Methods of producing hexahydrofuro[2, 3-b] furan-3-ol

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula (V) which can be used in pharmaceutical industry . The method involves reaction of a compound of formula (II) with a compound of formula (III) in the presence of a titanium salt of formula Ti(Hal)_n(OR)_4-n, where Hal is a halogen radical, n equals 0, 1, 2 or 3, R is an alkyl or arylalkyl, and subsequent reaction of the reaction product with an alcohol of formula (IV), where R¹ and R² denote alkyl or arylalkyl, where the aryl is phenyl or naphthyl.

EFFECT: novel efficient method of producing compounds of the given formula using novel intermediate compounds is disclosed.

16 cl, 9 ex

The present invention relates to methods for hexahydrofuro[2,3-b]furan-3-ol and especially its enantiomer (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, as well as some new intermediate products for use in such methods.

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-oxyradical is an important part pharmacological present in the structure of retroviral protease inhibitors, such as inhibitors described Glosh et al. in J. Med. Chem. 1996, 39(17), 3278-3290 and inhibitors described in WO 95/24385, WO 99/65870, WO 99/67254, WO 99/67417, WO 00/47551, WO 00/76961, WO 01/25240, US 6127372 and EP 0715618. These publications is incorporated herein by reference. One such protease inhibitor that is approved in the US for clinical use in the treatment of retroviral infections in humans and has the above structural part, is a compound that has allowed USAN name darunavir and chemical name (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-silt ether [(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](2-methoxypropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamino acid and the structure of the formula (And)

An important precursor in the synthesis of protease inhibitors described above and containing hexahydrofuro[2,3-b]furan-3-oxyradical, is the connection hexahydrofuro[2,3-b]furan-3-ol of the formula (I)

Despite the fact that what hexahydrofuro[2,3-b]furan-3-ol has three stereogenic center and theoretically there should be eight different stereoisomers, believe that there are only four stereoisomer. This is due to the rigidity of the structure of the bicyclic ring hexahydrofuro[2,3-b]furan-3-Ola, which makes him the TRANS-condensed isomers to be thermodynamically unfavorable. Only the stereoisomers having the CIS-condensed configuration, are thermodynamically stable, reducing the number of stereoisomers hexahydrofuro[2,3-b]furan-3-ol to endo - and Exo-diastereoisomer, and each comprises a pair of enantiomers, as shown below

More specifically, for obtaining such protease inhibitors containing enantiomeric (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-oxyradical, such as the protease inhibitor darunavir, related to the above (3R,3aS,6aR)-enantiomer of formula (Ia), is especially applicable

Due to the potential importance of the above protease inhibitors and the resulting need for the production of these compounds on a commercial scale, in the literature there have been numerous suggestions on ways you can get the above compounds of formulas (I) and (Ia).

Many of these proposals were included on the education structure of bicyclic besturen, from acyclic precursors, for example including intermediate education lactoovo the intermediate and then the recovery and cyclization of such methods, as the methods of preparation, are described in WO 03/022853, US 2004/0162340, WO 2004/033462, US 6867321, WO 2005/095410, and Ghosh et al., J. Org. Chem. 2004, 69, 7822-7829. These methods include a relatively large number of stages, and in some cases education nitromethylene intermediate compounds, requiring the use of nitromethane, which is harmful reagent. Another approach, described in WO 02/060905, involves the reaction of 2,3-dihydrofuran with alkylphosphonyl with the formation of a derivative of 2-alkyloxyaryl, which then cyclist in the presence of radiation. The use of radiation, however, is unsuitable for practical application of the method on an industrial scale. The use of radiation is also required in the method described in WO 03/024974, in which the furan is subjected to reaction with a carbonyl derivative in the presence of radiation. In WO 2004/002975 described method coming from 2,3-dihydrofuran, which is subjected to the reaction, for example, with harpokrates ether to effect the introduction of glyoxylate group at the 3-position of the furan ring and then restore with the formation of 1,2-dihydroxyethylene side chain and subsequent processing, for example, halogenides the m agent with the formation of compounds 3A-halogenerator[2,3-b]furan-3-ol, then restore. This method also has the disadvantage that require multiple steps when receiving from the source of furan, which is uneconomical for industrial scale.

A similar approach is proposed by Ghosh et al. in Tetrahedron Letters 40 (1999) 1083-1086, comprising the reaction of 2,3-dihydrofuran with acylglycerol and titanium tetrachloride to obtain the intermediate oxonium ion, which is then subjected to reaction with a nucleophile, while receiving derivatives of 3-(β-carboethoxy-α-hydroxymethyl)-2-substituted tetrahydrofuran. Examples of such nucleophiles include semiprozine and methanol. In only described example, the mixture of ethylglycol and 2,3-dihydrofuran in dichloromethane was added to a solution of titanium tetrachloride in dichloromethane at -78°C and was stirred for one hour. To the mixture at -78°C was added allyltrimethylsilane and the resulting mixture was stirred at a temperature of from -78°C to 23°C for one hour. The reaction extinguished aqueous solution of sodium bicarbonate and was extracted with ethyl acetate and the combined organic layers were dried, concentrated and then purified flash chromatography. This method suffers from some drawbacks, such as very low reaction temperature -78°C, which is almost impossible for the reaction to industrial scale is A. In addition, the authors of the present invention found that the use of the method with titanium tetrachloride, described by Ghosh et al., causes problems in subsequent processing to ensure effective removal of compounds of titanium, and the removal of the titanium salt is essential to avoid impurities and adverse reactions in the subsequent stages.

