triphenylsilane, 2-(p-biphenyl)-1-methylethanolamine, diisopropylperoxydicarbonate, cyclopentanecarbonyl, adamantanecarbonyl, triphenylmethyl, trimethylsilyl, phenylthiocarbamyl, para-nitrobenzylamine.

Other aminosidine groups are 2,7-di-tert-butyl[9-(10,10-dioxo-10,10,10,10-tetrahydromyrcenol)]methyloxycarbonyl; 2-trimethylsilylethynyl; 2-generatelockkey; 1,1-dimethyl-2,2-diplomaticcarbon; 1-methyl-1-(4-biphenyl)ethoxycarbonyl; p-nitrobenzenesulfonyl; 2-(p-toluensulfonyl)ethoxycarbonyl; m-chloro-p-aryloxyalkanoic; 5-benzimidazolecarbamic; p-(dihydroxyaryl)benzyloxycarbonyl; m-nitrophenylacetylene; o-nitrobenzenesulfonyl; 3,5-dimethoxybenzonitrile; 3,4-dimethoxy-6-nitrobenzisoxazole; N'-p-toluensulfonate; tert-aryloxyalkyl; p-decyloxybenzoate; 2,2-dimethoxycarbonylbenzoquinonediimines; di(2-pyridyl)methyloxycarbonyl; 2-furylmethanol; datasourcename; 2-dimethylpyrrole; 5-dibenzosuberyl and methanesulfonamide group. Preferred aminosidine group is BOC.

Other examples aminosidine groups well known in the art of organic synthesis and peptides and is described, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2^nded., John Wiley and Sons, New York, Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis, 1^stand 2^ndreviser ed., Springer-Verlag, New York, 1984 and 1993; Stewart and Young, Solid Phase Peptide Synthesis, 2^nded., Pierce Chemical Co., Rockford, IL 1984; L. Fieser and M. Fieser, Fieser and Fieser''s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). Suitable aminosidine groups are, for example, WO 98/07685.

The term "C_1-6-alkyl" in relation to groups or part of a group denotes a linear or branched saturated hydrocarbon radicals with 1-6 carbon atoms, such as methyl, ethyl, isopropyl, butyl, pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.

Preferably the compound of formula (1) is a compound of formula (1')below, where PG represents a tert-butoxycarbonyl or "Vos" and R₁represents hydrogen. The compounds of formula (1) and (1') are commercially available and can be obtained in different ways, described in the literature, for example, as described in WO 95/06030 (Searle & Co.), as described in EP 0754669, EP 1029856 and EP 1067125, Kaneka Corporation, and as described in EP 1081133 and ER, Ajinomoto KK.

The compound of the formula (2)

The compound of formula (1) is subjected aminating on epoxy group and get the connection formula (2)

The term "amination", as used herein, refers to the process in which a primary amine, isobutylamine injected into the organic molecule of formula (1). Amination of the compounds of formula (1) can be done in several ways, described in the literature, for example, as described in WO 95/06030 included in this description by reference.

In the preferred embodiment of the compound of formula (1') being in engagement with isobutylamine and get the connection formula (2')

Amination of epoxy compounds is described, for example, in March, Advanced Organic Chemistry, 368-69 (3^rdEd., 1985)and McManus et al., 3 Synth. Comm. 177 (1973), included in this description as a reference. The compounds of formula (2) and (2') can be obtained in an appropriate manner according to the procedure described in WO 97/18205.

Agent amination of isobutylamine may also serve as solvent, and in this case it will be added to its excess. In other embodiments, the process amination is carried out in the presence of one or more solvents other than isobutylamine. In the preferred embodiment of the above RA is the founders used in the processing of compounds of the formula (2) and (2').

Suitable solvents include proton, and bipolar aprotic aprotic organic solvents, such as, for example, alcohols, namely methanol, ethanol, isopropanol, n-butanol, tert-butanol and the like; ketones such as acetone; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; esters such as ethyl acetate; amines such as triethylamine; amides such as N,N-dimethylformamide or dimethylacetamide; chlorinated solvents such as dichloromethane and other solvents, such as toluene, dimethylsulfoxide, acetonitrile and mixtures thereof. The preferred solvent is toluene.

Interaction usually can be performed in a wide temperature range, for example, from about -20°C. to about 200°C, but preferably, although not necessarily, the interaction is carried out at the boiling temperature of the solvent, i.e. between 40°C and 100°C, preferably between 60°C. and 90°C.

Suitable equivalent ratio between the compound of formula (1) and the amination agent may range from 1:1 to 1:99, respectively. Preferably the ratio of equivalents between the compound of the formula (2) and the amination agent is from 1:5 to 1:20, even more preferably the ratio is from 1:10 to 1:15.

In the embodiment of the invention, the amination reaction is carried out in the presence of about 15 equival now of isobutylamine using as solvent of toluene and heated at about 79°C.

