Methods of producing (3r, 3as, 6ar) hexahydrofuro[2,3-b]furan-3-ol

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing diastereoismerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol (6), as well as a novel intermediate compound (3aR,4S,6aS)-4-methoxytetrahydrofuro [3,4-b]furan-2-one (4) for use in said methods. More specifically, the invention relates to a stereo-selective method of producing diastereoisomerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, as well as methods for crystallisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one and epimerisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one to (3aR,4S,6aS)-4- methoxytetrahydrofuro[3,4-b]furan-2-one.

EFFECT: improved method.

25 cl, 9 ex

The present invention relates to methods of producing (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, as well as to the new intermediate compound (3aR,4S,6aS)-4-methoxyacridine[3,4-b]furan-2-it is intended for use in the above methods. More specifically, the invention relates to a stereoselective process for the preparation of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol and method suitable for production on an industrial scale.

Hexahydrofuro[2,3-b]furan-3-ol is an important pharmacological fragment that is present in the structure of retroviral protease inhibitors, such as those described by Ghosh et al. in J. Med. Chem. 1996, 39(17), 3278-3290, EP 0715618, WO 99/67417 and WO 99/65870. These publications are incorporated herein as references.

There are several ways to get hexahydrofuro[2,3-b]furan-3-ol.

Ghosh et al. in J. Med. Chem. 1996, 39(17), 3278-3290 describe the enantioselective synthesis for the preparation of (3R,3aS,6aR)-and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-ol in optically pure form, starting from 3(R)-diethylmaleate and 3(S)-diethylmaleate respectively. Ghosh et al. also describe the synthesis of the racemic mixture of (3R,3aS,6aR)- and (3S,3aR,6aS)-enantiomers hexahydrofuro[2,3-b]furan-3-ol, starting with 2,3-dihydrofuran, with subsequent enzymatic separation of the final product. Pezeck et al. in Tetrahedron Lett. 1986, 27, 3715-3718 also describe the path for the synthesis of hexahydrofuro[2,3-b]furan-3-ol using ozonolysis. Hexahydrofuro[2,3-b]furan-3-ol is also described as an intermediate compound in the synthesis of optically active derivatives perpetrator[2,3-b]furan in the publication Uchiyama et al., in Tetrahedron Lett. 2001, 42, 4653-4656.

WO 03/022853 relates to an alternative method, which involves the synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol; this method begins with 2,3-duhsasana-2,3-dihydroxypropane, which is transformed into a derivative, including nitro methyl and one or two carboxylate parts. The specified derived subsequently transformed by the reaction of the Nave in tertrahydrofuran ring compound that restores and subjected to intramolecular cyclization reaction, to obtain (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol.

In order to transform the source material, i.e. 2,3-dvosemyanny-2,3-dihydroxypropane, derived, including one or two carboxylate side, WO 03/022853 describes various ways, which include the Wittig reaction using phosphorus reaction; the reaction Horner-Emmons with the use of phosphonates in the presence of a base; the reaction of condensation type knoevenagel using derived malonate; or, alternatively, with the use of reagents reformed, i.e. predecessors parts-C(=O)-O-, such as cyanide. In particular, the examples here is ocuserts in two ways: the ways of knoevenagel and Wittig.

Path knoevenagel, as shown in WO 03/022853 are adding diethylmalonate to the dry solution of starting material 2,3-O-isopropylideneglycerol, obtaining dimethyl ester 2-(2,2-dimethyl-[1,3]dioxolane-4-ylmethylene)of malonic acid with 2 incorporated by carboxylates. Because the original material was obtained in aqueous solution, it is necessary to make a complex selection procedure, including extraction with tetrahydrofuran and water removal. These extraction and removal of water requires large amounts of tetrahydrofuran and time. In addition, the yield of the reaction is the conversion of 2,3-O-isopropylideneglycerol in dimethyl ester 2-(2,2-dimethyl-[1,3]dioxolane-4-ylmethylene)of malonic acid by Klengel has a maximum value of approximately 77%, because there are unavoidable adverse reactions, even after optimizing the conditions.

Due to the fact that the obtained dekarboksilirovanie intermediate compound is a viscous oil, i.e. dimethyl ester 2-(2,2-dimethyl-[1,3]dioxolane-4-ylmethylene)malonic acid, it is necessary to enter in the subsequent reaction joining Michael in the form of a solution in methanol. Distillation of methanol after quenching in an aqueous solution of NaHCO₃after reaction of the Nave with acid and cyclization, but to extraction with an organic solvent such as this is latitat, has shortcomings. Since the intermediate compound, which is obtained by reaction of a Nave with acid and cyclization, i.e. methyl ester 4-methoxy-2-oxohexanoate[3,4-b]furan-3-carboxylic acid is labile in water connection and distillation of methanol requires relatively high temperatures (30-40°C), there is a decomposition of the intermediate compounds to polar compounds. These polar compounds remain in the aqueous phase and subsequently lost because they are not extracted into the organic phase. Because methanol cannot be removed prior to extraction, requires a significant amount for treatment of methyl ester 4-methoxy-2-oxohexanoate[3,4-b]furan-3-carboxylic acid.

During the decarboxylation of methyl ester 4-methoxy-2-oxohexanoate[3,4-b]furan-3-carboxylic acid there is a significant formation of by-product, i.e. (4-hydroxy-2-methoxyacridine-3-yl)acetic acid. In addition, the crystallization of 4-methoxyacridine[3,4-b]furan-2-it gives a solid brown color due to concomitant polymerizate.

In addition, for the purification of 4-methoxyacridine[3,4-b]furan-2-it requires at least two acid-base cascade extraction for removal of acid for the cyclization, resulting in a total yield of 4-methoxyacridine[3,4-b]FSD is n-2-she is 52% of the methyl ester 4-methoxy-2-oxohexanoate[3,4-b]furan-3-carboxylic acid, which is regarded as almost optimal.

All the factors mentioned above, prevent the use of synthesis knoevenagel. In fact, the stage decarboxylation in the scheme of synthesis is a disadvantage compared with the synthesis of Wittig, since such phase decarboxylation in the latter case is not required.

WO 03/022853 in example I describes the synthesis of Wittig, which uses triethylphosphate (TERA) to obtain ethyl ester 3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid. The subsequent addition of Michael to ethyl ether, 3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid has limitations in that it results in nitromethane adduct, i.e. ethyl ester 3-(2,2-dimethyl-[1,3]dioxolane-4-yl)-4-nitromalonic acid, ratio SYN:anti approximately 8:2. Subsequent recovery, followed by reaction of the Nave/cyclization, leads to the production of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, seriously contaminated his Exo-diastereoisomer, i.e. the (3R,3aR,6aS)hexahydrofuro[2,3-b]furan-3-I, with a ratio of endo:Exo approximately 8:2. Despite the fact that this process does not have several drawbacks inherent in the process knoevenagel, it does not give a pure endo-diastereoisomer, because there is no available stage of purification, such as crystallization, removal Negele is entrusted Exo-diastereoisomer, formed by the reaction of joining Michael in anticonspiracy.

An alternative synthesis of Wittig as described in example II WO 03/022853, the reaction product of joining Michael has the same disadvantage ratio SYN:anti (8:2), as in example I. Ethoxy-intermediate (3aR,4S,6aS)-4-ethoxyacrylate[3,4-b]furan-2-he (3aR,4R,6aS)-4-ethoxyacrylate[3,4-b]furan-2-it, the resulting reaction Nave/cyclization, was present in the ratio of (3aR,4S,6aS)/(3aR,4R,6aS) about 2.5/1, together with a large number of anisomerous, i.e. with a ratio of SYN:anti approximately 8:2. Purification of the intermediate compounds (3aR,4S,6aS)-4-ethoxyacrylate[3,4-b]furan-2-she (3aR,4R,6aS)-4-ethoxyacrylate[3,4-b]furan-2-it by removing unwanted antidiscrimination crystallization currently impossible. Restore mix and cyclization gave (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, seriously contaminated his Exo-diastereoisomer, i.e. the (3R,3aR,6aS)hexahydrofuro[2,3-b]furan-3-I, with a ratio of endo:Exo approximately 8:2. Like the process Wittig, referred to in example I, above, this process does not possess several drawbacks associated with the process of knoevenagel, but in its current form still does not give pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol with high the mi industrial outputs. In addition, the volumes of the reactors used in well-known specialists of the procedures are too large, and the number of transactions is too high; these factors is detrimental to the process cost-effective and thus make these processes are not optimal in an industrial scale.

Thus, there is a need for optimized processes for the industrial production of diastereoisomers pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol.

Unexpectedly, it was found that when used in the synthesis of Wittig and formed isomers of the intermediate compounds of formula (4) and (4') WO 03/022853 in the form of methylacetate (i.e. R' represents methyl, and R" represents hydrogen), the raw output of the intermediate compounds of formula (4)based on the intermediate compound of formula (2)is much higher compared to, for example, with ethoxy or isopropoxyaniline (where R"' represents ethyl or isopropyl, respectively, and R" is hydrogen).

Moreover, it has been unexpectedly found that the specified methylacetylene form intermediate compounds of formula (4) in isomeric form (3aR,4S,6aS) can crystallize from a mixture of (3aR,4S,6aS) and (3aR,4R,6aS) - isomers of compounds of formula (4) and a relatively large number of isomers (4').

Povyshen the th output and the possibility of crystallization of the isomeric forms of (3aR,4S,6aS) allow (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol in diastereoisomer pure form and with a high output.

The compound of the formula (4), (3aR,4S,6aS)-4-methoxyacridine[3,4-b]furan-2-it is in the remainder of this description will be called a compound of formula α-(4), or alpha-epimer, or α-isomer. Like this (3aR,4R,6aS)-4-methoxyacridine[3,4-b]furan-2-it is in the remainder of this description will be called a compound of the formula β-(4) or beta-epimer or β-isomer.

Surprisingly not only that methoxyacetyl formula α-(4) can be crystallized, but it is even more surprising that this crystallization is successful, despite the low ratio of alpha/beta less than 4/1 raw intermediate compounds of formula (4), beginner crystallization. It should be understood that in the process of knoevenagel required ratio alpha/beta at least 6:1, to get capable to crystallize the intermediate compound of formula α-(4).

Thus, the present invention relates to an improved method of Wittig and to the use of 4-alpha isomer 4-methoxyacridine[3,4-b]furan-2-it, in particular (3aR,4S,6aS), which makes a significant contribution to the ability of the industrial production of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol in diastereoisomer pure form.

In addition, it has been unexpectedly found that a mixture of any ratio of alpha - and beta-epimeres formula (4) can be transformed into the MCA is ü with a predominant content of alpha-epimer, which can then be isolated in pure form by crystallization. Essentially, the present invention relates to a new alkoxy-acetaline the epimerization of compounds of formula (4), which makes a significant contribution to the process cost-effective for production of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol.

In addition, it has been unexpectedly found that the blend with almost any ratio of alpha - and beta-epimeres formula (4) can be transformed in the course of a single phase crystalline alpha-epimer by simultaneous crystallization and epimerization, also known as induced crystallization asymmetric transformation. Essentially, the present invention relates to simultaneous crystallization and epimerization to isolate pure (3aR,4S,6aS)-4-methoxyacridine[3,4-b]furan-2-it.

Summary of the invention

The present relates to an improved method of Wittig and to the use of (3aR,4S,6aS)-4-methoxyacridine[3,4-b]furan-2-it as intermediate compounds, more specifically, in crystalline form, for the manufacture of diastereoisomers pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, which is suitable for production on an industrial scale.

The present invention relates to a new alkoxy-acetaline epimerization formula β-(4) in the compound of formula α-(4), which makes a significant contribution to the process cost-effective for manufacturing diastereoisomers pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol.

The present invention relates to simultaneous crystallization and epimerization to isolate diastereoisomers pure (3aR,4S,6aS)-4-methoxyacridine[3,4-b]furan-2-it.

Another variant of implementation of the present invention relates to a method, which allows to obtain (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol with higher than those of the methods described previously in this area, exit. Another objective of the present invention is to obtain able to crystallize and having a high purity intermediates which are suitable for the synthesis of diastereoisomers pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol.

Detailed description of the invention

The present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol having the structure of formula (6)

this method includes the use of intermediate compounds of formula (4)

The present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol having the structure of formula (6)

This method includes the use of intermediate is of the compounds of formula α-(4)

The present invention relates also to method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol having the structure of formula (6)

This method involves the following stages:

a) treatment of compounds of formula (3) with a base followed by treatment with an acid in the presence of methanol,

where R¹and R²is each, independently, hydrogen, hydroxyamino group, or may together form vicinal-diol-protective group,

R¹represents alkyl, aryl or aralkyl,

which leads to the formation of intermediate compounds of formula (4); and

b) recovery of the intermediate compounds of formula (4) reducing agent and the reaction of intramolecular cyclization, to obtain the compounds of formula (6).