The objective of the invention is the provision of a new and improved synthesis for the preparation of hexahydrofuro[2,3-b]furan-3-ol. An additional object of the invention is the provision of such a synthesis, which apply easily accessible and cheap source connection and applied reaction conditions, which are easily achievable by synthesis on an industrial scale. An additional object of the invention is the provision of a suitable method of obtaining derivatives of 3-(β-carboethoxy-α-hydroxymethyl)-2-substituted tetrahydrofuran and their analogues. An additional object of the present invention is the provision of new and suitable intermediate products which are applicable in the synthesis of hexahydrofuro[2,3-b]furan-3-ol. The next task of the invention is to provide a new and improved synthesis of (3R,3aR,6aR)-hexahydrofuro[2,3-b]furan-3-ol, applicable when receiving antiretroviral protease inhibitors.

Found that the use of certain salts ti is Ana, different from the titanium tetrachloride used Ghosh et al. in the above-described method offers several advantages described below. The authors of the present invention has also been found that purification of the crude product 3-(β-carboethoxy-α-hydroxymethyl)-2-substituted tetrahydrofuran can be improved by the use of some agents such as water-soluble complexing agents (for example, Rochelle salt or diethanolamine), for damping the reaction and removal of salts of titanium, which can be harmful to subsequent stages. Thus, the use of water-soluble complexing agent instead of sodium bicarbonate, described by Ghosh et al., leads to a significant improvement in the quality of the resulting product.

Application of the above method and the subsequent conversion of the resulting product, 3-(β-carboethoxy-α-hydroxymethyl)-2-substituted tetrahydrofuran provides a suitable synthetic route for obtaining hexahydrofuro[2,3-b]furan-3-ol and (3R,3aR,6aR)-enantiomer with a relatively small number of stages compared with the methods of the prior art and using low-cost raw materials and the reaction conditions that ensure the final product and intermediate products in good yield and purity.

According to one distinctive feature of nastoyascheevremya the authors of the invention, a method for obtaining compounds of formula (V), which comprises the reaction of 2,3-dihydrofuran formula (II) with a derivative of glyoxylate formula (III) in the presence of a titanium salt of the formula Ti(Hal)_n(OR)_4-nin which Hal represents a halogen radical, n is 0, 1, 2 or 3 and R represents an alkyl or arylalkyl, and subsequent reaction of the resulting reaction product with an alcohol of the formula (IV) with the formation of the compounds of formula (V)

in which R¹represents an alkyl or arylalkyl and R²represents an alkyl or arylalkyl.

Derived glyoxylate formula (III) is preferably a compound in which R¹represents a C_1-4alkyl group, especially ethyl group, or phenyl-C_1-4alkyl group, especially a benzyl group. Salt of titanium is preferably the salt of the formula Ti(Hal)_n(OR)_4-nin which Hal represents a chlorine atom or bromine, especially chlorine atom, and R represents a C_1-4alkyl group, for example through group, preferably ISO-propyl group, or arylalkyl group, for example phenyl-C_1-4alkyl group, especially benzyl, and n is 1 or 2, especially 2; in particular, the preferred salt of titanium for use according to the present invention is TiCl₂(OiPr)₂. It will be clear that such titanium salt mo the ut to be formed in situin the reaction mixture, for example, by reaction of a suitable titanium halide with a suitable connection Ti(OR)₄. Formed by the specific salt will depend on the number of connections Ti(OR)₄added to the halide of titanium, for example, adding one-third of the equivalent compound Ti(OR)₄will lead to the formation of compound TiHal₃(OR). The above preferred salt TiCl₂(OiPr)₂you can get thein situthe addition of TiCl₄and Ti(OiPr)₄to the reaction mixture. The method of obtaining the above connection TiCl₂(OiPr)₂described Mikami et al., J. Am. Chem. Soc., 1990, 112, 3949-3954. The method of obtaining TiCl(OiPr)₃described by Reetz et al., Chemische Berichte, 1985, 118, 1421-1440. Similarly, you can obtain other compounds of the formula Ti(Hal)_n(OR)_4-n.

Found that usually requires the presence of at least one group Hal in connection titanium, because the way how it was discovered, is less effective if you use a compound of the formula Ti(OR)₄. In connection titanium n therefore, preferably is 1, 2 or 3. The compound of the formula Ti(OR)₄usually used in combination with titanium tetrachloride to form a compound of the formula Ti(Hal)_n(OR)_4-nin which n is 1, 2 or 3.

Found that the application of the above titanium compounds is particularly suitable compared to Ter the chloride of titanium, used Ghosh et al., since the latter salt is unstable, corrosive liquid, whereas the titanium compounds used in the method according to the invention are generally stable solids, and therefore much more suitable for use with an industrial way. Also, found that the use of titanium tetrachloride described by Ghosh et al., leads to unacceptably high residual amounts of titanium by-products in the reaction mixture, which can cause a later stage of the synthesis hexahydrofuro[2,3-b]furan-3-ol not be holding or have very low outputs.