The compounds of formula (3)

The compound of the formula (3) is obtained by introduction sulfonyloxy group p-nitrobenzene-SO₂in the intermediate compound of formula (2)

Thus, in the preferred embodiment of the compound of formula (3') will get sulfonylamine the compounds of formula (2')

As such, the compounds of formula (2) and (2') will interact with the agent sulfonylamine with conversion into compounds of the formula (3) and (3').

The term "sulfonylurea"used in this description, refers to a process in which p-nitrobenzenesulfonyl group is introduced into an organic molecule of formula (2) and (2'). The term "sulfonation", as used herein, refers to the process of obtaining agent sulfonylurea. The term "agent sulfonylamine" refers to p-nitrobenzenesulfonyl derivatives, such as p-nitrobenzenesulfonyl one.

Agents sulfonylamine, in particular p-nitrobenzenesulfonyl halogenated, can be obtained by oxidation of thiols to sulphonylchloride using chlorine in the presence of water in strictly controlled conditions. In addition, you can turn sulfonic acid sulphonylchloride using such reagents as PCl₅and anhydrides using COO the appropriate dehydrating reagents. Sulfonic acid, in turn, can be obtained using procedures well known in the art. Such sulfonic acids are available commercially. Agents sulfonylamine can also be obtained by sulfonation procedures, described in "Sulfonation and Related Reactions", E.E. Gilbert, R.E. Krieger Publishing Co., Hungtington, N.Y. (1977); "Mechanistic Aspects of Aromatic Sulfonation and Desulfonation", H. Cerfontain, Interscience Publishers, NY (1968), and in US 6455738 "Process for sulfonation of an aromatic compound", which are all included in this description as a reference.

Treatment of compounds of formula (2) and (2') the agent sulfonylurea can be done in the presence of a solvent when heated from about 25°C to 250°C, preferably from 70°C to 100°C, and stirring. After sulfonylamine remaining agent sulfonylurea or any salt is preferably, though not necessarily, removed from the reaction mixture. Remove perform repeated washings with water, the pH of the separation of organic and aqueous phase, ultrafiltration, reverse osmosis, centrifugation and/or filtration or similar methods.

The compounds of formula (3) and (3') is produced by interaction sulfonylurea agent with intermediate compounds of the formula (2) and (2') in suitable solvents in an alkaline environment. Suitable alkaline environments are common dinucleophiles inorganic or organically the base and/or acid acceptors. Normal dinucleophiles inorganic or organic bases include, for example, hydrides, hydroxides, amides, alcoholate, acetates, carbonates or bicarbonates of alkaline earth metals or hydrides of alkali metals, such as, for example, sodium hydride, potassium hydride or calcium hydride, and amides of metals, such as sodium amide, potassium amide, diisopropylamide lithium or hexamethyldisilazide potassium, and alkanes metals, such as sodium methylate, sodium ethylate, tert-butyl potassium, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or ammonium carbonate, and organic nitrogen-containing compounds, such as trialkylamine, such as, for example, trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N,N-diisopropylethylamine, pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or you can use an excess of the appropriate piperidine. Preferably use triethylamine.

Suitable solvents specified above upon receipt of the compounds of formulas (2) and (2'), preferably such inert solvents, such as toluene, etilize is at, methylene chloride, dichloromethane and tetrahydrofuran.

Usually relationships equivalents calculated for the compounds of formula (1) or (1') and agent sulfonylamine, ranging from 1:1 to 1:3, respectively. Preferably the ratio of equivalents of the compounds of formula (1) or (1') and agent sulfonylamine is from 1:1 to 1:2, preferably the ratio is about 1:1,15.

The compounds of formula (4)

The compounds of formula (4) and (4') is produced by interaction of the nitro group of intermediate compounds of the formula (3) and (3'), respectively, with a reducing agent optionally in an atmosphere of hydrogen

Reducing agents suitable for nitrogroup reduction, are metal-containing reducing agents, such as complexes of boron, DIBORANE, borohydride sodium, borohydride lithium, borohydride sodium-LiCl, alumoweld lithium or diisobutylaluminum; metals such as iron, zinc, tin and the like; and containing transition metals, such as palladium-on-charcoal, platinum oxide, Raney Nickel, rhodium, ruthenium, etc. When used catalytic reduction, as the source of hydrogen can be used ammonium formate, sodium dihydrophosphate, hydrazine.

Suitable solvents for the recovery of the nitro group can be selected from water, alcohols, such as methanol, ethanol, isopropanol, tributyl alcohol, esters, such as ethyl acetate, amides, such as dimethylformamide, acetic acid, dichloromethane, toluene, xylene, benzene, pentane, hexane, heptane, petroleum ether, 1,4-dioxane, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl sulfoxide or mixtures thereof. In General, you can use any solvent suitable for use in the process of chemical recovery.