In one embodiment, the present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol having the structure of formula (6),

which includes stage

a) treatment of compounds of formula (3) with a base followed by treatment with an acid in the presence of methanol,

where R¹and R²defined above,

R¹defined above;

which leads to the education intermediate compounds of formula (4);

b) crystallization solvent of intermediate compounds of formula α-(4); and

(C) recovery of the intermediate compounds of formula α-(4) reducing agent and the reaction of intramolecular cyclization to obtain the compounds of formula (6).

In another embodiment, the present invention relates to the epimerization of acid compounds of the formula β-(4) in the compound of formula α-(4).

In another embodiment, the present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol having the structure of formula (6),

which involves the following stages:

a) treatment of intermediate compounds of the formula (3) with a base followed by treatment with an acid in the presence of methanol;

where R¹and R²defined above,

R¹defined above;

which leads to the formation of intermediate compounds of formula (4);

b) acid epimerization of the intermediate compounds of formula β-(4) in the intermediate compound of formula α-(4);

C) crystallization solvent of intermediate compounds of formula α-(4); and

d) recovery of the intermediate compounds of formula α-(4) with a suitable reducing agent and the reaction of intramolecular cyclization to obtain the compounds of formula (6).

In another embodiment, the present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol having the structure of formula (6),

which involves the following stages:

a) processing the specified intermediate compounds of formula (3) with a base followed by treatment with an acid in the presence of methanol

where R¹and R²defined above,

R¹defined above,

which leads to the formation of intermediate compounds of formula (4)

b) crystallization solvent of intermediate compounds of formula α-(4);

(C) the acid epimerization of the intermediate compounds of formula β-(4) in the mother solution, the above-mentioned stage of crystallization in the intermediate compound of formula α-(4)

d) crystallization solvent of intermediate compounds of formula α-(4), which gives the second gathering of the intermediate compounds of formula α-(4); and

e) recovery of the intermediate of formula α-(4) with a suitable reducing agent and the reaction of intramolecular cyclization to obtain the compounds of formula (6).

In yet another embodiment, the present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol of the formula (6), as described in the methods above, in which the epimerization and crystallization of the compounds of formula α-(4) is observed at the same time.

The present invention relates also to method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol of the formula (6), as described in the methods above, which compound of formula (3) is produced by interaction of the compounds of formula (2) with nitromethane and base.

In yet another embodiment, the present invention relates to a method of synthesis of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol of the formula (6), as described in the methods above, which compound of formula (2) is obtained by condensation of intermediate compounds of formula (1) or its hydrate, hemihydrate, or a mixture thereof with phosphonates of formula (R⁶O)₂P(=O)-CH₂-C(=O)OR¹,

where R¹and R²defined above,

R¹defined above,

R⁶represents alkyl, aryl or aralkyl.

The term "hidroxizina group"used in the present description, refers to the Deputy, which protects hydroxyl groups against undesirable reactions during the synthesis procedures, such as O-protective groups described in Greene and Muts, "Protctive Groups In Organic Synthesis," (John Wiley & Sons, New York, 3rd edition, 1999). Hydroxyamine groups include substituted methyl ethers, for example methoxymethyl, benzoyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tert-butyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example 2,2,2-trichloroethyl; Silovye esters, for example, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; and esters, such as acetate, propionate, benzoate and the like

The term "vicinal-diol protective group"used in the present description, refers to a protective group in the form of an acetal or Catala and artaphernes form. Specific examples of the protective group in the form acatalog or catalogo radicals include methylene, diphenylmethylene, ethylidene, 1-tert-butylamide, 1-fenretinide, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, isopropylidene, cyclopentolate, cyclohexylidene, cycloheptylamine, benzylidene, p-methoxybenzylidene, 2,4-dimethoxyaniline, 3,4-dimethoxyaniline, 2-nitrobenzylidene and the like, and specific examples of the protective group in artaphernes form includes methoxymethyl, ethoxymethylene, 1-methoxyaniline, 1-amoxicilian, 1,2-dimethoxyaniline, alpha methoxybenzylidene, 1-(N,N-dimethylamine)ethylidene, alpha-(N,N-dimethylamine)benzylidene, 2-oxacyclopentane etc. In a preferred embodiment, this is th invention vicinal-diol-protecting group is isopropylidene.

The term "alkyl"used in the present description individually or as part of another group refers to saturated monovalent hydrocarbon radicals having straight or branched hydrocarbon chain, or, in the case where there are at least 3 carbon atoms, cyclic hydrocarbons or their combinations, and containing from 1 to 20 carbon atoms (C_1-20alkyl), preferably from 1 to 10 carbon atoms (C_1-10alkyl), preferably from 1 to 8 carbon atoms (C_1-8alkyl), more preferably from 1 to 6 atoms of carbon (C_1-6alkyl), and, more preferably, from 1 to 4 atoms of carbon (C_1-4alkyl). Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "alkenyl"used in the present description individually or as part of another group, refers to monovalent hydrocarbon radicals having straight or branched hydrocarbon chain having one or more double bonds and containing from 2 to 18 carbon atoms, preferably from 2 to 8 carbon atoms, more preferably from 2 to 5 carbon atoms. Examples of suitable alkenyl radicals include ethynyl, propenyl, alkyl, 1,4-butadienyl etc.

The term "quinil", ispolzuemyi in the present description individually or as part of a group, refers to monovalent hydrocarbon radicals having straight or branched hydrocarbon chain having one or more triple linkages and containing from 2 to 10 carbon atoms, more preferably from 2 to 5 carbon atoms. Examples of suitable etkinlik radicals include ethinyl, PROPYNYL, (propargyl), butynyl etc.

The term "aryl", as used in the present description individually or as part of another group, refers to an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen atom, and includes monocyclic and polycyclic radicals, such as phenyl, diphenyl, naphthyl.

The term "alkoxy"used in the present description individually or as part of another group, refers to an alkyl ether radical, where the term "alkyl" is defined above. Examples of alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.

The terms "aralkyl and arakaki"used in this description, separately or in combination, means an alkyl or CNS radicals, as defined above, in which at least one hydrogen atom substituted on the aryl radical, as defined above, such as benzyl, benzyloxy, 2-phenylethyl, dibenzylamine, hydroxyphenylethyl, methylphenylethyl etc.

The term shall arelaxation", used in the present description individually or in combination, means a radical of the formula aralkyl-O-C(O)-, in which the term "aralkyl" defined above. Examples alcoxycarbenium radical are benzyloxycarbonyl and 4-methoxyphenylacetylene.

The term "cycloalkyl"used in this description, separately or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical, where each of the cyclic portion contains from about 3 to 8 carbon atoms, more preferably, from about 3 to 6 carbon atoms. Examples of these cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "cycloalkenyl"used in this description, separately or in combination, means an alkyl radical, as defined above, which is substituted cycloalkenyl radical, as defined above. Examples of these cycloalkenyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylmethyl, 1-cyclohexylethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl etc.

The term "heteroseksualci"used in this description, separately or in combination, refers to the saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members, and, most preferably, from 5 to 6 ring members, which contains one or more heteroatomic ring members selected from nitrogen, oxygen and sulfur, and which optionally is substituted by one or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl, etc. and/or on a secondary nitrogen atom (i.e.- NH-) - hydroxyl, alkyl, alcoxycarbenium, alkanoyl, phenyl or phenylalkyl, and/or tertiary nitrogen atom (i.e. =NH-) - oxide. Heteroseksualci also includes benzododecinium monocyclic cycloalkyl group having at least one specified heteroatom. Heteroseksualci, in addition to sulfur and nitrogen, also includes sulfones, sulfoxidov and N-oxides containing tertiary nitrogen geterotsiklicheskikh groups.

The term "heteroaryl"used in this description, separately or in combination, refers to an aromatic monocyclic, bicyclic or tricyclic geteroseksualnoe the radical defined above, and optionally substituted as defined above for aryl and geterotsiklicheskie.

Examples of these geterotsiklicheskikh and heteroaryl groups amlawdaily, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, imidazol-4-yl, 1-benzyloxycarbonylamino-4-yl, pyrazolyl, pyridyl, 2-(1-piperidinyl)pyridyl, 2-(4-benzylpiperazine-1-yl-1-pyridinyl), pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl, thiazolyl, 2-indolyl, 2-chinoline, 3-chinoline, 1 oxido-2-chinoline, ethenolysis, 1-ethenolysis, 3-ethenolysis, tetrahydroquinoline, 1,2,3,4-tetrahydro-2-chinolin, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-1-oxoethylidene, honokalani, 2-benzofuranyl, 1-, 2-, 4 - or 5-benzimidazolyl etc.

The term "silyl"used in the present description, refers to the silicon atom optionally substituted by one or more alkyl, aryl or aranceles groups.

The term "isomer", "isomeric form", "stereochemical isomeric form or stereoisomeric forms"used in this description, define all the possible isomeric as well as conformational forms, consisting of the same atoms connected by the same communication sequence, but with different spatial patterns that are not interchangeable, which the compounds or intermediate compounds formed during this process may have. If not included or indicated, the chemical designation of compounds include the indicates the mixture of all possible stereochemical isomeric forms, which the specified connection can have. This mixture may contain all diastereoisomer, epimere, enantiomers and/or conformers of the basic molecular structure of the compounds. More specifically, stereogenic centers may have the R - or S-configuration, diastereoisomer can be SYN or anti configuration, the substituents on bivalent cyclic saturated radicals may be CIS - or TRANS-configuration, and alkeneamine radicals can have the E - or Z-configuration. All stereochemical isomeric forms of the compounds in pure form or in mixture with each other, are included in the scope of the present invention.

The term "diastereoisomer" or "diastereoisomeric form" applies to molecules with identical chemical structure and containing more than one stereocenter, which differ from each other in configuration relative to one or more specified stereocentres.

The term "epimer" in the present invention refers to molecules with identical chemical structure and containing more than one stereocenter, but which differ from each other in configuration relative to only one of these stereocenters. In particular, the term "epimer" includes compounds of formula (4), which differ in the orientation relationship between the carbon atom 4 (p-4) and Deputy methoxy, i.e. with the organisations of formula α-(4) and β-(4), respectively, where C-4 is a 4S and 4R, respectively.

Pure stereoisomeric forms of the intermediate compounds of the formula(1), (4), (6) and the source material referred to in this description are defined as isomers, containing no other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds or of the source material. Accordingly, the term "stereoisomer clean connection or source material refers to compounds or source material, having a stereoisomeric excess of at least 50% (i.e. at least 75% of one isomer and a maximum of 25% of the other possible isomers), up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and no other), preferably to compounds or source material, having a stereoisomeric excess of 75% to 100%, more preferably to compounds, source material or reagents having a stereoisomeric excess of 90% to 100%, even more preferably, the compounds or intermediate compounds having a stereoisomeric excess of from 94% to 100% and, most preferably, having a stereoisomeric excess of from 97% to 100%. The terms "enantiomerically pure" and "diastereoisomers clean" should be understood in the same way, but taking into account the enantiomeric excess, and according to the respectively diastereoisomeric excess in this mixture.

Essentially, in the preferred embodiment of the present invention use S-2,3-O-isopropylideneglycerol as source material in enantiomeric excess of greater than 95%, more preferably, in enantiomeric excess of 97%, even more preferably, the enantiomeric excess of > 99%.

The compounds of formula (1)

The compounds of formula (1) can be obtained from commercially available sources. The synthesis of compounds of formula (1) in enantiomerically pure form or in racemic form, described in the literature. For example, 2,3-O-isopropylidene-S-glyceraldehyde described in C. Hubschwerlen, Synthesis 1986, 962; obtaining 2,3-O-isopropylidene-R-glyceraldehyde described in C.R. Schmid et al., J. Org. Chem. 1991, 56, 4056-4058; and receiving 2,3-O-isopropylidene-(R,S)-glyceraldehyde described in A. Krief et al., Tetrahedron Lett 1998, 39, 1437-1440. Thus, the indicated intermediate compound of formula (1) can be purchased, obtained before the reaction or be formed in situ. In a preferred embodiment of the present invention the specified connection receive in situ, for example, by oxidation in aqueous or partially aqueous solution. When the specified connection is in an aqueous or partially aqueous solution, it is usually partially present in the form of its hydrate or hemihydrate.