The alcohol of formula (IV) is preferably_1-4alkanol, such as methanol, ethanol or propanol, especially isopropanol, or phenyl-C_1-4alkanol, such as benzyl alcohol.

As the initial reaction of 2,3-dihydrofuran with derivative glyoxylate and subsequent reaction with an alcohol of the formula (IV) is usually carried out in an organic solvent, preferably an aprotic solvent such as dichloromethane, ethyl acetate, 1,2-dichloroethane, tetrahydrofuran (THF), or a 2-methyltetrahydrofuran.

These reactions are suitably carried out at a temperature of at least -20°C, preferably at least -10°C. and especially at least -5°C, preferably is conducted at room temperature. The use of such temperatures is in contrast with the use of temperature -78°C, described by Ghosh et al. in Tetrahedron Letters to the method specified above. First, more elevated temperatures used according to the present invention, are significantly more suitable for carrying out the method on an industrial scale.

Another advantage of the method according to the invention in comparison with the method described by Ghosh et al., as was found by the authors of the present invention is that the connection of titanium can be used in less than stoichiometric amount, for example 0.5 equivalent or less, whereas in method Ghosh requires the use of an equivalent amount of the titanium compounds. The use of smaller quantities of titanium is more cost-effective and causes fewer side products that you want to delete, and the way the authors of the invention is therefore suitable from the point of view of environmental protection.

After completion of the reaction with the alcohol of formula (IV), the reaction mixture is usually treated with an alkaline reagent to absorb or termination of any additional reactions and formation of side products, and the alkaline reagent usually provides pH 8-11, preferably about 10. In the method of Ghosh et al. (Tetrahedron Letters) for damping the reaction is used an aqueous solution of bicarbonate soda who I am. However, the inventors found that the use of water-soluble complexing agent as an alternative quenching reagent provides significantly improved handling. As water-soluble complexing agent can be used as ionic compounds, such as signatory salt (tartrate tetrahydrate sodium-potassium), and neutral organic molecules, such as diethanolamine. So, the addition of Rochelle salt or diethanolamine in an aqueous solution to the organic reaction mixture obtained in the above way, quench the reaction and allows any residual connection titanium easily separated in the aqueous phase and leaves the organic phase containing the desired compound of formula (V), which usually contains less than 5 ppm of titanium compounds. The resulting compound of formula (V) obtained as a mixture of stereoisomeric forms and can be used as such for the next stage in the synthesis hexahydrofuro[2,3-b]furan-3-ol.

The above method, starting with 2,3-dihydrofuran, provides the desired compounds of formula (V) with high or even quantitative outputs and good quality with the use of reagents that are readily available from commercial sources, and reaction conditions that can be applied on an industrial scale.

Term is n "alkyl" alone or in combination with any other term includes, except when specified otherwise, to a saturated aliphatic hydrocarbon radical with unbranched or branched chain, or in the case when there is at least three carbon atoms, a cyclic saturated aliphatic hydrocarbon radicals containing 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, or more preferably 1-4 carbon atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "aryl", alone or in combination with any other term, refers to carbocyclic aromatic part and includes monocyclic, bicyclic and other polycyclic radicals. Examples of aryl radicals include, but are not limited to, phenyl and nattily radicals.

The term "halogen" refers to fluorine atom, chlorine, bromine or iodine.

The term "stereoisomeric forms used here, defines all possible isomers formed from the same atoms connected in the same sequence of relationships, but having different three-dimensional structures that are not aplaycasinogameh, which may have compound of the present invention. If not specified or not specifically mentioned, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, which may be of the specified connection. This mixture may contain all of the diastereomers and/or enantiomers of the basic molecular structure of the compounds. It is assumed that, except when otherwise noted, all stereoisomeric forms of the compounds used in the present invention, as in the pure (individual) form or in mixture with each other, included in the scope of the present invention.

Pure stereoisomeric forms of these compounds, i.e. when you specify a specific stereoisomeric form, is defined as isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate products having a stereoisomeric excess of at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomer) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and no other isomer), more specifically, compounds having a stereoisomeric excess of 90% to 100%,even more specifically, having a stereoisomeric excess of from 94% to 100%, and most specifically, having a stereoisomeric excess of from 97% to 100%.

Pure stereoisomeric forms of these compounds can be obtained by applying known in this field techniques. For example, the enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, the enantiomers can be divided chromatographic methods using chiral stationary phases. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds stereoselective. If you want a specific stereoisomer, the specified connection is preferably synthesized by stereoselective methods of getting. In these methods are mainly applied enantiomerically pure source materials.

The resulting compound of formula (V)obtained above, can be applied at the next stage of the synthesis hexahydrofuro[2,3-b]furan-3-ol without division or allocation of its stereoisomers.

The above compounds of formula (V), except for those compounds in which R¹represents methyl or ethyl and R²is the Wallpaper methyl, are new compounds, and therefore, the inventors proposed as an additional characteristic of the invention the compounds of formula (Va)

and their stereoisomeric forms and racemic mixtures,

in which R¹represents an alkyl or arylalkyl and R²represents an alkyl or arylalkyl, provided that when R²represents methyl, R¹is not the stands or ethyl. R¹preferably represents C_1-4alkyl group such as propyl, especially isopropyl, or phenyl-C_1-4alkyl group, especially a benzyl group. R²preferably represents C_1-4alkyl group such as ethyl or propyl, especially isopropyl, or phenyl-C_1-4alkyl group, such as benzyl. The compounds of formula (V)in which R¹represents ethyl or methyl and R²represents methyl, described by Ghosh et al. in Tetrahedron Letters 40 (1999) 1083-1086, above.