The specified stage of recovery can be performed at temperatures from -78°C to 55°C, preferably from -10°C to 50°C., with preferred temperatures are in the range from 0°C to 50°C, more preferably from 5°C to 30°C. the reaction Time can vary from 30 minutes to 2 days, more preferably from 1 hour to 24 hours. According to a preferred embodiment of the phase recovery is performed with the use of palladium-on-charcoal, suspended in methanol. In another preferred embodiment it is possible to use more coal.

Relationship of equivalents of the compounds of the formula (3) or (3') and hydrogen ranges from 1:1 to 1:10, respectively. More preferably, the ratio of equivalents of the compounds of the formula (3) or (3') and hydrogen is from 1:1 to 1:5, preferably the ratio is about 1:3.

The compounds of formula (5)

Connection fo the formula (5) is produced by removing the protective group of intermediate compounds of formula (4) and (4') under normal conditions in an acidic environment. On the other hand, you can use an alkaline environment

Remove aminosidine group can be achieved under conditions that do not affect the rest of the molecule. Such methods are well known in the art and include hydrolysis in the acidic environment, hydrogenolysis, etc. and also use commonly known acids in suitable solvents.

Examples of the acid used to remove aminosidine include such inorganic acids as hydrochloric acid, nitric acid, hydrogen chloride, sulfuric acid and phosphoric acid and such organic acids as acetic acid, triperoxonane acid, methanesulfonate acid and p-toluensulfonate acid: a Lewis acid such as boron TRIFLUORIDE; acidic cation-exchange resin, such as Dowex 50W^TM. Of these preferred acids are inorganic and organic acids. More preferred are hydrochloric acid, sulfuric acid, phosphoric acid triperoxonane acid and most preferred hydrochloric acid.

The solvent used during the removal of the protective group of intermediate compounds of formula (4) and (4'), has no adverse effect on the reaction and, at least to some extent dilutes the original substance. Suitable solvents are the SJ such aliphatic hydrocarbons, as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; such halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers like diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; such esters as methyl acetate, ethyl acetate, methylpropionate and ethylpropane; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; such sulfoxidov as dimethyl sulfoxide and mixtures thereof. Preferred are aromatic hydrocarbons, alcohols and esters. Alcohols and water are preferable, and water, isopropanol, ethanol and methanol are particularly preferred. Also preferred are mixtures of methanol, water and isopropanol or ethanol and mixtures of ethanol and water.

The reaction temperature depends upon such factors as the nature of the original substances, solvents and acids. However, as a rule, it is from -20°C to 150°C and preferably from 30°C to 100°C, even more preferably, the temperature of education phlegmy. Used the reaction time depends on the reagents, temperature, and other similar factors. Typically it ranges from 5 minutes to 72 hours, and preferably from 15 mi the ut to 4 hours.

Examples of reagents and methods for the removal of amines aminosidine groups can also be found in Protective Groups in Organic Synthesis, Theodora W. Greene, New York, John Wiley and Sons, Inc., 1981, included in this description by reference.

As is known to experts in the art, the choice of method will determine the reagents and methods used for removing aminosidine group.

The ratio of equivalents of the compounds of the formula (3) or (3') and acid in the solvent can vary from 1:2 to 1:50, respectively. Preferably the ratio of equivalents of the compounds of the formula (3) or (3') and acid is from 1:2 to 1:8, more preferably the ratio is about 1:2.

In the preferred embodiment of the present invention the compound of formula (5) is crystallized. Crystallization of the compounds of formula (5) is conducted by dissolving the compound of the formula (5) in a mixture of solvents, by setting the pH of the solution and the concentration of the compounds of formula (5). You can add crystals of compounds of formula (5).

The mixture of solvents used for crystallization may consist of one or more miscible with water, solvents and water, or the solvent system consists of one or more is not miscible with water, solvents and water.

Examples of solvents miscible with water include alcohols With₁-C₄, the AK methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol; such cyclic ethers like tetrahydrofuran or dioxane; amides such as dimethylformamide, dimethylacetamide, N-organic; dimethyl sulfoxide, acetonitrile, a mixture of the above solvents with each other or with water or water.

Examples of solvents that are not miscible with water, are hydrocarbons such as pentane, hexane, cyclohexane, methylcyclohexane, heptane, toluene, xylene; esters With₄-C₈as methylformate, ethyl formate, methyl acetate, ethyl acetate; ethers With₄-C₈as diethyl ether, tert-butyl methyl ether, isopropyl ether; chlorinated solvents, such as methylene chloride, dichloromethane, chloroform, dichloroethane, and chlorobenzene; or a dual or multi-component mixture. When using such is not miscible with water, the solvent, the compound of formula (5) is retrieved by the separation of organic and aqueous phase.