Accordingly, the image is the buy relates to a method, in which R¹and R²together form vicinal-diol-protective group, which, in particular, represents an acid-labile protective group, which remains unchanged during stage impacts the basis of subsequent reactions of the Nave. Preferably, the specified vicinal-diol-protective group selected from the group consisting of methylene, diphenylmethylene, ethylidene, 1-tert-butylethylamine, 1 phenylethylamine, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, isopropylidene, cyclopentylamine, cyclohexylidene, cycloheptylamine, benzylidene, p-methoxybenzylidene, 2,4-dimethoxyaniline, 3,4-dimethoxybenzidine and 2-nitrobenzylidene. In a more preferred embodiment of the present invention R¹and R²together form dialkylamines, such as isopropylidenebis or 3-pentylidene radical. In the most preferred embodiment of the present invention R¹and R²together form isopropylidene radical. The particular advantage of the use of isopropylidene compared to other protective groups is that the reagents required for the protection of the diol, i.e. dimethoxypropane, 2-methoxypropene or acetone, are commercially available and inexpensive.

Interest vicinal-diol-protective groups are protective the group, which do not form one or more stereogenic centers in the intermediate compounds of formula (1), (2) and (3).

The above-mentioned hidroxizina group and vicinal-diol-protective group easily hatshepsuts ways known in the art, such as hydrolysis, recovery, etc. that are chosen properly depending on the protective group. According to a more preferred variant implementation of the present invention, vicinal-diol-protective group is an acid-labile protective group, where the term "acid-labile"as used in the present description, refers to vicinal-diol-protective groups, which are easily hatshepsuts when using acidic conditions.

The compounds of formula (2)

The compounds of formula (1) or their hydrates, palpitate or mixture are then transformed into compounds of the formula (2) with the use of phosphonates in the presence of a base. In the reaction are used phosphonates of the formula (R⁶O)₂P(=O)-CH₂-C(=O)OR¹,

where R¹represents alkyl, aryl or aralkyl,

R⁶represents alkyl, aryl or aralkyl.

Accordingly, R¹represents a C_1-6alkyl, aryl or arils_1-6alkyl, in particular With_1-6alkyl, more specifically, R¹represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl, preferably, R¹represents methyl, ethyl or tert-butyl, and most preferably, R¹represents ethyl.

Examples of phosphonates include, among others, ethyl 2-(diethylphosphino)propionate, ethyl 2-(dimethylphosphino)propionate, triethylphosphate (TERA).

Preferably, the compound of formula (1) and phosphonate are present in the reaction mixture in the range of molar ratio of about 0.9:1 to 1.1:to 0.9, most preferably in a molar ratio of approximately 1:1. When the compound of formula (1) are obtained in situ, its content in the reaction mixture should be identified and found approximately 1 equivalent of the added phosphonate.

Suitable temperature for the condensation reaction are in the range of about -5°C to 50°C, preferably from about -2°C to 35°C, more preferably, from about 0°C to 35°C.

Examples of suitable bases that can be used for the conversion of compounds of formula (1) in the compounds of formula (2)include, without limitation, bonds alkylamines, carbonates of sodium, potassium, lithium or cesium, hydroxides or alkoxides of sodium, potassium, lithium or cesium, and mixtures thereof. Preferably, the base is a carbonate of potassium, more preferably, the basics is of type in the form of solids, not a solution in water. Also more preferably, the amount of potassium carbonate in the form of solids is at least about 2.5 equivalents, based on compound of formula (1).

Preferably, the pH of the reaction mixture is maintained within the range of from about 7 to 13, more preferably in the range from 8 to 12, even more preferably, the pH is maintained within the range of from about 9 to 11.

Suitable solvents for this reaction are water, any hydrocarbon, ether, halogenated hydrocarbons or aromatic solvents known in the art for condensation reactions. The latter will include, without limitation, pentane, hexane, heptane, toluene, xylene (xylenes), benzene, mesitylene (mesitylene), tert-butyl methyl ether, dialkyl ethers (ethyl, butyl), diphenyl ether, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, acetonitrile, dichlorobenzene, dichloroethane, dichloromethane, cyclohexane, ethyl acetate, isopropylacetate, tetrahydrofuran, dioxane, methanol, ethanol and isopropanol. Preferably, water is used as solvent, as a single solvent or in a mixture with another solvent, for example tetrahydrofuran.

In one embodiment of the present invention to the reaction mixture containing compounds form the s (2), can be applied procedure by separating the organic and aqueous phase and the subsequent extraction of the aqueous phase additional portion of the compounds of the formula (2) using an organic solvent other than the organic phase. Essentially, tertrahydrofuran ring phase can be separated from the aqueous phase, and the latter can be extracted, for example, two portions of toluene. Preferred solvents for the extraction are ethyl acetate, toluene, tetrahydrofuran. The most preferred solvent is toluene.

The compounds of formula (2), preferably, does not purify on silica gel. Although you will get less pure compounds of the formula (2)than purified on silica gel the product, the quality is sufficient for obtaining the compounds of formula (4) with satisfactory quality and output. No cleanup phase and ultimately simplifies the production process of the present invention.

The compounds of formula (2) can be obtained in two isomeric forms, E - and Z-isomers; S-isomer is the preferred isomer.

The compounds of formula (3)

The compounds of formula (2) can then be subjected to reaction joining Michael at which the nitromethane added as a predecessor of the formyl group to α,β-nensis nomu ether intermediate compounds of the formula (2) together with the base.

Nitromethane is commercially available in the form of a solution in methanol and is preferable in this composition.

Examples of bases which are suitable for the catalysis of the addition reactions of Michael, are the hydroxide or alkoxides of sodium, potassium, lithium, cesium, TBAF (fluoride, Tetra-n-butylamine), DBU (1,8-diazabicyclo[5.4.0.]undec-7-ene), TMG (1,1,3,3-tetramethylguanidine), preferably, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, lithium methoxide, TBAF, DBU, TMG and mixtures thereof, more preferably, DBU and TMG, and, most preferably, DBU.

When DBU is used as the base in the conversion of the compounds of the formula (2) in the compounds of formula (3), preferably, the amount of added base above about 0.5 equivalents, based on the compounds of the formula (2), more preferably, above about 0.8 equivalent, more preferably, from about 0.8 to 1.2 equivalents, most preferably, from about 0.9 to 1.1 equivalents. In a preferred embodiment of the present invention DBU is present in amount of about 1 equivalent.

You can use any solvent suitable for the implementation of the response of the accession of Michael. Examples of suitable solvent is methanol, ethanol and acetonitrile. Predpochtitel is but the solvent is methanol, which allows to carry out the procedure in a single vessel, with the subsequent transformations of the compounds of the formula (3) in the compounds of formula (4).

There is predominantly the SYN-form of accession of the compounds of formula (3). The ratio of SYN/anti approximately 8/2.

The compounds of formula (4)

The compounds of formula (4), i.e. α-(4) and β-(4) are obtained through a series of transformations, starting from compounds of the formula (3), using the reaction of the Nave, in the corresponding formyl derivative, simultaneous acid catalyzed remove protection from diol and two cyclization reactions. These transformations carried out by the action of the intermediate compounds of formula (3) base with subsequent effects on the reaction mixture acid in the presence of methanol, preferably, by adding or pouring the reaction mixture into acid in the presence of methanol, resulting in a gain of the intermediate compound of formula (4). The above reaction also give the compounds of formula (4').

In the reaction of the Nave primary or secondary nitroalkane converted into the corresponding carbonyl compound (N. Kornblum Organic reactions 1962, 12, 101 and H.W. Pinnick Organic Ractions 1990, 38, 655). In the classical procedure, nitro the Kahn deprotonated base in α-position to microfunction with subsequent acid hydrolysis of the intermediate "nitronates" salt by adding a strong acid, present in excess, getting a carbonyl derivative.

Suitable bases may choose a specialist in the field of organic synthesis. Suitable bases include, without limitation, inorganic bases such as hydroxides and alkoxides of alkali metals, alkaline earth metals and ammonium. Examples of suitable bases are diisopropylamide lithium, sodium methoxide, potassium methoxide, lithium methoxide, tert-piperonyl potassium, digitoxin calcium, digitoxin barium and Quaternary hydroxides of alkylamine, DBN (1,3-diazabicyclo[3.4.0]non-5-ene), DBU, DABCO (1,4-diazabicyclo[2.2.2]octane), TBAF, TMG, potassium carbonate and sodium carbonate, or a mixture thereof. Preferred bases are sodium methoxide, potassium methoxide, lithium methoxide, TBAF, DBU, TMG, or mixtures thereof, more preferred bases are sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof, and most preferred is sodium methoxide.

As for the acid, you can use any acid, preferably a strong acid, more preferably a mineral acid such as concentrated sulfuric acid, concentrated hydrochloric acid and, most preferably, sulfuric acid.

By using anhydrous conditions or nearly anhydrous conditions and methanol as the e of the solvent in the reaction of the Nave, get circular mutilateral formyl group. Methyl substituents in the intermediate compounds of formula (4) and (4') come from the solvent of methanol.

Alternatively, if the reaction of the Nave and the previous reaction joining Michael perform in nematolosa solvent, such as acetonitrile, instead they will get other acetals, other than compounds of the formula (4) and (4'), usually a mixture of Polyacetal and alkylate corresponding to the substituent R¹in the compounds of the formula (3). These polyacetylene and acetaline related compounds can be transformed into desirable methylacetate formulas (4) and (4'), again performed by the interaction of the latter with methanol in acid conditions.

Alternatively, when the previous reaction joining Michael performed with the use of DBU or TMG and the compounds of formula (3) is not isolated, and the subsequent reaction of the Nave is performed with the use of a strong base, in particular sodium methoxide or lithium methoxide, unexpectedly obtained a significant increase in the yield of compounds of formula (4). Essentially, the presence of DBU or TMG during the reaction of the Nave with a strong base is a preferred embodiment of the present invention.

For example, when the reaction of the accession of Michael with nitromethane methane is carried out in the e hydroxides, the alkoxides or TBAF in different quantities, the output of the compounds of the formula (3), based on the compounds of the formula (2), is approximately 80%. When the subsequent reactions of the Nave and the cyclization is performed with isolated compounds of the formula (3), using sodium methoxide as additional grounds and sulfuric acid in methanol as the acid solution, it is possible to obtain an output of the compounds of formula (4) 43%, based on the compounds of the formula (2), with the ratio α(4)/β(4) at least about 3/1.

When the reaction is joining Michael carried out with about 1 equivalent of DBU or TMG, based on the compounds of the formula (2), the output of the compounds of the formula (3), based on the compounds of the formula (2), is approximately 80%. However, when subsequently reaction of the Nave and the cyclization is performed with isolated compounds of the formula (3), combined with 1.0 equivalent of sodium methoxide or lithium, based on the compounds of the formula (2), the compound of formula (4) can be obtained 53-58% yield, based on the compounds of the formula (2), with the ratio α(4)/β(4) at least about 3/1.

Bicyclic intermediate compounds of formula (4) are the expected products of the cyclization, originating from intermediate compounds of formula (3) in the SYN-configuration. Premiato the basic compounds of formula (4') are the expected products of the reaction, originating from intermediate compounds of formula (3) in the anti-configuration, which is not tsiklitiria and expected are the reaction products originating from the intermediate compounds of formula (3) in the SYN-configuration, since the cyclization of SYN-isomers usually not completed fully. The TRANS configuration of the substituents on the carbon atom number 3 (C-3) and carbon atom number 4 (C-4) tertrahydrofuran ring on the ring of the intermediate compounds of formula (4') prevents the formation of a lactone ring, as observed with the intermediate compounds of formula (4).

Preferably, the damping of the acid reaction of the Nave and the cyclization is carried out by using an excess of concentrated sulfuric acid, preferably from 2 to 10 equivalents, based on the compounds of the formula (2), more preferably from 2.5 to 5 equivalents, more preferably 3 to 4 equivalents, and most preferably, approximately 3.5 equivalent, in the form of a solution in methanol of 20% wt. up to 80% wt., preferably, in the form of a solution in methanol of 40% wt. up to 60% wt. The greater the excess of sulphuric acid gives a higher ratio of alpha/beta for compounds of formula (4), but also requires more basis for subsequent neutralization with alkaline damping. For example, when 3.5 equivalent of sulfuric acid, of p which accounts for compounds of formula (2), used for acid damping in the form of a 50% wt. solution in methanol, can be achieved, the ratio α(4)/β(4) to 4/1.