The compounds of formula (V) are thus applicable as intermediates in obtaining the compounds of formula (I). Especially applicable compound of formula (V) is acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate.

According to an additional characteristic of the present invention the inventors have proposed a way to floor the treatment of compounds of formula (VI), which includes the restoration of the compounds of formula (V) with the formation of the compounds of formula (VI)

The recovery of the compounds of formula (V) is usually carried out using hydride reducing agent, such as alkali metal borohydride such as lithium borohydride, sodium borohydride, potassium borohydride, acetoxyvalerenic sodium, triacetoxyborohydride sodium or cyanoborohydride sodium, reducing agent-based aluminum hydride, such as sociallyengaged, DibalH (diisobutylaluminium) or hydride aluminum, or zinc borohydride. Alternatively, the recovery can be performed by catalytic hydrogenation. The hydrogenation can be carried out with the use of a heterogeneous catalyst, such as activated Nickel catalyst, such as catalyst, commercially available from Degussa as IN 111W, activated Nickel catalyst doped with molybdenum or a combination of chrome/iron, such as catalyst, commercially available from Degussa as VK 113W, or activated copper catalyst, such as catalyst, commercially available from Degussa as W. The hydrogenation can also be carried out with the use of a homogeneous catalyst, such as ruthenium, according to the method of Milstein, ACIE 2006, 45, 1113. Recovery can also be performed by hydrosilation, for example, with p the physical alteration of polymethylhydrosiloxane (PMHS) or triethylsilane, for example, in combination with a catalyst Zn(II) (Mimoun, J. Org. Chem., 1999, 64, 2582-2589, ruthenium catalyst (Fuchikami et al., Tetrahedron Letters, 42 (2001), 2149-2151), tetrabutylammonium fluoride (TBAF or Triton B) (Lawrence et al., Synlet, 1997, 989-991), potassium fluoride or cesium fluoride (Coriu et al., Synthesis, 1982, 981 and 1981, 558) or the catalyst is titanium (IV) (Buchwald et al., J. Org. Chem. 1995, 60, 7884-7890).

Sodium borohydride is particularly preferred as the reducing agent. Recovery is usually carried out in an organic solvent, conveniently in a polar solvent such as ethanol or tetrahydrofuran. When used borhydride reducing agent, after the recovery is completed, it is desirable to extinguish the reaction of the complexing compound to form a complex with any residual boron compound in the reaction mixture and in order to avoid additional adverse reactions and formation of undesirable side products. The inventors have discovered that treatment of the reaction mixture diethanolamine, for example, in the form of its hydrochloride as a reagent for damping provides especially good results in terms of purity desired in the final product. Alternative to extinguish the reaction is predominantly possible to use the ammonium chloride. The resulting compound of formula (VI) are obtained in the form of a mixture of stereoisomeric forms and it can be used the AK itself for the next stage in the synthesis hexahydrofuro[2,3-b]furan-3-ol.

The above compounds of formula (VI) are new compounds, and therefore, the inventors proposed as an additional characteristic of the invention the compounds of formula (VI)

and their stereoisomeric forms and racemic mixtures,

in which R¹represents an alkyl or arylalkyl, preferably_1-4alkyl group such as methyl, ethyl or propyl, especially isopropyl, or phenyl-C_1-4alkyl group, such as benzyl.

Particularly preferred new compound of the formula (VI) is 1-(2-isopropoxypyridine-3-furanyl)-1,2-ethanediol.

Thus, the compounds of formula (VI) are used as intermediates in the synthesis of compounds of formulas (I) and (Ia).

According to an additional characteristic of the present invention the inventors proposed a method of obtaining the compounds of formula (I), which contains the cyclization of the compounds of formula (VI) with the formation of the compounds of formula (I)

in which R²preferably represents C_1-4alkyl group such as methyl, ethyl or propyl, especially isopropyl, or phenyl-C_1-4alkyl group, such as benzyl.

The cyclization of the compounds of formula (VI) can be performed, for example, by treatment with an acid, usually a strong proton acid is one such as hydrochloric acid, p-toluensulfonate acid, methanesulfonate acid, camphorsulfonic acid, resin amberlyst, TFA, p-bromobenzophenone acid or acetic acid. The reaction is usually carried out in an organic solvent, for example a polar solvent, such as tetrahydrofuran, dichloromethane, ethyl acetate, ethanol, methanol or acetone, suitably at a temperature from -20°C to 50°C. When using tetrahydrofuran, the preferred temperature is the temperature from 40°to 50°, preferably 45°C. To neutralize the reaction mixture and the completion of the reaction add a base, such as triethylamine or pyridine. The method leads to the formation of a mixture of two diastereoisomers formula (I), namely endo-diastereoisomer containing 3R,3aS,6aR and 3S,3aR,6aS-enantiomers, and Exo-diastereoisomer containing 3S,3aS,6aR - and 3R,3aR,6aS-enantiomers above. Two diastereoisomer you can easily divide the conventional manner, for example by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate (1/9) as eluent.