Regulation of the concentration of the compound of formula (5) can be done by adding water or other suitable solvent or by evaporation, distillation of the solvent or any other methods of concentration. In the preferred method of crystallization maintain the concentration of the compounds of formula (5) from 0.1% to 40% (wt./wt.), preferably from 1% to 30%, more PR is doctitle from 2% to 20% and even more preferably from 4% to 15%, wt./wt.

Control or immediate (current) control the concentration of the compounds of formula (5) in solution can be accomplished in any way known to experts in the art, such as chromatography HPLC, density measurement, titration, etc.

Preferably the solvent used for crystallization of the compounds of formula (5)is the same solvent used during the removal of the protective group of intermediate compounds of formula (4) or (4'). On the other hand, if you use several solvents, one or more solvents used for crystallization of the compounds of formula (5)are the same one or more solvents used for the removal of the protective group of intermediate compounds of formula (4) or (4').

Regulation of the pH of the solution containing the compound of the formula (5), can be done by adding bases, such as sodium hydroxide, sodium carbonate, potassium hydroxide, lithium hydroxide, ammonia, hydrazine, calcium hydroxide, methylamine, ethylamine, aniline, Ethylenediamine, triethylamine, hydroxide of tetraethylammonium, amines With₂-C₁₈the ammonium hydroxide With₄-C₁₈, sodium methoxide, potassium methoxide, organic base₁-C₄any of the grounds listed above, and mixtures thereof. the pH of the solution is, containing the compound of the formula (5), will be maintained in the alkaline region, more preferably 7, more preferably pH will be more than 8, even more preferably more than 9.

In one embodiment, after adding the base suspension is stirred for 1-48 hours, preferably 1-10 hours, even more preferably 1-5 hours.

The operating temperature used for the deposition of compounds of formula (5), may vary from -20°C to 50°C. Preferably, the operating temperature during deposition can vary from -15°C to 10°C, even more preferably from -10°C to 10°C, most preferably about 5°C. In another embodiment the compound of formula (5) is collected by centrifugation and dried in vacuum at about 65°C.

Preferred crystalline compound of the formula (5) is in free base form. On the other hand, other suitable compounds are crystalline compounds of the formula (5) in the form of a salt, where the salt is chosen from among the hydrochloride, hydrobromide, triptoreline, fumarata, chloracetate and methansulfonate and similar salts.

Intermediate compounds of formula (5) are also active inhibitors of retroviral proteases.

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ilen derived

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol and its predecessor is in it is possible to synthesize so, as described in WO 03/022853. (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol and its predecessors appropriately activated agents combination with the formation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ilen derived, which can be carbamoylethyl compound of the formula (5). Activation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its predecessors conducted prior to their combination with the compound of the formula (5). This activation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its predecessors and their combination with the compound of the formula (5) is carried out in the same reactor as removing the activated intermediate is not necessary, which is an additional advantage of this method.

The predecessors of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol are such compounds in which the oxygen functional alcohol groups such protected O-protective groups as tert-butylamine group ("EGM"), acetate, benzyl group, benzylamino group, allyl, such silylamine groups as tert-butyldimethylsilyl (TBS), trimethylsilylacetamide (SEM), such alkoxyalkyl group, as methoxyethoxymethyl (MEM), methoxymethyl (IOM), tetrahydropyranyl (TNR), tetrahydropyranyl (not), and similar groups. When using predecessors 3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, removing the protective group can be the make up of the combination or directly in situ. Remove sportsedan group in acid or alkaline medium, preferably an acidic environment. Protective groups are well known in the art, see, for example, T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, 1991.

On the other hand, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its predecessors can be obtained through dynamic diastereoselective division receices mixtures hexahydrofuro[2,3-b]furan-3-ol. In this case Reznichenko mixture is subjected to the action of certain enzymes, such as pancreatic lipase pig Pancreatin candida cylindracca and the like, in the presence of suitable solvents and reagents such as acetic anhydride and vinyl acetate. This alternative method allows to obtain in situ the desired enantiomer (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, which can be conveniently activated by the method in one reactor; the unwanted stereoisomer is blocked or becomes inert.

Examples of agents of the combinations used in the reactions carbamylcholine are carbonates such as bis(4-nitrophenyl)carbonate, disuccinimidyl (DSC), carbonyldiimidazole (CDI). Other agents combinations are such chloroformiate, as p nitrophenylphosphate, such phosgene as phosgene and triphosgene.

In particular, when (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is treated with disuccinimidylsulfite, ucaut 1-([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione. The specified connection is preferred derivatives of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl

In the case of activation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its predecessors agent combinations it is recommended that the presence of alcohol in concentrations from 1% to 20% (wt./wt.), preferably in a concentration of from 2% to 15% (wt./wt.), even more preferably in a concentration from 4% to 10% (wt./wt.).