Damping of the acid reaction of the Nave and cyclization can be carried out at temperatures in the range of approximately -40°C to 70°C, preferably at temperatures in the range of about -25°C to 15°C, more preferably, at temperatures in the range of approximately -20°C to 5°C, most preferably at temperatures in the range of about -15°C. to 0°C. the reaction Time may vary up to about 24 hours, respectively, in the range of about from 15 minutes to 12 hours, even more suitably in the range of about from 20 minutes to 6 hours.

To highlight the compounds of the formula (4) may require treatment with water to remove salts and part of the intermediate compounds of formula (4'). The base will neutralize previously used acid as the acidic water can cause hydrolysis of methylacetate the compounds of formula (4) to palacecasino related compounds, resulting in loss of product. Essentially, the selection of the compounds of formula (4) is optimally alkaline reaction quenching, preferably, the aqueous alkaline reaction quenching, followed by extraction of the compounds of formula (4) is not miscible with water and organic solvent. Prefer the Ino, the acid mixture, the resulting reactions of the Nave and cyclization add in an alkaline aqueous solution.

Because during the alkaline aqueous reaction quenching requires a large volume of the reactor, it is preferable to minimize the specified volume as possible. This can be done in various ways, for example, through the use of bases with high solubility, or by using bases in the form of suspension. Essentially, suitable grounds for processing the compounds of formula (4) are the bicarbonate or carbonate, preferably sodium bicarbonate, potassium, lithium or cesium, more preferably, sodium bicarbonate or potassium, most preferably, potassium bicarbonate, as completely in solution and in the form of suspension. Essentially, the application of a saturated solution of potassium bicarbonate to alkali damping instead of a saturated solution of sodium bicarbonate has, because of its higher solubility, the advantage that the volume of the aqueous phase can be further reduced, and suddenly found that the resulting potassium sulfate is much better filtered than sodium sulfate.

Mainly, during alkaline damping pH is maintained within the range of from about 2 to 9, preferably from about 3 to 8, more preferably, approximately the t of 3.5 to 7.5. Also mainly, at the end of the alkaline damping pH is set to approximately from 3.5 to 6, preferably, from about 3.5 to 5, most preferably, approximately from 3.8 to 4.5. These required levels of pH can be achieved by the use of carbonates and bicarbonates, as described above. Optional, you can use the optional base or acid to maintain the pH at a certain level by the end of the reaction quenching. In the preferred range of pH methanol can evaporate from the reaction mixture after alkaline quenching and prior to extraction with an organic solvent, at temperatures in the range of about from 0°C to 65°C, preferably from about 20°C. to 45°C. Under these conditions, the compounds of formula (4) do not decompose, even if the duration of the reaction. Removal of the methanol by evaporation prior to extraction with an organic solvent has the advantage that the extraction efficiency is greatly increased, thus using less organic solvent, and productivity increases even more.

Suitable organic is not miscible with water solvents are any ester, a hydrocarbon, a simple ether, halogenated hydrocarbons or aromatic solvents. These solvents include, without limitation, pentane, who exan, heptane, toluene, xylene (xylenes), benzene, mesitylene (mesitylene), tert-butyl methyl ether, dialkyl ethers (ethyl, butyl), diphenyl ether, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, dichlorobenzene, 1,2-dichloroethane, 1,1,1-trichloroethane, ethyl acetate, isopropylacetate, preferably ethyl acetate.

In order to improve the yield after extraction of the compounds of the formula (4), can be added to the mixture prior to the extraction of soluble salts. The preferred salt comprises NaCl.

One of the advantages of the method described in the present invention, in comparison with the previously known synthesis Klengel, is that during the alkaline water quenching is not necessary to simultaneously extracted the compounds of formula (4) an organic solvent. The absence of organic solvent during alkaline quenching additionally helps to reduce the volume of the reactor, and filtering the resulting inorganic salt is much easier. When using synthesis Klengel requires the presence of an organic solvent during alkaline damping to avoid loss of product.

In order to further isolate the compound of formula α-(4), you can use the crystallization of the specified connection.

Crystallization

The compound of formula α-(4) mo is but to crystallize from the solvent, such as organic, inorganic solvents or water and their mixtures. Suitable solvents for crystallization include isopropanol, tert-amyl alcohol, tert-butanol, ethyl acetate, ethanol and methyl isobutyl ketone. Especially preferred is isopropanol, tert-amyl alcohol and tert-butanol, as they give a high yield of crystallization and the product of high purity. More preferably isopropanol or tert-amyl alcohol, most preferably isopropyl alcohol.

If the solvent used for crystallization is isopropyl alcohol, the preferred concentration before crystallization of the compounds of formula α-(4) is approximately from 5 to 30 wt.%, more preferably, from about 10 to 25 wt.%, even more preferably, from about 15% to 20% wt.

Crystallization gives compound α-(4) high purity, although there may be small quantities of the compounds of formula β-(4), i.e. less than about 5%, particularly in amounts less than about 3%.

The epimerization

The compound of the formula (4) in its beta isomeric form can be epimerization in the compound of formula α-(4) using acids, for example organic or inorganic acid, preferably in the absence of water and in the presence of methanol

The epimerization is preferably carried out using MeSO₃H in methanol or any comparable acid of similar strength, as it prevents the formation of side products. Preferably, the applied amount of MeSO₃H in methanol is in the range of about from 0.05 to 1.5 equivalents, based on the compounds of the formula (4), more preferably, from about 0.1 to 0.3 equivalent.

The temperature for the implementation of the epimerization is approximately 0°and approximately to the boiling temperature under reflux, preferably, from about 20°C. and about the boiling point under reflux, more preferably, approximately at the boiling temperature under reflux.

For some of the methods described above, there are several alternative ways. For example, in one embodiment of the present invention, after receiving a mixture of compounds of formula α-(4) and the compounds of formula β-(4), the compound of formula α-(4) crystallized and the synthesis procedure continue to obtain the compounds of formula (6). In another embodiment of the present invention the expert can select the crystallization of the compounds of formula α-(4), the implementation of the epimerization of the remaining mother liquor, which will gain a relatively large amount of unwanted epimer β-(4), obtaining a mixture with a relatively large number of epimer α-(4), and the implementation of the second crystallization epimer α-(4). For example, when crystallized raw mixture of compounds of formula (4), with the ratio of α-(4)/β-(4) in the range of about 3.5/1 to 4/1, highlight the first collection of α-(4), and the remaining mother liquor has a ratio of α-(4)/β-(4) in the range of about 0.3/1 to 1.5/1. After the epimerization of epimer β-(4) ratio of α-(4)/β-(4) in the mother solution is about 3/1 and receive a second collection of α-(4) by crystallization, having a purity of at least comparable to the purity of the first collection of α-(4).

Alternatively, it is possible to carry out simultaneous crystallization of epimer α-(4) and the epimerization reaction of β-(4) epimer α-(4). In another embodiment, the present invention can begin with the epimerization of β-(4) epimer α-(4) and subsequently crystallize the epimer α-(4). In yet another embodiment, the present invention can begin with the epimerization of β-(4) epimer α-(4), subsequently crystallize the epimer α-(4), applying a second epimerization of the remaining mother liquor and additional crystallization, giving the second collection epimer α-(4).

Essentially, in one embodiment of the present invention the mother liquor from a previous crystallization of the compounds of formula α-(4) of isopropanol can is about to Aimersoft evaporation of isopropanol, location of the residue in methanol and boiled under reflux for about 30 minutes to 4 hours with MeSO₃H, preferably in amounts of from about 0.1 to 0.3 equivalent. If the reaction mixture is subsequently poured into aqueous NaHCO₃, extracted with EtOAc and the organic phase in the solvent are placed in isopropanol, you can get a second helping of pure compounds of formula α-(4)by crystallization.

In a preferred embodiment of the present invention a mixture of epimeres α-(4) and β-(4) can be transformed in a single phase at 100% or almost 100% of the alpha-isomer with a 100% or almost 100% yield, i.e. without the formation of by-products, by direct crystallization of epimer α-(4) and simultaneous epimerization of β-(4) epimer α-(4); this process is known as induced crystallization asymmetric transformation. Induced crystallization asymmetric transformation can be performed by dissolving a mixture of epimeres α-(4) and β-(4) in methanol in the presence of approximately 0.10 equivalent MeSO₃H, based on the sum of both epimeres, and evaporation of the methanol under vacuum at a temperature of from about 30°C. to 40°C. This alternative implementation of the present invention is particularly preferable as a mixture of epimeres α-(4) and β-(4) can transformyour is only in the epimer α-(4) in one stage, that reduces the cost of products and gives one party of α-(4) homogeneous quality.

In a preferred embodiment of the present invention the neutralization of the acid, such as MeSO₃H, to carry out switching of the solvent with methanol in the solvent for crystallization, such as isopropanol. Specified neutralization can be accomplished by adding a slight molar excess of base, from the calculation used for the epimerization acid. As a basis you can use any base, if only the salt of the base with the acid used for the epimerization, not condominium crystals epimer α-(4). For example, in the case of MeSO₃H as the acid for the epimerization, you can use a tertiary amine, preferably triethylamine, giving methansulfonate salt triethylamine, which is not containerwith crystals epimer α-(4) during crystallization from isopropanol. Add been certified with qi net₃in a small excess in comparison with MeSO₃H to neutralize allows to avoid the formation of isopropyl acetals as by-products that could be formed in acidic conditions during the subsequent switching of the solvent from methanol to isopropanol. Then switching the solvent from methanol to isopropanol and crystallization give Obedinenie formula α-(4) high purity without contamination or with minimal contamination methansulfonate salt of triethylamine.

The compound of formula (6)

The compound of formula (6) is obtained by reduction of compound of formula α-(4) with subsequent cyclization reaction. Intermediate connection with the recovery of the compounds of formula α-(4) is a compound of the formula (5).

The compound of the formula (5) is preferably not isolated, but directly subjected to cyclization with obtaining the compounds of formula (6).

Stage of recovery can properly perform the action on the intermediate compound of formula α-(4) metal hydrides, such as lithium borohydride, sodium borohydride, sodium borohydride is lithium chloride, in a suitable anhydrous solvent.

Examples of suitable anhydrous solvents include, without limitation, dichloromethane, toluene, xylene, benzene, pentane, hexane, heptane, petroleum ether, 1,4-dioxan, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4 dioxane, 1,2-dimethoxyethane and, in General, any anhydrous solvent, suitable for use in the process of chemical reactions with the use of reducing agents listed above. The preferred solvent is tetrahydrofuran. According to a preferred variant implementation of the present invention stage restore the surveillance carried out using lithium borohydride or sodium borohydride in tetrahydrofuran.

In the case of using lithium borohydride as the reducing agent, the amount of reducing agent is in the range of about from 1 to 1.5 equivalents based on the compound of formula α-(4), preferably, from about 1.1 to 1.3 equivalent.

The specified stage of recovery can be performed at temperatures from about -78°C to 55°C, preferably from about -15°C to 45°C, and most preferably, from about 0°C to 40°C. the reaction Time may be approximately up to 24 hours and usually varies between approximately 2 and 24 hours.

The compound of the formula (5) can be converted into the desired compound of formula (6) by a cyclization reaction. The cyclization reaction is observed in the intramolecular transacetalization and can be done in any compatible acid organic solvent or in combination miscible with water, solvent and water and in the presence of a strong organic or inorganic acid. The specified reaction respectively perform the action on the connection formulas (5) a catalytic amount of a strong acid. In a preferred embodiment of the present invention is a strong acid selected from the group consisting of hydrochloric acid and sulfuric acid in tetrahydrofuran. the shown phase cyclization is preferably carried out at temperatures below about 5°C, more preferably, below about -5°C.

In a particularly preferred embodiment of the present invention for a compound of formula (5), which after reduction with lithium borohydride or sodium in tetrahydrofuran receive in the form of a complex with boron, are concentrated mineral acid, and decomplexer the compounds of formula (5), and the cyclization of the compounds of formula (5) to compounds of formula (6) takes place simultaneously. Preferably, use a strong mineral acid, more preferably, concentrated sulfuric acid or concentrated hydrochloric acid, most preferably concentrated hydrochloric acid. The amount of hydrochloric acid can vary from 1.0 to 1.4 equivalents, based on the number of used lithium borohydride or sodium, but preferably, from 1.1 to 1.3 equivalent.

With regard to the allocation of the compounds of formula (6) in its pure form, it is desirable to remove inorganic salts, which are derived from reagents used for the recovery stage, decomplexer and cyclization. This can be accomplished by the procedure of extraction using aqueous organic solvent, but preferably it is done by adding a small excess of base compared the Yu acid, used to decomplexer the compounds of formula (5) and his reactions cyclization to compounds of formula (6). Subsequently, the solvent is changed to a more non-polar solvent, which leads to the precipitation of the salts resulting from the recovery and decomplexer.