After separation of the above diastereoisomers endo-diastereoisomer can be applied directly when receiving protease inhibitors, requiring stereoisomeric this part, if necessary, after the separation of its constituent enantiomers,accepted way, for example, according to the method described by Ghosh et al. in Tetrahedron Letters, Vol. 36, No. 4, 505-508, 1995, or WO 02/060905, acylation, for example, acid chloride or anhydride of the acid, conveniently in an aprotic solvent such as tetrahydrofuran or dichloromethane, in the presence of a base such as sodium carbonate or triethylamine. The resulting mixture of esters are then subjected to reaction with a suitable astraslim enzyme, such as lipase Ps30, under conditions that allow the course of the reaction is primarily one of racemic esters with the formation of a mixture of alcohol predominantly one enantiomer and the remaining unreacted complex ester of the corresponding mainly the other enantiomer. The mixture of alcohol and ether complex can then divide the conventional manner, for example by chromatography on silica gel. Enantiomeric unreacted ester can be converted into the corresponding alcohol, for example, by reaction with methyllithium in tetrahydrofuran.

If desired, Exo-diastereoisomer can be turned into endo-diastereoisomer conventional manner, for example, as described by Ghosh et al. in J. Org. Chem. 2004, 69, 7822-7829, the sequence of oxidation/restore, including the intermediate formation of a ketone of the formula (I')

Thus, according to the above method of Ghosh et al., Exo-d is stereoisomer oxidized to the ketone of the formula (I') perruthenate of tetrapropylammonium (TRR) and 4-methylmorpholine-N-oxide (NMO) and the resulting ketone restore, for example, hydride regenerating agent such as sodium borohydride, in an organic solvent, for example a polar solvent, such as ethanol, thus obtaining the corresponding endo-diastereoisomer. Alternatively, the above oxidation can be performed by the system NaOCl/1-oxide 2,2,6,6-tetramethylpiperidine (TAMRA).

It should be clear that the above method of oxidation and reduction can also be carried out on the basis of a mixture of endo - and Exo-forms, which thus avoids the need for any pre-separation of diastereoisomers.

According to an additional characteristic of the invention the inventors proposed a method of obtaining hexahydro[2,3-b]furan-3-ol, which includes the following stages:

a) reaction of 2,3-dihydrofuran formula (II) with glyoxylate derivative of the formula (III) in the presence of a titanium salt of the formula Ti(Hal)_n(OR)_4-nin which n is 0, 1, 2 or 3 and R represents an alkyl or arylalkyl, and subsequent reaction of the resulting reaction product with an alcohol of the formula (IV) with the formation of the compounds of formula (V)

in which R¹represents an alkyl or arylalkyl and R²represents an alkyl or arylalkyl, and

b) recovering the resulting compound of formula (V) with the formation connected to the I of the formula (VI)

and

(C) cyclization of the compounds of formula (VI) with the formation of the compounds of formula (I)

and, if desired, then (i) the separation of the formed compounds of formula (I) for separation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol of the formula (Ia)

and/or

(ii) oxidizing the resulting compound of formula (I) with the formation of the compounds of formula (I')

and then restore the compounds of formula (I') in the endo-isomer of compounds of formula (I).

Compounds of formula (I) and (Ia) are particularly applicable when getting medicines. According to a preferred variant implementation of the present compounds of formulas (I) and (Ia) are used as precursors upon receipt of antiviral drugs, in particular drugs against HIV, more specifically, HIV protease inhibitors.

Compounds of formula (I) and (Ia) and all intermediate products leading to the formation of these compounds are of particular interest when receiving HIV protease inhibitors, as described by Ghosh et al. Bioorganic & Medicinal Chemistry Letters 8 (1998) 687-690 and WO 95/24385, WO 99/65870, WO 99/67254, WO 99/67417, WO 00/47551, WO 00/76961, WO 01/25240, US 6127372 and EP 0715618, all of which are incorporated herein by reference, and especially the following HIV protease inhibitors:

(3R,3S,6aR)-hexahydrofuro[2,3-b]furan-3-silt ether [(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamino acid, that is, the above darunavir (inhibitor 1 protease HIV);

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

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

Thus, the present invention also relates to inhibitors 1, 2 or 3 HIV protease or any pharmaceutically acceptable salts or prodrugs obtained with the use of the compounds of formula (I)obtained according to the present invention in the chemical synthesis of these HIV protease inhibitors. Such chemical synthesis described in the literature, for example, in the above patent and literature references.

The compound of the above formula (Ia) can be applied after formation of the activated derivative for the synthesis of inhibitor 1 protease, i.e. darunavir above formula (A), as described, for example, in WO2005/063770, the contents of which are incorporated herein by reference, in the following way, which contains

(i) the introduction of isobutylamine in the compound of formula (I)

where

PG is aminosidine group;

R₁represents hydrogen or C_1-6alkyl;

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

(iii) the restoration of the nitro group of the resulting compound of stage (ii);

(iv) removing the protecting formed at the connection stage (iii), and

(v) a combination formed of the connection stage (iv) with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-alprozolam with the formation of the above compounds (A).

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

obtaining the compounds of formula (2')

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

nitrogroup reduction of compounds of formula (3') to obtain the compounds of formula (4')

remove protection from the compounds of formula (4') to obtain the compounds of formula (5)

combinations of the compounds of formula (5) with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-alprozolam with the formation of compound (A).