Interaction derived (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-Il with a compound of formula (5) will be carried out in the presence of suitable solvents, such as tetrahydrofuran, dimethylformamide, acetonitrile, dioxane, dichloromethane or chloroform, and optionally such grounds as triethylamine, while also embodied the combination of solvents and bases disclosed in the description above. Among the preferred solvents are aprotic, such as tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, and the like.

In one embodiment, during the combination of derived (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-Il with a compound of formula (5) specified derivative is present in a concentration of from 1% to 15% (wt./wt.), preferably in a concentration of from 5% to 12% (wt./wt.), even more preferably in a concentration of from 8% to 12% (wt./wt.).

The reaction carbamylcholine implement p and a temperature of from -70°C to 40°C, preferably from -10°C. to 20°C.

The connection is obtained by a combination of derived (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-Il with a compound of formula (5)is a compound of formula (6). The compound of formula (6) preferably will collateralise alcohols, such as ethanol, methanol, and the preferred form of MES is ethanolate. Solvation of the compounds of formula (6) described in PCT/EP 03/50176 (Tibotec N.V.), are included in this description by reference

Each method of obtaining above, the reaction products, for example the compounds of formula(3), (3'), (4), (4'), (5) and the final product of formula (6), can be isolated from the reaction mixture and, if necessary, to further purify by methodologies known in the art, such as, for example, extraction, crystallization, distillation, grinding into powder and chromatography.

For therapeutic use salts of the compounds according to the invention are salts in which the counterion is pharmaceutically or physiologically acceptable. However, salts with pharmaceutically unacceptable counterions can also find application, for example, upon receipt or purification of pharmaceutically acceptable compounds of the present invention. All salts, whether they are pharmaceutically acceptable or not included in the scope of the present from which retene.

Pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of products, soluble or dispersible in water or oil, include the conventional nontoxic salts or Quaternary ammonium salt, which are formed, for example, with inorganic or organic acids or bases. Examples of such salts accession acids include acetates, adipate, alginates, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrates, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, econsultancy, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalates, phosphates, pamoate, pectinate, persulfates, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartratami, thiocyanates, tozilaty and undecanoate. Examples of salts of joining bases include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metals such as calcium and magnesium salts, salts with organic bases, such as salts dicyclohexylamine, salts of N-methyl-D-glucamine and salts with amino acids such as arginine, lysine, etc. basic nitrogen-containing groups can the be quaternity such agents, as the lower alkylhalogenide, such as methyl-, ethyl-, propyl - and butyl chloride, -bromide and-iodide, diallylsulfide similar to the dimethyl-, diethyl-, dibutil and tamilselvan, long chain halides such as decyl-, lauryl-, myristyl and sterilised, -bromide and-iodide, aralkylated, such as benzyl and fenilatilamin, and others. Other pharmaceutically acceptable salts include ethanolate and sulphate salts of sulfates.

The term "polymorphic form" refers to the property of the compounds of the formula (5) and (6) exist in the amorphous form, polymorphic form, in crystalline form with different structures, varying in hardness, shape and size of the crystals. Different crystalline forms can be detected by the methods of crystallography or indirectly, by assessing the differences in physical and/or chemical properties associated with a particular polymorpha. Polymorphs differ in physical properties such as solubility, dissolution, stability in the solid state, as well as in behavior when processing the powder flowability and compaction during tableting.

The terms "pseudopolymelia form" or "solvate" refers to aggregates consisting of molecules of compounds of formula (6) and its salts from the captured molecules solvents or formed with them a complex in the ratio mol/mol and with different degree of salt is operation.

Intermediate compounds according to the invention can also exist in tautomeric forms. Assume that such forms, although not shown explicitly in the compounds described herein, are included in the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates referred to in this description are defined as isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate compounds with a stereoisomeric excess of at least 80% (i.e. having at least 90% of one isomer and a maximum of 10% of the other possible isomers) and to stereoisomeric excess of 100% (i.e. with 100% of one isomer and no other isomers), in particular compounds or intermediate compounds with a stereoisomeric excess of 90% to 100%, even more preferably from stereoisomeric excess from 94% to 100% and most preferably from stereoisomeric excess of from 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood in a similar way, but the enantiomeric excess and, consequently, diastereomeric excess in mixtures of interest.

Pure stereoisomer of the diversified forms of the compounds and intermediates of this invention can be obtained, using procedures known in the art. For example, the enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Their examples are tartaric acid, dibenzoyltartaric acid, ditawarkannya acid and camphorsulfonic acid. On the other hand, the enantiomers can be divided chromatographic techniques using an optically active stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction stereospetsifichno. It is preferable if you want a specific stereoisomer, the specified connection it is possible to synthesize stereospecificity ways. In the above methods will mainly be used enantiomerically pure source materials.