As the base used for treatment of compounds of formula (6), you can use any base, if only the solubility of its salts with a mineral acid used for decomplexer and the reaction of cyclization of compounds of formula (5) in the compound of formula (6), in the final solvent after the change of the solvent is low. If, for example, lithium borohydride in tetrahydrofuran is used for recovery, concentrated aqueous HCl used for decomplexer/cyclization, and the ethyl acetate is the ultimate solvent, tertiary amines are suitable bases for the neutralization of acids, especially triethylamine. In this case, a boron salt and hydrochloride of triethylamine almost completely precipitate and the compound of formula (6) remains in solution. After filtering off solids remains a solution of the compounds of formula (6) with high purity, which can be processed into any desired form.

There is the observation that the other enantiomer of the compounds of formula (6), namely Obedinenie formula (6d), (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-ol, is an active part for HIV protease inhibitors.

In essence, identical with the methods, procedures, reagents and conditions described in this invention, including the appropriate crystallization and the epimerization can be applied to obtain the compounds of formula (6d), using the compounds of formula (1d), its predecessors, and other intermediate compounds for obtaining the compounds of formula (6d), such as compounds of formula (4d), below.

The compounds of formula (6) and (6d) also finds particular application to the manufacture of medicines. According to a preferred variant implementation of the present invention the present compounds of formula (6) and (6d) are used as precursors in the manufacture of antiviral drugs, in particular drugs against HIV, more specifically, HIV protease inhibitors.

The compound of formula (6) and all intermediate compounds leading to the formation of the specified stereoisomers pure compounds are of particular interest for the manufacture of HIV protease inhibitors, as described in WO 95/24385, WO 99/65870, WO 00/47551, WO 00/76961 and US 6127372, WO 01/25240, EP 0715618 and WO 99/67417 included in this description as a reference, and, in particular, the following inhib the Torah HIV protease.

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-silt ether [(1S,2R)-2-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amine]-1-(phenylmethyl)propyl]carbamino acid (inhibitor of HIV-1 protease);

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-silt ether [(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](2-methylpropyl)amine]-2-hydroxy-1-(phenylmethyl)propyl]carbamino acid (inhibitor of HIV protease 2);

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-silt ether [(1S,2R)-3-[(1,3-benzodioxol-5-ylsulphonyl)(2-methylpropyl)amine]-2-hydroxy-1-(phenylmethyl)propyl]carbamino acid (inhibitor of HIV protease 3), or any pharmaceutically acceptable salt.

Thus, the present invention also relates to inhibitors of HIV protease 1, 2, 3 or any pharmaceutically acceptable salt, or prodrug obtained using the compounds of formula (6)obtained according to the present invention, for the chemical synthesis of these HIV protease inhibitors. Specified chemical synthesis described in the literature, for example in WO 01/25340, EP 0715618 and WO 99/67417.

Essentially, protease inhibitors, mentioned above, can be obtained using the following General procedure. N-protected aminoethoxy formula

where R represents aminosidine group, and R²represents radicals of alkyl, aryl, cycloalkyl, cycloalkenyl and aralkyl; criminal code of the above radicals, optionally substituted group selected from alkyl radicals and halogen, nitro, cyano, trifluoromethyl, -OR⁹and-SR⁹where R⁹represents the radicals hydrogen, alkyl and halogen; receive from the corresponding chloroethane in the presence of base and solvent. A suitable solvent system to obtain aminoethoxy include ethanol, methanol, isopropanol, tetrahydrofuran, dioxane and the like, including mixtures thereof. Suitable base to obtain the epoxide from the restored chloretone include potassium hydroxide, sodium hydroxide, tert-piperonyl potassium, DBU and the like

Alternatively, the protected aminoethoxy can be obtained starting from L-amino acids, which interacts with a suitable aminosidine group in a suitable solvent, obtaining aminosidine ester of L-amino acids of the formula:

where R"' represents carboxylate group, for example methyl, ethyl, benzyl, tertiary butyl and the like; R²defined above; and P' and P" are independently selected from aminosidine groups, including, without limitation, arylalkyl, substituted arylalkyl, cycloalkenyl and substituted cycloalkenyl, allyl, substituted allyl, acyl, alkoxycarbonyl, arelaxation and silyl.

In addition, P' and P" protective groups can form a heterocyclic ring with the volume of nitrogen, to which they are attached, for example 1,2-bis(methylene)benzene, phthalimide, succinimide, maleimide and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic group can be mono-, di - or tizamidine, such as nitrophthalimide.

Aminosidine ester of L-amino acids are then reduced to the corresponding alcohol. For example, aminosidine ester of L-amino acids can be restored by hydride diisobutylaluminum at -78°C in a suitable solvent, such as toluene. Preferred reducing agents include lithium hydride-aluminum, lithium borohydride, sodium borohydride, borane, lithium hydride or three-tert-butoxyaniline, the complex of borane/THF.

The resulting alcohol is then converted, for example, by oxidation Swarna to the corresponding aldehyde of the formula:

where P', P" and R²defined above. Thus, a solution of alcohol in dichloromethane is added to a cooled (-75°C to -68°C.) solution of oxalicacid in dichloromethane and DMSO in dichloromethane and stirred for 35 minutes.

Acceptable oxidizing agents include, for example, a complex of sulfur trioxide-pyridine and DMSO, oxalicacid and DMSO, acetylchloride or anhydride and DMSO, cryptomaterial or anhydride and DMSO, meta is sulphonylchloride and DMSO or tetrahydrothiophene-S-oxide, toluensulfonate and DMSO, triftormetilfullerenov (anhydride TFMCC) and DMSO, pentachloride phosphorus and DMSO, dimethylphosphoric and DMSO and isobutylparaben and DMSO.

The aldehydes of this process can also be obtained by means of restoring protected phenylalanine and analogues of phenylalanine or its amide or ester derivatives, such as sodium amalgam with HCl in ethanol or lithium, or sodium, or potassium, or calcium in ammonia. The reaction temperature may range from -20°C to 45°C, and preferably from about 5°to 25°C. Two additional ways of obtaining asutamisega aldehyde include oxidation of the corresponding alcohol bleach in the presence of catalytic amounts of a free radical 2,2,6,6-tetramethyl-1-pyridyloxy. In the second method, the oxidation of alcohol to aldehyde is performed with the use of catalytic amounts of perruthenate of tetrapropylammonium in the presence of N-methylmorpholin-N-oxide.

Alternatively, a derivative of a carboxylic acid protected phenylalanine or a derivative of phenylalanine, described above, can be restored with hydrogen and a catalyst such as Pd on barium carbonate or barium sulphate, with an additional delay catalyst agent such as sulfur or thiol (recovery Rosenmund) or without it.

Diastereoisomer can be divided, for example, by chromatography or, alternatively, can be divided diastereoisomeric products after they have responded, at the subsequent stages. For compounds having the (S) stereochemistry, instead of L-amino acids, you can use the D-amino acid.

Adding hermeticity or promotility to the chiral aminoaldehyde is vysokoustoychivy. Preferably, hermeticity or promotility formed in situ in the reaction dehalogenating and n-utillity. Acceptable methyltyrosine halogenmethyl include chloromethane, bromochloromethane, dibromomethane, diiodomethane, Braverman etc. Sulphonate ester product of accession, for example, is hydrobromide to formaldehyde, also is methyltyrosine agent.

Tetrahydrofuran is the preferred solvent, however, you can use alternative solvents, such as toluene, dimethoxyethane, ethylene dichloride, methylenechloride, as a pure solvent or in a mixture. Bipolar aprotic solvents such as acetonitrile, DMF, N-organic, are suitable as solvents or part of the solvent mixture. The reaction can be performed in an inert atmosphere, such as nitrogen or argon. n-Utility can be replaced by other organometallics reagents such as motility, tert-utility, second-utility, finality, FamilyTree and the like, the Reaction can be performed at temperatures from about -80°C to 0°C, but preferably from approximately -80°C to -20°C.

The conversion of aldehydes to their epoxy derivative can also be carried out in several stages. For example, adding anion thioanisole obtained, for example, of the reagent butyl or abillity to secure aminoaldehyde, oxidation of the obtained protected aminosulfonic alcohol using a well-known oxidizing agents such as hydrogen peroxide, tert-butylhypochlorite, bleach or periodate sodium, gives sulfoxide. Alkylation sulfoxide, for example, methyliodide or what romida, metallosalen, methylethylketon, methylcatechol, ethylbromide, isopropylamino, benzylchloride or the like is carried out in the presence of organic or inorganic bases.

Alternatively, protected aminosulfonyl alcohol can be alkilirovanii, for example, alkylating agents, listed above, to obtain the salts of sulfone, which are then converted into these epoxides tertiary amine or mineral bases.

The desired epoxides are formed when using the most preferred conditions, diastereoselective, the quantitative ratio of at least about 85:15 (S:R). The product can be cleaned by chromatography, obtaining diastereoisomers and enantiomerically pure product, but it is much better to use it directly, without purification, for the manufacture of inhibitors of retroviral protease. The above process is applicable to mixtures of optical isomers, as well as to the separated compounds. If it is desirable specific optical isomer, it can be selected by selecting the source material, for example, L-phenylalanine, D-phenylalanine, L-phenylalanine, D-phenylalanine, D-hexahydrotriazine and the like, or can be separated into intermediate or final stages. Chiral excipients, such as one or two equivalent Kam is alsultanova acid, citric acid, camphoric acid, 2-methoxyphenylacetic acid, etc. can be used for the formation of salts, esters or amides of the compounds of the present invention. These compounds or derivatives can crystallize or separate chromatography using a chiral or achiral column, which is well known to specialists.

Then aminoethoxy interacts in a suitable solvent system with an equal amount or, preferably, an excess of the desired amine of formula R³NH₂where R³represents hydrogen, alkyl, halogenated, alkenyl, quinil, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, heteroseksualci, heteroaryl, geterotsiklicheskikh, aryl, aralkyl, heteroalkyl, aminoalkyl and mono - and disubstituted aminoalkyl radicals, where these substituents selected from the radicals alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroaryl, heteroalkyl, geterotsiklicheskie and geterotsiklicheskikh, or, in the case of disubstituted aminoalkylindole radical, the said substituents along with the nitrogen atom to which they are attached, form heterologously or heteroaryl radical.

The reaction can be carried out in a wide temperature range, for example, from about 10°to 100°C., but preferably though not necessary, to carry out the reaction at a temperature at which the solvent begins to boil under reflux.

Proper solvents include proton, nephratonia and bipolar aprotic organic solvents, such as, for example, systems in which the solvent is an alcohol, such as methanol, ethanol, isopropanol and the like, ethers such as tetrahydrofuran, dioxane and the like, and toluene, N,N-dimethylformamide, dimethylsulfoxide and mixtures thereof. The preferred solvent is isopropanol. Examples of amines corresponding to the formula R³NH₂include benzylamine, isobutylamine, n-butylamine, isopentylamine, isoamylamine, cyclohexanemethylamine, naphthalenemethylamine etc. resulting product is a derivative of 3-(N-protected amine)-3-(R²)-1-(other³)propan-2-ol, hereinafter in the present description called linesperson and represented by the formula:

where P, P', P", R²and R³defined above. Alternatively, instead of aminoethoxy you can use halogenases.

Amerosport defined above, and then interacts in a suitable solvent with sulphonylchloride (R⁴SO₂Cl) or sulfanilamidam in the presence of an acid acceptor. Suitable solvents that can be used for the reaction include methylene chloride, tetrahydro the uranium. Suitable acid acceptors include triethylamine, pyridine. The preferred sulphonylchloride are methanesulfonanilide and benzosulphochloride. Received sulfonamidnuyu derivative can be represented, depending on the use of the epoxide, the formulas:

where P, P', P", R², R³and R⁴defined above. Data intermediate compounds are suitable for the manufacture of protease inhibitors and are also active inhibitors of retroviral proteases.

Sulphonylchloride formula R⁴SO₂X can be obtained by the interaction of the appropriate Grignard reagent or alkylate with sulfurylchloride or sulfur dioxide, with subsequent oxidation by halogen, preferably, chlorine. You can also oxidize thiols to sulphonylchloride using chlorine in the presence of water under carefully controlled conditions. In addition, the sulfonic acid can be converted to sulphonylchloride using such reagents as PCl₅and also the anhydrides, using suitable dehydrating reagents. Sulfonic acid, in turn, can be obtained using procedures well known in the art. These sulfonic acids are also commercially available. Instead of sulphonylchloride you can use sulfanilate tidy (R ⁴SOX) or sulfurylchloride (R⁴SX) to obtain compounds in which part-SO₂- replaced by part-SO - or-S -, respectively.