The compound of formula (1)

The compound of formula (1) is

where

PG is aminosidine group;

R₁represents hydrogen or C_1-6alkyl.

Compound of formula (1) preferably is a compound of formula (1'), as shown below, where PG represents a tert-butyloxycarbonyl or “Boc” and R₁represents hydrogen. Compounds of formulas (1) and (1') are commercially available and can be obtained in several ways available in the literature, for example, as described in WO95/06030 (Searle & Co.), as described Kaneka Corporation in EP 0754669, EP 1029856 and EP 1067125, and as described Ajinomoto KK in EP 1081133 and EP 1215209.

The compound of the formula (2)

The compound of formula (1) is subjected aminating the epoxide with obtaining the compounds of formula (2).

Used here, the term “amination” refers to the way in which the primary amine, isobutylamine injected into the organic molecule of formula (1). Amination of the compounds of formula (1) can be done in several ways available in the literature, for example, as described in WO95/06030, which is described here as a reference.

In a preferred embodiment, the compound of formula (1') is subjected to reaction with isobutylamine with obtaining the compounds of formula (2').

Amination of epoxides is described, for example, in March, Advanced Organic Chemistry 368-69 (3rd Ed. 1985) and McManus et al., 3 Synth. Comm. 177 (1973), which is incorporated herein by reference. Appropriate compounds of formulas (2) and (2') can be obtained according to the method described in WO97/18205.

The amination agent, isobutylamine, can function also as a solvent, in this case, you can add the excess isobutylamine. In other embodiments, implementation of the method of amination is carried out in the presence of one or more solvents other than isobutylamine. In a preferred embodiment, the above-mentioned solvents used in the formation of compounds of the formulas (2) and (2').

In the embodiment of the invention, the amination reaction is carried out in the presence of about 15 equivalents of isobutylamine using toluene as solvent and heated to boiling under reflux at approximately 79°C.

The compound of the formula (3)

The compound of the formula (3) is obtained by introduction sulfonyloxy part, p-nitrobenzene-SO₂in the intermediate product of the formula (2).

Thus, in the preferred embodiment, the compound of formula (3') can be obtained by sulfonylamine the compounds of formula (2').

As such, the haunted, compounds of the formulas (2) and (2') is subjected to reaction with sulfonylureas agent for making the compounds of formulas (3) and (3').

The term “sulfonyloxy agent” includes a p-nitrobenzenesulfonamide, such as p-nitrobenzenesulfonamide.

Treatment of compounds of formulas (2) and (2') sulfonylureas agent can be carried out in the presence of a solvent when heated from about 25°C to 250°C, preferably from 70°C to 100°C, and stirring. After sulfonylamine any remaining sulfonyloxy agent or its salt is preferably, though not necessarily, removed from the reaction mixture. This removal can be performed by repeated washing with water, the pH of the separation of organic and aqueous phase, ultrafiltration, reverse osmosis, centrifugation and/or filtration or the like.

The compound of the formula (4)

Compounds of the formulas (4) and (4') is obtained by restoring the nitro group of intermediate compounds of the formulas (3) and (3'), respectively, regenerating agent, optionally in an atmosphere of hydrogen.

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

The compounds of formula (5)

The compound of the formula (5) is obtained by removing protection from intermediates of formula (4) and (4') in the conventional acidic conditions. Alternatively, you can apply the basic terms.

Remove aminosidine group can be performed using conditions that will not affect the rest of the molecule. These methods are well known in this field and include acid hydrolysis, hydrogenolysis, and the like, for example, using commonly known acids in suitable solvents.

Examples of the reagents and methods of removal from amines aminosidine groups can additionally be found in the publication Protective Groups in Organic Synthesis by Theodora W. Greene, New York, John Wiley and Sons, Inc., 1981, incorporated herein by reference.

As should be clear to the person skilled in the art, the choice aminosidine group used in the previous stage of the method, will determine the reagents and methods used to remove the specified aminosidine group.

Receiving darunavir

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol of the formula (Ia), obtained as described above, appropriately activate agent combination with the formation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-improving, which then carbamoylethyl compound of the formula (5) to obtain the desired inhibitor 1 protease, namely darunavir.

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

In particular, when (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is subjected to reaction with disuccinimidylsulfite, get 1-([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione. The specified connection is preferred (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-alprozolam.

The reaction of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-improving with the compound of the formula (5) can be carried out in the presence of suitable solvents, such as tetrahydrofuran, dimethylformamide, acetonitrile, dioxane, dichloromethane or chloroform, and optionally with a base such as triethylamine, although also used additional to the munali abovementioned solvents and bases.

Among the solvents, preferred solvents are aprotic solvents, such as tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, and the like.

The above reaction carbamylcholine suitably carried out at a temperature from -70°C to 40°C, preferably from -10°C. to 20°C.

According to a particularly preferred feature of the present invention the inventors have proposed darunavir, that is, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-silt ether [(1S,2R)-3-[[(4-AMINOPHENYL)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamino acid of the formula (A), is always synthesized using intermediate product of the formula (I) and especially the intermediate product of the formula (Ia)obtained according to the present invention.

Examples

There is a view that the following examples are an illustration of the present invention. These examples are presented to illustrate the invention in the form of examples and should not be construed as limiting the scope of the invention.