The racemates of the diastereomers of the compounds and intermediates of this invention can be divided separately by conventional means. The most beneficial physical methods of separation are, for example, selective crystallization and chromatography, for example, a column.

Specialist in the art it is clear that the compounds and intermediate compounds of this invention contain, m is Nisha least two asymmetric center and thus can exist in various stereoisomeric forms. Such asymmetric centers in the figures below, indicated by asterisks (*)

The absolute configuration of each asymmetric center, which can be present in the compounds and intermediate compounds of this invention may be indicated stereochemical descriptors R and S, and such designation R and S corresponds to the rules defined in Pure Appl. Chem., 1976, 45, 11-30.

This also implies that the present invention includes all isotopes occurring in the compounds of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. For example, as a common example, without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Reagents and solvents used in the description, you can replace them with functional alternatives or functional derivative, known to specialists in this field of technology. Such reaction conditions as the time of mixing, cleaning and temperature can be optimized for the reaction. Similarly, the reaction products can be removed from the environment and, if necessary, to further purify according to the method is ologian, generally known in the art, such as, for example, extraction, crystallization, grinding into powder and chromatography. A number of intermediates and starting compounds used in the above methods of preparation, are known compounds, while others can be obtained according to methods known in the art to obtain these or similar compounds.

The compounds of formula (5) and all intermediate compounds leading to the formation of stereoisomers pure compounds are of particular interest in obtaining 4-aminobenzenesulfonamide as HIV protease inhibitors as disclosed in WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465, WO 97/18205 and WO 02/092595 included in this description as a reference, and in particular HIV protease inhibitor compounds of formula (6), and any of their salts accession, polymorphic and/or pseudopolymorphic form.

Thus, the present invention also relates to HIV protease inhibitors such as the compound of the formula (6), and any of their salts accession, polymorphic and/or pseudopolymorphic forms obtained with the use of any intermediate compounds described herein, where the intermediate compound, and the compound of formula (6) receive, as described in the present invention.

Thus, the present invention also relates to inhib the factors of HIV protease, such as the compound of the formula (6), and any of their salts accession, polymorphic and/or pseudopolymorphic forms obtained using the compound (5) as an intermediate compound, where the compound of formula (5)and the compound of formula (6) are obtained as described in the present invention.

The following examples are intended to illustrate the present invention. The examples are provided as examples of the invention and should not be construed as limiting the scope of the invention.

EXAMPLES

Example 1. Obtain tert-butyl methyl ether (1-benzyl-2-hydroxy-3-isobutylamino)carbamino acid

To 154,4 kg isobutylamine add tert-butyl ester (1-oxiranyl-2-phenylethyl)carbamino acid (53.3 per kg) and then the solution is heated under reflux. Under reduced pressure from the reaction mixture to remove isobutylamine and then replace it with toluene.

Example 2. Obtain tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)carbamino acid

To the solution obtained in example 1, add 26.7 kg of triethylamine and the resulting solution was heated to 82-88°C. To the solution is gradually added a solution of 4-nitrobenzenesulfonamide (53 kg) in toluene and stirred. The reaction mixture is washed with water.

The washed solution of tert-b is delovogo ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)carbamino acid is heated and then add toluene and n-heptane. The resulting solution is cooled and contribute seed crystals of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)carbamino acid. After watching the deposition of a crystalline substance precipitated and the solution is stirred and then gradually cooled to 20-30°C. the resulting crystalline substance is filtered off and washed with a mixed solvent consisting of toluene and n-heptane, and get wet crystals of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)

carbamino acid (output 87-91% relative to the tert-butyl methyl ether (1-oxiranyl-2-phenylethyl)carbamino acid).

Example 3. Obtain tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-aminobenzenesulphonyl)amino]propyl)

carbamino acid

The wet crystals of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)

carbamino acid is suspended in ethanol (approximately 950 l) and then hydronaut in the presence of 10 wt.% palladium on coal at a temperature of about 5-30°C. Palladium on coal removed from the reaction mixture by filtration and then the filtrate is concentrated under reduced pressure to obtain a solution of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-aminobenzenesulphonyl)amino]propyl)carb is mirovoi acid in ethanol.

Example 4. Getting 4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylacetophenone

A solution of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-aminobenzenesulphonyl)amino]propyl)

carbamino acid obtained in example 3, refluxed and then add concentrated hydrochloric acid (35-37 kg). The solution is stirred.

Then the obtained solution is cooled to a temperature of 40±3°C and then add water. the pH of the solution was adjusted to about 9.5 to an aqueous solution of sodium hydroxide, the formation of crystals of 4-amino-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylacetophenone. To the resulting solution was still add water to bring the concentration of 4-amino-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylacetophenone to 5.5-5.8 wt.% and then the resulting solution is cooled to a temperature of 6±4°C. the resulting crystalline substance is filtered off and washed with a mixed solvent consisting of water and ethanol, and then washed with water. The obtained wet crystal substance is dried in vacuum and get the product of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-aminobenzenesulfonamide. The output is 75-85% relative to the tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)carbamino acid.