After receiving sulfonamidnuyu derived aminosidine group R or aminosidine group P' and P" are removed under conditions which will not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. Preferred method involves removal of the protective group, for example, remove group carbobenzoxy by hydrogenolysis using palladium on charcoal, in a suitable solvent system, such as alcohol, acetic acid, etc. or mixtures thereof. If the protective group is tert-butoxycarbonyl group, you can delete it using inorganic or organic acid, such as HCl, or triperoxonane acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting product is an amine salt of the formula:

The specified amine can be attached to the carboxylate represented by the formula:

where R represents a group of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-hydroxy, and L represents a corresponding delete the group, such as halide. A solution of free amine (what do aminoacetate salt) and about 1.0 equivalent of carboxylate is mixed in a suitable solvent system, and not necessarily, are the basis of up to five equivalents, such as, for example, N-methylmorpholine, approximately at room temperature. Proper solvents include tetrahydrofuran, methylene chloride or N,N-dimethylformamide and the like, including mixtures thereof.

Alternatively, the amine can be attached to an activated succinimidylester (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol. Activation of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol can be done, for example, the interaction with disuccinimidylsulfite and triethylamine.

EXAMPLES

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

All reactions were carried out in nitrogen atmosphere. The solvents and reagents used in the form in which they were purchased, without further purification. Spectra¹H NMR were recorded at 200 MHz in CDCl₃or DMSO-d₆the NMR spectrometer Bruker AC-200. Quantitative¹H NMR was carried out with chlorobenzene as an internal standard. All of these outputs were adjusted to account for impurities in the product.

Gas chromatography (GC) and the definition of S-2,3-O-isopropylideneglycerol error within acceptable limits in aukcionnyh mixtures was performed using Agilent 6890 GC (EPC) and column Betadex (24305, Supelco or equivalent) of 60 m and a film thickness of 0.25 µm, using pressure on the head of the column of 26.4 kPa, flow in the column of 1.4 ml/min split flow of 37.5 ml/min and temperature of injection of 150°C. is Used, the temperature change was: initial temperature 60°C (3 min), rate 5°C/min, the intermediate temperature is 130°C (1 min), 25°C/min, final temperature of 230°C (8 min). Detection was performed with FID detector at 250°C. retention Time was as follows: chlorobenzene (internal standard) to 13.9 min, S-2,3-O-isopropylideneglycerol - of 15.9 min, R-2,3-O-isopropylideneglycerol of 16.2 minutes

The GC analysis and the determination of the ethyl ester of R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid with an error within acceptable limits was performed using the above equipment, but using a temperature of injection of 250°C. is Used, the temperature change was: initial temperature 80°C (1 min), rate 5°C/min, final temperature of 225°C (10 min). Detection was performed with FID detector at 250°C. retention Times were as follows: toluene - 7,3 min, chlorobenzene (internal standard) of 9.4 min, S-2,3-O-isopropylideneglycerol to 10.7 min, R-2,3-O-isopropylideneglycerol - 10,9 min, ethyl ester of Z-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid with 20.4 min, ethyl ester E-R-3-(2,2-dimethyl-[1,3]dioc the olan-4-yl)acrylic acid and 22.6 min, ethyl ester E-S-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid is 22.9 min, triethylphosphate (TERA) of 25.5 minutes

The GC analysis for compounds α-(4) and β-(4) was performed using Agilent 6890 GC (EPC) and columns CP-Sil 5 CB(CP7680 (Varian) or equivalent) of 25 m and a film thickness of 5 μm, using pressure on the head of the column of 5.1 kPa, separate flow 40 ml/min and temperature of injection of 250°C. is Used, the temperature change was: initial temperature 50°C (5 min), rate 10°C/min, final temperature 250°C (15 min). Detection was performed with FID detector at 250°C. retention Time was as follows: chlorobenzene (internal standard) - 17,0 min, α-(4) - 24,9 min, β-(4) is 25.5 minutes

Example 1

Getting S-2,3-O-isopropylideneglycerol and conversion to the ethyl ester of R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid

To a well stirred suspension KIO₄(530 g, 2.3 mol, 2.3 EQ.), KHCO₃(230 g, 2.3 mol, 2.3 EQ.) in water (1200 g) was added dropwise a solution of L-5,6-O-isopropylidene-1,4-lactone (218,5 g, 1 mol) in water (135 g) and tetrahydrofuran (1145) for 3 h at 32-34°C. the Reaction mixture was stirred for 4.5 h at 32°C. According to GC oxidation was completed, because the content of S-2,3-O-isopropylideneglycerol amounted to 4.38% wt. and no longer increased. The reaction mixture was cooled to 5°C. and kept at the above-mentioned fact is the temperature value within 14 PM Solids (consisting mainly of KIO₃) was removed by filtration and the precipitate remaining on the filter was washed with tetrahydrofuran (115 ml) and another portion of tetrahydrofuran (215 ml) by resuspendable. From the filtrate (2975 g) took a sample and analyzed by quantitative¹H NMR (DMSO-d₆), who showed that the content of S-2,3-O-isopropylideneglycerol in the filtrate was 3,69% wt., which corresponded to 109.6 g (0,843 mol) and yield 84%, based on L-5,6-O-isopropylidene-1,4-lactone.

To 2953 g of the obtained filtrate (containing 108,8 g = 0,837 mol S-2,3-O-isopropylideneglycerol) at 13°C was added dropwise with stirring, triethylphosphate (TERA, 194,7 g, 97% purity, 0,843 mol, 1,01 EQ.) for 25 min at 13-17°C. Then portions were added K₂CO₃(838 g, 6,07 mol, 7,26 EQ.) for 30 min at 17-25°C. the Final pH of the reaction mixture amounted to 11.6. The reaction mixture was stirred for 17 h at 20°C. Water tertrahydrofuran ring and the phases were separated and the aqueous phase was extracted twice 660 ml of toluene. United tertrahydrofuran ring and the toluene phase was concentrated under vacuum (260-25 mbar, temperature 28-56°C) for 8 h, obtaining 175,5 g liquid light yellow color.

Quantitative¹H NMR showed the content of 78 wt.%. ethyl ester E-R-3-(2,dimethyl-[1,3]dioxolane-4-yl)acrylic acid 2.5% wt. ethyl ester of Z-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, 4,4% wt. TERA (4.1 mol.% from the original number) and 6.8 wt.%. of toluene. This represents an overall yield of ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid 141,2 g (0,706 mol), which accounted for 71% yield based on L-5,6-O-isopropylidene-1,4-lactone and 84% yield based on S-2,3-O-isopropylideneglycerol. GC showed that E.E. ethyl ester E-R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid was >99%.

Example 2

The mixture of compounds α-(4) and β-(4) of the ethyl ester of R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid using different types and amounts of the bases without releasing connection joining nitro

Example 2A

The use of DBU in the reaction joining Michael and NaOMe as an additional base in the reaction of the Nave

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid (21.2 g butter, 94.5% of wt. purity, 0.1 mol) was added nitromethane (13,0 g of 51.7% wt. solution in methanol, 0.11 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise DBU (15.2 g, 0.1 mol, 1 EQ.) for 25 min and the funnel was rinsed with methanol (1 g). The reaction mixture was heated to 20°C and stirred at the same temperature for 17 hours the resulting solution (50 g) were divided into two equal parts; one 25 g h is any further processed, as described in example 2B. Another 25 g portion was cooled to 0°C. and dropwise added NaOMe (10.0 g 29,6% wt. solution in methanol, to 0.055 mol, 1.1 EQ.) for 10 min at 0°C and the funnel was rinsed with methanol (1.6 g). The reaction mixture was stirred for 50 min at 0°C, and then extinguished in a solution of H₂SO₄(17.9 g, 96% wt., 0,175 mol, 3.5 EQ.) in methanol (30,4 g) at 0-5°C by adding dropwise for 60 min under vigorous stirring. The funnel was rinsed with methanol (2×4 g). The resulting reaction mixture was stirred for 2 h at 0°C, and then extinguished in the mix a mixture of saturated aqueous NaHCO₃(300 ml) and ethyl acetate (100 ml) at 0-5°C by adding dropwise within 15 minutes of the Final pH was 6.9. Added another portion of ethyl acetate (50 ml) and the pH was brought to 4.2 with H₂SO₄(96% wt.). After separation of the phases the aqueous phase was extracted with ethyl acetate (1×150 ml, 3×100 ml). The combined organic phases were concentrated under vacuum at 40-50°C. to obtain 8.1 g of the solid orange color. According to the quantitative analysis¹H NMR of this solid contained 4,2 g (0,026 mol) compounds α-(4) and β-(4), which corresponds to a total yield of 53%, based on the ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid. The ratio of α-(4):β-(4) was 3.1:1.

Example 2B

The use of DBU in R. the action of joining Michael and without an additional base in the reaction of the Nave

Other 25 g of the solution obtained in the reaction of joining Michael in example 2A, was cooled to 0°C and extinguished in a solution of H₂SO₄(7,8 g, 96% wt., 0,076 mol, 1.5 EQ.) in methanol (13,2 g) at 0°C by adding dropwise during 40 min under vigorous stirring. The funnel was rinsed with methanol (7.7 g). The resulting reaction mixture was stirred for 4 h at 0°C, and then processed according to the procedure of example 2A, to obtain a solid substance, which, according to quantitative analysis¹H NMR, contained 2.8 g (0,0175 mol) compounds α-(4) and β-(4), which corresponds to a yield of 35%based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid.

Example 2C

The use of TMG in the reaction joining Michael and NaOMe as an additional base in the reaction of the Nave

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid (47,5 g butter, 84.2% of wt. purity, 0.2 mol) was added nitromethane (26,0 g of 51.7% wt. solution in methanol, 0.22 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise TMG (23 g, 0.2 mol, 1 EQ.) within 20 min and the funnel was rinsed with methanol (2 g). The reaction mixture was heated to 20°C and stirred at the same temperature for 22 hours, the Solution was cooled to 0°C. and dropwise added NaOMe (40,2 g 29,6% wt. solution in methanol, 0.22 mol, 1.1 EQ.) for 15 min at 0°C and funnel prom is Wali methanol (6.4 g). After stirring for 70 min at 0°C. the mixture is put in a solution of H₂SO₄(71,6 g, 96% wt., 0.7 mol, 3.5 EQ.) in methanol (to 121.6 g) at 0-5°C by adding dropwise over 70 min under vigorous stirring. The funnel was rinsed with methanol (2×15 g). The resulting reaction mixture was stirred for 145 min at 0°C, and then extinguished in the mix a mixture of saturated aqueous NaHCO₃(1200 ml) and ethyl acetate (400 ml) at 0°C by adding dropwise within 30 minutes Final pH was 7.4. After adding another portion of ethyl acetate (200 ml) the pH was brought to 4.2 with H₂SO₄(96% wt.). After separation of the phases the aqueous phase was extracted with ethyl acetate (4×400 ml). The combined organic phases were concentrated under vacuum at 40-50°C, with the receipt of 38.5 g of solid yellow-orange color, which, according to quantitative analysis¹H NMR, contained α-(4) (12.2 g, 0,077 mol) and β-(4) (4.6 g, 0,029 mol), which corresponds to a total yield of 53%, based on the ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, and the ratio of α-(4):β-(4) of 2.7:1.

Example 2D

Use only NaOMe in reaction joining Michael in the reaction of the Nave

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid (47,5 g butter, 84.2% of wt. purity, 0.2 mol) in methanol (200 g) was added nitromethane (26,0 g 51,7% m is S. solution in methanol, 0.22 mol, 1.1 EQ.) and the solution was cooled to 0°C. was Added NaOMe (40 g 30% wt. solution in methanol, 0.22 mol, 1.1 EQ.) and the reaction mixture was stirred for 18 h at 0°C, and then extinguished in a solution of H₂SO₄(58 g, 96% wt., of 0.57 mol, 2.9 EQ.) in methanol (140 g) at-3-0°C by adding dropwise over 75 min under vigorous stirring. The reaction mixture was stirred for 4 h at 0°C and subsequently kept for 16 h at -30°C. According to the quantitative analysis¹H NMR, the total output (in the reaction mixture) of α-(4) and β-(4), based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, 45%, and the ratio of α-(4):β-(4) of 2.5:1. The reaction mixture was then extinguished in the mixed solution of NaHCO₃(80 g) in water (1 l) at 0-5°C by adding dropwise within 90 minutes By the end of the quenching solution was added NaHCO₃(4 g) in water (50 ml)to bring the pH to 5-5 .5. After separation of the phases the aqueous phase was extracted with ethyl acetate (4×500 ml) and the combined organic phases were concentrated under vacuum at 30-40°C, to obtain 32 g of oil red. According to the quantitative analysis¹H NMR of this oil contained 13,2 g (0,084 mol) of α-(4) and β-(4), which corresponds to a total yield of 42%, based on the ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, and the ratio of α-(4):β-(4) 3:1.