Gas chromatography (GC) was performed under the following conditions: column: 5% phenyl-, 95% methylpolysiloxanes, L=25 m; ID=320 μm; film width = 0,52 μm; injector with decomposition at 250°C with the ratio of 1/50; volume of injection: 1 µl. Program: 5 min at 50°C., then the heating rate 15°C/min to 240°C for 5 minobe flow: 3.0 ml/min The quality of the product of the reaction determines the percentage amount of the desired compounds in this product, determined by gas chromatography with flame ionization detection (FID) (% area GC).

In the following examples, “DCM“ refers to dichloromethane, “AcOEt” refers to ethyl acetate, THF refers to tetrahydrofuran and “TEMPO” refers to 1-oxide 2,2,6,6-tetramethylpiperidine.

Comparative example

(A) Acylhydrolase-(2-ethoxyacrylate-3-yl)acetate

To a mixture of freshly ethylglycol (40 mmol; 1,000 EQ.; 3,620 ml; 4,084 g) and 2,3-dihydrofuran (44 mmol; 1,100 EQ.; 3,338 ml; 3,084 g) in dry dichloromethane (100 ml; 1,560 mol; 132,5 g) was added dropwise a solution of titanium tetrachloride (44 mmol; 1,100 EQ.; 44,00 ml; 59,84 g) in 1 M DCM at -78°C and the resulting mixture was stirred for 1 h, the Reaction mixture becomes yellow and heterogeneous. To the mixture, which became heterogeneous, was added dropwise ethanol (120 mmol; 3,000 EQ.; 6,986 ml; 5,528 g). The cooling bath was removed to allow the reaction mixture to warm to room temperature over 1 h Slowly at room temperature was added sodium bicarbonate (100 ml; 103,4 mmol, 104,7 g). After 10 min the reaction mixture was extracted twice with ethyl acetate (600 ml; 6,132 mol; 540,2 g). The organic solvent evaporated under reduced pressure is, getting the green oil containing white solids (of 9.45 g, GC: area 14%).

GC: retention time: 13,4 minutes

MS (E 70 eV): 217 (0,5%; M-H); 173 (11%, M-OEt); 155 (59%, 173-H₂O); 145 (21%, M-CO₂Et); 71 (100%, 173-CHOCO₂Et).

Determination of titanium in this crude mixture was carried out using the method ICP (inductively coupled plasma): 96 ppm titanium.

(C) Attempt recovery of the product from (A)

In a 50-ml round-bottom flask is loaded with ethanol (9.6 ml) and tetrahydroborate sodium (1.1 EQ.; 5.46 mmol, 210 mg) at 0°C dropwise over 1 h was added acylhydrolase-(2-ethoxyacrylate-3-yl)acetate (1.44 g; 4,96 mmol; 1 EQ.), dissolved in ethanol (5.8 ml). The reaction mixture is allowed to warm to room temperature and stirred for two days. Then to the reaction mixture at 0°C was added dropwise ammonium chloride (1.5 EQ.; 7,44 mmol; 400 mg)dissolved in water (3.5 ml). The reaction mixture was stirred for 4 h at room temperature and the solvent evaporated under reduced pressure, thus obtaining a brown solid. Then the crude mixture was added ethyl acetate (7.7 ml) and the mixture was heated at 40°C for 30 minutes After filtration through dicalite homogeneous mixture was evaporated to dryness under reduced pressure, thus obtaining the original substance.

Example 1

Eting is droxi-(2-isopropoxypyridine-3-furanyl)acetate

In a round bottom flask of 50% wt./mass. the solution acylglycerol in toluene (4,74 g, 23,21 mmol, 1.1 EQ.) was stirred under reduced pressure at 60°C until complete evaporation of the toluene. Then at room temperature was added 80 ml of dry DCM, followed by addition of TiCl₂(OiPr)₂(5 g, 21.1 mmol). After a period of stirring 0.5 h at room temperature dropwise over 10 min was added 2,3-dihydrofuran (1.48 g, 21.1 mmol, 1 EQ.), dissolved in 15 ml of DCM, and the mixture was stirred for 5 h at room temperature. Then was added dropwise isopropanol (16 ml, 211 mmol, 10 EQ.) and the mixture was stirred over night. Finally, at room temperature was added dropwise a basic aqueous mixture of Rochelle salt (20 g in 200 ml water, 2 g of Na₂CO₃) and the mixture was stirred over night. Two layers were separated and the organic layer was dried Na₂SO₄and concentrated in vacuum. The oil obtained (3,45 g, H.H.: the area of 85%) can be used directly in the next stage.

Determination of titanium: <5 ppm

MS (E.I. 70 eV): 173 (16%, M-OⁱPr); 159 (22%, M-CO₂Et); 155 (100%, 173-H₂O); 71 (98%, 173-CHOCO₂Et).

MC (C.I., ammonia): (M+H)⁺: 233,1353 (theory: 233,1389); (M+NH₄)⁺: 250,1593 (theory: 250,1654).