Example 5. Getting 4 am the but-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzosulfimide

Suspended in methanol 50,00 g of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)

carbamino acid obtained according to the procedures described in WO 99/48885, WO 01/12599 and WO 01/46120, 2 mol.% ethanolamine and palladium on charcoal, purge with an inert gas and create a vacuum. When the temperature in the reactor 22-30°C serves approximately 3.0 EQ. hydrogen at a pressure. Then the catalyst is removed by filtration. Colorless (to slightly yellowish solution process 21,70 g hydrochloric acid (37 wt.%), and the mixture is refluxed for 2 hours. Upon completion of the conversion of the methanol is removed by distillation. Conduct a deposition of a mixture of solvents Meon/water/IPA 1:8:6,5. At a temperature of 0-7°C add portions 30% sodium hydroxide solution until such time as the pH becomes pH>12,5. Through 4-48 hours dropped to precipitate a white substance is filtered off, washed with water and isopropanol. Wet the reaction product is dried in vacuum at 65^aboutC. Method gives 36,94 g of powder from white to yellowish.

Example 6. Getting 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl)benzosulfimide

Suspended in ethanol 50,00 g of tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-nitrobenzenesulfonyl)amino]propyl)

carbamino acid obtained according to the about procedures, described in WO 99/48885, WO 01/12599 and WO 01/46120, and palladium on charcoal purge with an inert gas, and create a vacuum. When the temperature in the reactor 22-30°C serves approximately 3.0 EQ. hydrogen at a pressure. Then the catalyst is removed by filtration. After distillation of the alcohol in the flask remains tert-butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-aminobenzenesulphonyl)amino]propyl)

carbamino acid as a colourless foam with a yield of 97%. tert-Butyl methyl ether (1-benzyl-2-hydroxy-3-[isobutyl(4-aminobenzenesulphonyl)amino]propyl)

carbamino acid are dissolved in methanol, treated 21,70 g hydrochloric acid (37 wt.%) and refluxed for 2 hours. After complete conversion of the greater part of the alcohol is removed by distillation. Hydrochloric acid salt of 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl)benzosulfimide precipitated, removing the greater part of the alcohol by distillation and adding dichloromethane to the warm (40°C) solution. Under stirring and cooling to room temperature, hydrochloric acid salt immediately precipitates. The precipitation of 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl)benzosulfimide carried out by dissolving chloroethanol salt in a mixture of solvents Et/water, 1:1. At a temperature of 0-7^aboutTo add portions 30% sodium hydroxide solution up until the pH value reaches a pH>12,5. Che is ez 4-48 hours dropped to precipitate a white substance is filtered off, washed with water and dried in vacuum. The method gives 33,78 g of powder from white to yellowish.

Example 7. Getting ethanolate (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate

120 mmol of disuccinimidyl (95%) in acetonitrile was added 100 mmol of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in ethyl acetate. Then add a solution of 140 mmol of triethylamine in ethyl acetate and stirred. The mixture is cooled and treated with a suspension of 92 mmol 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzosulfimide in ethyl acetate. Add in ethanol 20 mmol of methylamine in the form of a 41% aqueous solution and the mixture is warm. The reaction mixture is washed twice with a 10% solution of Na₂CO₃and water. The solvent is evaporated and add ethanol. Distilled off another part of the solvent. Maintain a temperature of about 40-45°C and initiate the crystallization seed. After mixing, the mixture is cooled, stirred for 90 min, cooled and then stirred for 60 minutes Dropped precipitated substance is filtered off and washed with ethanol. Wet the reaction product is dried in vacuum at 40°C. Suspended and dissolved in absolute ethanol to 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylamino the and. A clear solution is cooled down and make seed. Upon cooling, the mixture is crystallization. Continue stirring for 60 min, then the mixture is cooled, stirred and filtered, the product washed with cold absolute ethanol. The wet product is dried in vacuum at 40°C. the Yield was 42.1 g = 71%.

Example 8. Getting ethanolate (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate

To 105 mmol of bis(4-nitrophenyl)carbonate in acetonitrile was added 100 mmol of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in ethyl acetate. Then add a solution of 250 mmol of triethylamine in ethyl acetate and stirred. The mixture is treated with a suspension of 95 mmol of 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzosulfimide in ethyl acetate. Add in ethanol 20 mmol of methylamine in the form of a 41% aqueous solution. The reaction mixture is washed three times with a 10% solution To₂CO₃and water. The solvent is evaporated and add ethanol. Distilled off another part of the solvent. Maintain a temperature of about 40-45°C and initiate the crystallization seed. After mixing, the mixture is cooled, stirred for 90 min, cooled and then stirred for 60 minutes Dropped precipitated substance is filtered off and washed with ethanol. The wet product of reaction the AI is dried in vacuum at 40°C. Suspended and dissolved in absolute ethanol to 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate. A clear solution is cooled down and make seed. Upon cooling, the mixture is crystallization. Continue stirring for 60 min, then the mixture is cooled, stirred and filtered, the product washed with cold absolute ethanol. The wet product is dried in vacuum at 40°C. Yield 47.9 g = 81%.