P the emer 3

Obtaining pure α-(4) of the ethyl ester of R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid using DBU in response accession of Michael, NaOMe as an additional base in the reaction of the Nave and crystallization of α-(4) of isopropanol

Example 3A

The use of non-improved handling procedures for

α-(4) and β-(4)

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid (42,3 g, 94.5% of wt. purity, 0.2 mol) was added nitromethane (26,0 g of 51.7% wt. solution in methanol, 0.22 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise DBU (of 30.4 g, 0.2 mol, 1 EQ.) within 20 min and the funnel was rinsed with methanol (4 g). The reaction mixture was heated to 20°C, stirred for 16.5 hours at this temperature and then cooled to 0°C. Then was added dropwise NaOMe (40,4 g 29,6% wt. solution in methanol, 0.22 mol, 1.1 EQ.) for 20 min at 0°C and the funnel was rinsed with methanol (6.4 g). The reaction solution was stirred for 50 min at 0°C, and then extinguished in a solution of H₂SO₄(71,6 g, 96% wt., 0.7 mol, 3.5 EQ.) in methanol (to 121.6 g) at 0-5°C by adding dropwise over 70 min under vigorous stirring. The funnel was rinsed with methanol (2×16 g) and the reaction mixture was stirred for 2 h at 0-2°C, and then extinguished in the mix a mixture of saturated aqueous NaHCO₃(1.2 l) and ethyl acetate (400ml) with 0-9°C by adding dropwise over 17 minutes The final pH at 7.2. The funnel was rinsed with methanol (40 ml) and the pH was brought to 4.0 using H₂SO₄(96% wt.) at 9°C. After adding ethyl acetate (200 ml) and separation of the phases the aqueous phase was extracted with ethyl acetate (600 ml, 3×400 ml). The combined organic phases were concentrated under vacuum at 40-50°C, obtaining 35,9 g of semi-solid substances yellow-orange color, which according to the quantitative analysis¹H NMR contained 16.5 g (0.104 g mol) of α-(4) and β-(4), which corresponds to a total yield of 52%, based on the ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid. The ratio of α-(4):β-(4) was 3.0:1.

Raw semi-solid product was dissolved in isopropanol (69,5 g) at 80°C. the resulting solution was cooled to 60°C, were placed in the seed and cooled further to 0°C for 2 h, which resulted in the crystallization of α-(4). The solids were isolated by filtration, washed with isopropanol (30 ml, 20°C) and dried in air, to obtain 12.0 g of crystalline product is not quite white, which according to the quantitative analysis¹H NMR consisted of 9.8 g of α-(4) (31% yield based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid) and 0.38 g of β-(4) (1,2% yield based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid). This corresponds to a yield of crystallization of 60% (expressed is denied α-(4)/[consumption of α-(4) + β-(4)]) and the ratio of α-(4):β-(4) 26:1.

Example 3B

Using enhanced processing procedure for α-(4) and β-(4)

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid (47,5 g, 84.2% of wt. purity, 0.2 mol) was added nitromethane (26,0 g of 51.7% wt. solution in methanol, 0.22 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise DBU (of 30.4 g, 0.2 mol, 1 EQ.) for 30 min at 0-20°C and the funnel was rinsed with methanol (4 g). The reaction mixture was heated to 20°C., was stirred for another 18 h at the same temperature and cooled to 0°C. Then was added dropwise NaOMe (40 g 29,6% wt. solution in methanol, 0.22 mol, 1.1 EQ.) for 20 min at 0°C and the resulting solution was stirred for 1 h at 0°C. the mixture is Then extinguished in a solution of H₂SO₄(72 g, 96% wt., 0.7 mol, 3.5 EQ.) in methanol (72 g) at 0-5°C by adding dropwise within 3 h with vigorous stirring. The reaction mixture was stirred for another 2 h at 0-5, and then extinguished in the stirred suspension KHCO₃(99 g) in water (200 ml) at 0-5°C by adding dropwise within 1 h of the Final pH was 4.1. After warming to 20°C. the salt was removed by filtration and washed with ethyl acetate (500 ml). The aqueous mother liquor filtrate (454 g) was concentrated under vacuum at 35°C. to remove methanol, to the final weight 272 g and were extracted with ethyl acetate (6×500 ml; the first portions of promanagement after filtration of the salts, then fresh). The combined organic phases were concentrated under vacuum at 40-50°C, with the receipt of 40.4 g of solid, which according to GC contained 14.5 g of α-(4) and 3.4 g of β-(4), which corresponds to a total yield of 57%, based on the ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid and the ratio of α-(4):β-(4) of 4.3:1.

Raw solid product was dissolved in ethyl acetate (300 ml) and the solution washed with saturated aqueous NaCl (25 ml) and water (10 ml). The organic layer, which, according to GC contained 14.1 g of α-(4) and 3.4 g of β-(4), concentrated under vacuum, obtaining 42,4 g muddy solids. To 38 g of the specified raw product was added isopropanol (62 g) and the solid was dissolved by heating to 60°C. the resulting solution was cooled to 50°C, were placed in the seed and cooled further to 0°C for 2 h, which resulted in the crystallization of α-(4). The solids were isolated by filtration, washed with isopropanol (2×20 ml, 0°C) and dried in air to obtain 12.9 g of crystalline product is not quite white, which according to GC contained 12.2 g of α-(4). This corresponds to 39% yield based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid) and output crystallization 78% (production of α-(4)/[consumption of α-(4) + β-(4)]). β-(4) could not be found.

Example 4

Obtaining pure α-(4) of this is viewed in ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid by crystallization of α-(4), the epimerization of β-(4) and the second crystallization of α-(4)

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid (42,3 g, 94.6% wt. purity, 0.2 mol) was added nitromethane (26,0 g of 51.7% wt. solution in methanol, 0.22 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise DBU (of 30.4 g, 0.2 mol, 1 EQ.) for 30 min at 0-20°C and the reaction mixture was heated to 20°C and was stirred for another 18 h at the same temperature. The reaction mixture was cooled to 0°C. and dropwise added NaOMe (40 g 29,6% wt. solution in methanol, 0.22 mol, 1.1 EQ.) at 0°C. the resulting solution was stirred for 1 h at 0°C and extinguished in a solution of H₂SO₄(72 g, 96% wt., 0.7 mol, 3.5 EQ.) in methanol (72 g) at 0-5°C by adding dropwise during 1.5 h with vigorous stirring. The reaction mixture was stirred for 2 h at 0-5°C, and then extinguished in the stirred suspension NaHCO₃(100 g), water (400 ml) and ethyl acetate at 0-5°C by adding dropwise within 1 h In parts was added NaHCO₃(40 g)to maintain the pH value above a 3.5. Salt was removed by filtration at 0-5°C and washed with ethyl acetate (300 ml). After separation of the phases the aqueous phase was extracted with ethyl acetate (300 ml wash liquid after filtration of the salts, 3×150 ml of fresh). The combined organic phase was concentrated under vacuum, was added ethyl acetate (200 ml) and see what camping was concentrated under vacuum again obtaining a 33.2 g of semi-solid substances, which according to the quantitative analysis¹H NMR contained 13.5 g of α-(4) and 4.0 g of β-(4), which corresponds to the total output, based on the ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, 53% and the ratio of α-(4):β-(4) of 3.5:1.

The raw product was dissolved in isopropanol (70 g) at 60°C. the resulting solution was cooled to 50°C, were placed in the seed and cooled further to 0°C, which led to the crystallization of α-(4), which was isolated by filtration, washed with cold (0°C.) isopropanol (2×15 ml) and dried in the air. Received 12.3 g of α-(4), which, according to quantitative analysis¹H NMR was clean for 97.1% of wt. and did not contain β-(4). This corresponds to the (first collection) 38% yield based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid) and output crystallization 68% (production of α-(4)/[consumption of α-(4) + β-(4)]).

The combined mother liquor and wash liquid after the first crystallization (108 g, containing 4.0 g of β-(4) and 1.2 g of α-(4)) was concentrated under vacuum to 17.9 g of liquid. Subsequently was added methanol (9,05 g) and MeSO₃H (0,91 g, 0,29 EQ.) and the mixture is boiled under reflux. After 2 hours boiling under reflux the epimerization reaction was completed (the ratio of α-(4):β-(4) >3). After cooling to 20°C was added triethylamine (0.96 g, 1 EQ., based on MeSO₃

The residue was re-dissolved in isopropanol (13,9 g) at 50°C. After cooling to 45°C and the mixture was placed the seed and cooled to 0°C, leading to crystallization of the compound α-(4), which was isolated by filtration, washed with cold (0°C.) isopropanol (2×6 ml) and dried in the air. This gave 2.24 g of α-(4), which according to the quantitative analysis¹H NMR was clean for 95.3% of the wt. and did not contain β-(4). This corresponds to the (second collection) 6% yield based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, and the output of crystallization 43% (production of α-(4)/[consumption of α-(4) + β-(4)] after epimerization). Thus, the total yield of α-(4) (the first and the second collection), based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, amounted to 44%.

Example 5

Crystallization of α-(4), starting with the raw mixtures of α-(4) and β-(4) of solvents other than isopropanol

Example 5A

From tert-butanol

The raw mixture (6.5 g) of α-(4) and β-(4)obtained in example 2A (containing 3,37 g of α-(4) + β(4) in a ratio of 3.1:1) was dissolved in tert-butanol (16 g) at 72°C. Cooling to 55°C, making the seed and further cooling to 25°C resulted in the crystallization of α-(4), which was isolated by filtration, washed with isopropanol (5 ml, 20°C) and dried under vacuum. This gave compound α-(4) (1.85 g)that if the natural enemy analysis ¹H NMR was clean $ 82.9 wt.%, which corresponds to the output of crystallization 46% (production of α-(4)/[consumption of α-(4) + β-(4)]) with a ratio of α-(4):β-(4) 30:1.

Example 5B

Of tert-amyl alcohol

The raw mixture of 7.25 g) α(4) and β-(4) (containing 3,44 g of α-(4) + β(4) in a ratio of 2.9:1) was dissolved in tert-amyl alcohol (15.7 g) at 70°C. Cooling to 60°C, making the seed and further cooling to 40°C did not lead to crystallization. After depositing the seed at 40°C. the solution was further cooled and crystallization of α-(4) started at 27°C. the Mixture was then cooled to 2°C and the crystals of α-(4) were isolated by filtration, washed with tert-amyl alcohol (7.5 ml, 20°C) and dried under vacuum. This gave 2.35 g of the product is not quite white, which according to the quantitative analysis¹H NMR consisted of 1,91 g of α-(4) and 0.11 g of β-(4), which corresponds to the output of crystallization 59% (production of α-(4)/[consumption of α-(4) + β-(4)]) and the ratio of α-(4):β-(4) 18:1.

Example 6

Crystallization of pure α-(4) of a mixture of α-(4) and β-(4) with the simultaneous epimerization of β-(4)

A solution of α-(4) light brown (5.0 g, 96.6 percent wt. the purity of 30.6 mmol, did not contain β-(4)) and MeSO₃H (0.3 g, 0.1 EQ.) in methanol (200 ml) was stirred at 20°C for 92 h, which resulted in epimerization to the ratio of α-(4):β-(4) of 3.6:1. The reaction mixture was then concentrated under vacuum (20 mbar; 45°C) the obtaining of 5.2 g of a sticky solid. The latter was placed in methanol (50 ml) and again concentrated under vacuum (20 mbar; 50°C) with the receipt of 5.1 g of dry solids in a light brown colour, which according to the quantitative analysis¹H NMR contained α-(4) with a purity of 90% wt. (4.6 g, 29 mmol). β-(4) could not be found. Thus, almost all (96%) of the original α-(4) was restored.

Example 7

Obtaining pure α-(4) of the fresh S-2,3-O-isopropylideneglycerol using improved procedures and crystallization of α-(4), the epimerization of β-(4) and the second crystallization of α-(4)

To 175 g of ethyl ester E-R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid obtained as described in example 1 (78% wt. purity, to 136.5 g of 0.68 mol) was added nitromethane (88,6 g of 51.7% wt. solution in methanol, 0.75 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise DBU (103,4 g of 0.68 mol, 1 EQ.) for 35 min at 10-21°C and the funnel was rinsed with methanol (7 g). After stirring for 18 h at 20°C. the resulting solution was dark red color was cooled to 0°C. and dropwise added NaOMe (134,6 g of 30% wt. solution in methanol, 0,748 mol, 1.1 EQ.) for 35 min at 0°C and the funnel was rinsed with methanol (10 g). After stirring for 30 min at 0°C. the reaction mixture was extinguished in a solution of H₂SO₄(243 g, 96% wt., 2,38 mol, 3.5 EQ.) in methanol (243 g) at 0-5°C by adding paraply for 3 h with vigorous stirring and the funnel was rinsed with methanol (2×15 g). After stirring for 2 h at 0-2°C. the reaction mixture was extinguished in stirred suspension of knso₃(353 g) in water (680 ml) at 0-6°C by adding dropwise over 1 h To the end of clearing the pH was 7 and it was brought to 4.1 using H₂SO₄(96% wt.) at 0°C. After warming to 20°C. the salt was removed by filtration and washed with ethyl acetate (3×375 ml). The wash liquid is later used for extraction. Uterine fluid filtrate (1380), which according to GC contained is 3.08% wt. α-(4) and 0.82 wt.%. β-(4) (which corresponds to the total output, based on the ethyl ether E-R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, 50%, and the ratio of α-(4):β-(4) of 3.75:1), concentrated under vacuum to remove methanol. To the obtained residue (760 g) was added water (80 g) and the pH was brought to 4.1 using H₂SO₄(96% wt.). The resulting aqueous solution was extracted with ethyl acetate (700 ml, 4×500 ml). The combined organic phases were concentrated under vacuum at 35-40°C. to 181 g of residue. Volatile substances together evaporated 3× with isopropanol (2×140 g and 90 g), with the remainder (146 g), consisting of a raw mixture of α-(4) + β-(4).

The raw mixture (146 g) was dissolved in isopropanol (202 g) at 70°C. Insoluble material was removed by filtration and washed with isopropanol (5 ml); the weight after drying was 0,33, Phil is spending (346 g) was cooled to 50°C, that led to spontaneous crystallization of α-(4). The suspension was then cooled to 1°C for 4 h and the crystals were isolated by filtration, washed with isopropanol (2×100 ml, 0°C) and dried under vacuum for 17 h at 35°C, to obtain the crystalline product is not quite white (44,2 g). According to the quantitative analysis of GC it consisted of 89,0% wt. α-(4) and 1.0% wt. β-(4), which corresponds to a total yield of 37%, based on the ethyl ether E-R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, and the ratio of α-(4):β-(4) 89:1.

The mother liquor and the washing liquid after the first crystallization of α-(4) (a total of 374 g) was concentrated under vacuum to 90.8 g, was added methanol (120 ml) and the resulting mixture was concentrated to 83, again, was added methanol (120 ml) and the mixture was concentrated to 83, To the residue was added methanol (45 g) and MeSO₃H (2.66 g, 0,0277 mol, 0.2 EQ., based on the total number of α-(4) + β-(4)present in the mother solution and rinsing liquids), and the solution boiled under reflux. After 1 h the boil under reflux (60-65°C) GC showed the completion of the epimerization (the ratio of α-(4):β-(4) was 3.1:1) and the solution was cooled to 33°C, neutralized with triethylamine (2,94 g of 1.05 EQ., based on MeSO₃H) and then concentrated under vacuum. In the obtained residue was added isopropanol (120 ml) and the mixture was concentrated in conditions the vacuum to obtain 88 g of residue.

The residue was dissolved in isopropanol (37 g) at 47°C. the resulting solution was cooled to 2°C for 2.5 h; crystallization began spontaneously at 30°C. the Crystalline product is isolated by filtration, washed with isopropanol (3×20 ml, 0°C) and dried under vacuum for 17 h at 35°C) to give 10.1 g of a crystalline white product, which according to GC consisted of 96,4% wt. α-(4) and 0,065% wt. β-(4), which corresponds to the total output, based on the ethyl ether E-R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, 9%, and the ratio of α-(4):β-(4)>1000:1.

Thus, the overall output of the first and second collection of α-(4), based on ethyl ether E-R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid, amounted to 46%.

Example 8

Obtaining pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol of the intermediate α-(4)

To a solution of intermediate compound α-(4) (180 mol, 30 kg) in tetrahydrofuran (160 kg) was added over 30 minutes lithium borohydride (1.1 EQ., 198 mol, 43,1 kg of a solution of 10% lithium borohydride in tetrahydrofuran). The reaction mixture was heated to 50°C for 1 hour and stirred at this temperature for another 2 hours. The resulting suspension was cooled to -10°C. and for 4 hours was added hydrochloric acid (1.2 EQ. relatively LiBH₄, 238 mol, 27.2 kg) 32% hydrochloric acid), maintaining the internal temperature <-5°C. N the after stirring at -10°C. for 2 hours was added triethylamine (1.1 EQ. relatively Hcl, 261 mol, 26,5 kg) for one hour while maintaining the internal temperature <0°C. was Prepared by the solvent, running on the system "phase switch" with the ethyl acetate by distillation of the solvents under atmospheric pressure to a residual content of CA. 100 kg, add ethyl acetate (360 kg) and additional distillation of a solvent mixture of tetrahydrofuran/ethyl acetate with continuous addition of ethyl acetate to maintain a constant volume. The procedure continued until the establishment of the ratio of tetrahydrofuran/ethyl acetate = 4:1 (with confirmation by gas chromatography). The resulting mixture was cooled to 0°C, filtered and formed on the filter cake was washed with two portions of ethyl acetate (2×30 kg). The collected filtrate was evaporated to obtain the target product (18 kg).

Example 9

Obtaining pure α-(4) of the ethyl ester of R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid by direct crystallization of α-(4) of the raw mixture of β-(4) and α-(4) and simultaneous epimerization of β-(4) α(4)

To ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl) acrylic acid (399,5 g, 75.1% of wt. purity, 1.5 mol) was added nitromethane (915,0 g 11% wt. solution in methanol, of 1.65 mol, 1.1 EQ.) and the solution was cooled to 0°C. Then was added dropwise DBU (233,3 g, 1.5 mol, 1 EQ.) during 50 min at 0-5°C and the reaction Messageware to 20°C and was stirred for another 16 h at the same temperature. The reaction mixture was cooled to 0°C. and dropwise added NaOMe (594,0 g of 15 wt.%. solution in methanol, of 1.65 mol, 1.1 EQ.) for 50 min at 0°C. the resulting solution was stirred for 1 h at 0°C and extinguished in a solution of H₂SO₄(368 g, 96% wt., 3.6 mol, 2.4 EQ.) in methanol (370 g) at 0-5°C by adding dropwise within 3 h with vigorous stirring. The reaction mixture was stirred for 2 h at 0-5°C, and then extinguished in stirred suspension of knso₃(457,6 g) in water (870 ml) at 0-5°C by adding dropwise within 1 h In parts was added knso₃to maintain the pH value above a 3.5. The formed salt was removed by filtration at 0-5°C and washed with methanol (530 ml). After concentration under vacuum the combined filtrate and washings to approximately 1000 ml of the aqueous phase was extracted with toluene (2×2100 ml, 3×1050 ml). The combined organic phases were concentrated under vacuum to obtain 202,9 g of semi-solid substances.

Then added methanol (42.6 g) and S₃N (6,06 g of 0.04 EQ.) and the mixture was heated to 50°C. After stirring for 2 h at the same temperature, the mixture was cooled to 20°C. and stirring continued for a further 12 hours After cooling to -5°C was added triethylamine (6.60 g, 1.1 EQ., based on S₃N) and the mixture was stirred for another 2 h Crystalline α-(4),which were isolated by filtration, washed with cold (-5°C) isopropanol (3×70 ml) and dried in the air. This gave to 120.0 g of α-(4), which, according to quantitative GC analysis, it was clean at a 99.0% wt. and contained 0,09% wt. β-(4). This corresponds to 51%yield based on ethyl ether R-3-(2,2-dimethyl-[1,3]dioxolane-4-yl)acrylic acid.

1. The way to obtain (3R,3S,6R)hexahydrofuro[2,3-b]furan-3-ol, having the structural formula (6)

including the stage of recovery of the intermediate compounds of formula α-(4)

the target product of the formula (6).

2. The method according to claim 1 which further includes the crystallization of the intermediate α-(4) using the solvent until it is restored.

3. The method according to claim 1 or 2 which further includes
a) obtaining the intermediate of formula α-(4) by epimerization with acid intermediate compounds of the formula β-(4)

and
b) crystallization of the intermediate α-(4) using the solvent until it is restored.

4. The method according to claim 3, which further includes after crystallization of the intermediate α-(4)
a) the acid epimerization of the intermediate compounds of formula β-(4) in the mother solution phase crystallization in the intermediate compound of formula α-(4)

and
b) crystallization of the intermediate α-(4) using the solvent until it is restored.

5. The method according to any of PP or 4, in which the epimerization of the compounds of formula β-(4) in the compound of formula α-(4) and crystallization of the compound α-(4) hold simultaneously.

6. The method according to claim 5, in which the simultaneous epimerization of the compounds of formula β-(4) in the compound of formula α-(4) and crystallization of the compound α-(4) is carried out in methanol in the presence of acid by evaporation or partial evaporation of methanol.

7. The method according to any of claim 2 to 6, additionally including
a) the stage of obtaining a mixture of epimeres formula (4)

by treating the compounds of formula (3) with a base followed by treatment with an acid in the presence of methanol

where R₁and R₂each independently represents hydrogen, hydroxy-protective group, or may together form vicinal-diol-protective group,
R₁represents alkyl, aryl or aralkyl;
to obtain the intermediate compounds of formula (4)

and (b) the stage of recovery of the intermediate compounds of formula α-(4) regenerating agent and the reaction of intramolecular cyclization to obtain the compounds of formula (6)

9. The method according to claim 8, in which the compounds of formula (2) is obtained by condensation of intermediate compounds of formula (1) or its hydrate, hemihydrate, or a mixture thereof with phosphonates of formula (R⁶O)₂P(=O)-CH₂-C(=O)OR¹where
P₁and R₂defined in claim 2,
R₁defined in claim 2,
R₆represents alkyl, aryl or aralkyl

10. The method according to any of claims 7 to 9, in which R₁and R₂together form a radical dealkylation.

11. The method according to claim 8, in which the base used for the conversion of compounds of formula (2) in the compounds of formula (3)represents (1,8-diazabicyclo[5.4.0.]undec-7-ene)(DU) or (1,1,3,3-tetramethylguanidine)G) or their derivatives.

12. The method according to claim 9, in which the phosphonate of the formula (R⁶O)₂P(=O)-CH₂-C(=O)OR¹is triethylphosphate (TERA).

13. The method according to claim 7, in which the conversion of compounds of formula (3) in the compounds of formula (4) is carried out using a base selected from the group consisting of sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof.

14. The method according to any of PP or 11, in which the conversion of compounds of formula (2) in the compounds of formula (4) assests who are using DBU or TMG as the basis for the conversion of compounds of formula (2) in the compounds of formula (3), without the allocation of the compounds of formula (3) and using sodium methoxide or lithium as additional grounds for the conversion of compounds of formula (3) in the compounds of formula (4).

15. The method according to any of claims 7, 13 and 14, in which the acid used for the conversion of compounds of formula (3) in the compounds of formula (4)represents a concentrated sulfuric acid in an amount of from 2.5 to 5 equivalents based on the compound of the formula (2) in the form of 20-80 wt.% solution in methanol.

16. The method according to any one of claims 1 to 15, in which the crystallization of the compounds of formula α-(4) is carried out in alcohol.

17. The method according to clause 16, in which the alcohol is a isopropanol, tert-amyl alcohol or tert-butanol.

18. The method according to any of claims 4 to 7, in which the epimerization of the compounds of formula β-(4) in the compound of formula α-(4) is performed with the use of 0.05 to 1.5 equivalents SO₃N in methanol.

19. The method according to any of claims 4 to 7, in which the epimerization is carried out at a temperature from 40°C to the boiling temperature under reflux.

20. A method of converting compounds of the formula β-(4) in the compound of formula α-(4), which includes the epimerization acid

21. The method according to claim 20, in which the epimerization of the compounds of formula β-(4) in the compound of formula α-(4) is performed with the use of 0.05 to 1.5 equivalents S₃H in methanol.

22. The method according to claim 20 or 21, in which the epimerization is carried out at a temperature of 40°C and the boiling point under reflux.

23. Intermediate compound having the formula α-(4)described in item 3.

24. The intermediate compound with the formula β-(4)described in item 3.

25. The intermediate compound according to item 23 in crystalline form.