Example 9. Getting ethanolate (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate

To 110 mmol of disuccinimidyl (95%) in acetonitrile was added 100 mmol of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in acetonitrile. Then add 300 mmol of pyridine and stirred. The mixture is cooled and treated with a suspension of 95 mmol of 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzosulfimide in acetonitrile and then add 100 mmol of triethylamine. Then add 20 mmol of methylamine in the form of a 41% aqueous solution and the mixture is warm. Distilled 80 g of solvent, add MTBE and the reaction mixture is washed with 10% solution of Na₂CO₃, a mixture of sodium sulfate and sulfuric acid and again with a 10% solution of Na₂CO₃. The solvent is evaporated and add ethanol. Distilled the school one part solvent. Maintain a temperature of about 40-45°C and initiate the crystallization seed. After mixing, the mixture is cooled, stirred for 90 min, cooled and then stirred for 60 minutes Dropped precipitated substance is filtered off and washed with ethanol. Wet the reaction product is dried in vacuum at 40°C. Suspended and dissolved in absolute ethanol to 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropionate. A clear solution is cooled down and make seed. Upon cooling, the mixture is crystallization. Continue stirring for 60 min, then the mixture is cooled, stirred and filtered, the product washed with cold absolute ethanol. The wet product is dried in vacuum at 40°C. the Output of 48.1 g = 81%.

1. The method of obtaining the compounds of formula (6)

its salts accession, polymorphic and/or pseudopolymorphic forms, characterized in that the method includes the stage
(i) the introduction of isobutylamine in the compound of formula (1')

with the formation of the compounds of formula (2')

(ii) introducing p-nitrophenylacetylene group in the compound of the formula (2') with the formation of the compounds of formula (3')

(iii) Voss is the resolution of the nitro group of compounds of formula (3') with the formation of the compounds of formula (4') after filtration of the reaction mixture

(iv) removing the protective group from compounds of formula (4') with the formation of the compounds of formula (5)

(v) combinations of the compounds of formula (5) with (3R,3S,6R)-hexahydrofuro[2,3-b]furan-3-ilen derivative obtained by the activation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol or its predecessor by carbamylcholine cross-linking agent with the formation of the compounds of formula (6)where the specified predecessor (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol includes compounds in which the oxygen functional alcohol groups protected 0-protective group selected from tert-butylamino group, acetate, benzyl groups, benzylamine groups, allyl, silylamine groups, alkoxyalkyl groups, tetrahydropyranyl.

2. The method according to claim 1, where the stage (i) is carried out in toluene.

3. The method according to claim 2, where the stage (ii) is carried out in toluene, ethyl acetate, methylene chloride, dichloromethane or tetrahydrofuran.

4. The method according to claim 3, where the stage (iii) is carried out in the presence of 10 mol.% primary or secondary amine with palladium-on-coal in a hydrogen atmosphere.

5. The method according to claim 4, where the stage (iv) is carried out in acidic or alkaline medium.

6. The method according to claim 5, where the compound of formula (5) is crystallized by dissolving it in a mixture of solvents, bringing the pH to a value of more than 9 and maintaining the concentration of the compounds is Oia formula (5) in solution at a level of from 4 to 15% (wt./wt.).

7. The method according to claim 6 where the compound of formula (5) is crystallized at a temperature of from 0 to 10°C.

8. The method according to claim 7, where, during the crystallization add seed crystals of the compounds of formula (5).

9. The method of claim 8, where the solvent mixture contains one or more solvents, miscible with water, and the water.

10. The method of claim 8, where the solvent mixture contains one or more solvents that are immiscible with water, and the water.

11. The method according to claim 9, where the mixture solvent is a methanol, isopropanol and water in the ratio 1:6,5:8 respectively.

12. The method according to claim 11, where (3R,3S,6R)-hexahydrofuro[2,3-b]furan-3-ol or its predecessor prior to combination with the compound of the formula (5) enter into interaction with bis (4-nitrophenyl)carbonate.

13. The method according to claim 11, where (3R,3S,6R)-hexahydrofuro[2,3-b]furan-3-ol or its predecessor prior to combination with the compound of the formula (5) enter into interaction with disuccinimidylsulfite.

14. The method according to item 12 or 13, where the interaction of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol or its predecessor derived from carboxylic acids activate the base.