Example 2

Acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate

In a 1-liter round-bottom flask, the titanium tetrachloride (17,83 mmol; 1,96 ml; to 3.38 g) was dissolved in dichloromethane (70 ml; 1,092 mol; 92,75 g) at room temperature. Then at room temperature was added dropwise Tetra(isopropoxy) titanium (17,83 mmol; 5,28 ml 5,07 g)dissolved in dichloromethane (70 ml; 1,092 mol; 92,75 g). After a period of stirring 1 h for 30 min at room temperature was added dropwise ethylglycol (1.1 EQ.; 39,24 mmol; 3.55 ml; 4.0 g) without toluene, dissolved in dichloromethane (8,75 ml; to 136.5 mmol, 11,59 g). After 15 min during 30 min at room temperature was added 2,3-dihydrofuran (2.5 g; 1,000 EQ.; 35,67 mmol; 2,70 ml)dissolved in dichloromethane (17.5 ml; 273,0 mmol; 23,19 g). After a period of stirring 3 h was added dropwise isopropyl alcohol (10 equiv.; 356,7 mmol; 27,26 ml; 21,44 g). After 3 h, to the reaction mixture was added a mixture of potassium carbonate (1.75 g; 12,66 mmol) and Rochelle salt (17.5 g; 83,25 mmol)dissolved in water (175 ml; 9,72 mol, 175 g). After stirring for two days two layers were separated and the organic layer was washed (2×100 ml), water (200 ml; 11,10 mol; 200,0 g). The organic solvent evaporated under reduced pressure, thus obtaining the desired product (of 7.48 g; GC: 92% of the area).

Determination of titanium:

before processing Rochelle salt: 14,5%; after treatment Rochelle salt: <5 ppm

¹H NMR (CDCl_{3 , 400 MHz): 5,23 (e, 0,42H, J=4 Hz); 5,20 (d, 0,48H, J=2 Hz); 5,16-5,08 (m, 0,14H); of 4.45 (d, 0,42H, J=4 Hz); 4,30-to 4.15 (m, 3H); 4,11-of 3.96 (m, 0,8H); 3,96-3,81 (m, 2,85H); 3,54 (user. C, 0,4H); 2,97 (user. C, 0,60H); 2,60-to 2.42 (m, 1,1H); 2,28-of 2.15 (m, 0,49H); 1,97-to 1.79 (m, 1,79H); of 1.30 (t, 3,8H, J=8 Hz); 1,24-to 1.21 (m, 0,46H); 1,21-of 1.16 (m, 3,12H); 1,16-of 1.12 (m, 3H).}

_{¹³C NMR (CDCl3, 400 MHz): 174,1; 172,9; 103,9; 102,2; 70,2; 69,6; 69,4; 66,6; 61,9; 61,2; 49,9; 47,0; 25,1; 23,9; 23,7; 21,9; 21,7; 14,2.}

Example 3

Acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate

In a 1-liter round-bottom flask, the titanium tetrachloride (17,83 mmol; 1,96 ml; to 3.38 g) was dissolved in dichloromethane (70 ml; 1,092 mol; 92,75 g) at room temperature. Then at room temperature was added dropwise Tetra(isopropoxy) titanium (17,83 mmol, 5,28 ml 5,07 g)dissolved in dichloromethane (70 ml; 1,092 mol; 92,75 g). After a period of stirring 1 h at room temperature during 30 min was added dropwise ethylglycol (1.1 EQ.; 39,24 mmol; 3.55 ml; 4.0 g) without toluene, dissolved in dichloromethane (8,75 ml; to 136.5 mmol, 11,59 g). After 15 min during 30 min at room temperature was added 2,3-dihydrofuran (2.5 g; 1,000 EQ.; 35,67 mmol; 2,70 ml)dissolved in dichloromethane (17.5 ml; 273,0 mmol; 23,19 g). After a period of stirring 3 h was added dropwise isopropyl alcohol (10 equiv.; 356,7 mmol; 27,26 ml; 21,44 g). After 3 h, to the reaction mixture was added a mixture of potassium carbonate (1.75 g; 12,66 mmol) and diethanolamine 9.5 g; 90,6 mmol)dissolved in water (175 ml; 9,72 mol, 175 g). After stirring for two days two layers were separated and the organic layer was washed (2×100 ml), water (200 ml; 11,10 mol; 200,0 g). The organic solvent evaporated under reduced pressure, thus obtaining the desired product (7.0 g; GC: 96% of the area).

Determination of titanium:

after processing diethanolamine: <5 ppm

Example 4

Acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate

In a round bottom flask loaded with 400 ml of DCM and Ti(OiPr)₄(56,8 g, 0.2 mol)dropwise at room temperature over 30 min was added TiCl₄(22 ml, 0.2 mol), dissolved in 400 ml of DCM. After a period of stirring 17 hours, dropwise at room temperature was added acylglycerol without toluene (45,2 g, 0.22 mmol, 1.1 EQ.), dissolved in 50 ml of DCM. After 15 min dropwise over 30 min was added 2,3-dihydrofuran (14 g, 0.2 mol, 1 EQ.), dissolved in 100 ml of DCM, and the mixture was stirred for 3 h at room temperature. Then added dropwise isopropanol (153 ml, 2 mol, 10 EQ.) and the mixture was stirred for 4 h at room temperature. Finally, was added dropwise a basic aqueous mixture of Rochelle salt (100 g in 1000 ml of water, 10 g of K₂CO₃) and the resulting mixture was stirred over night at room temperature. Two layers of abdelali and the organic layer was dried Na ₂SO₄, was filtered and was evaporated in vacuum. The oil obtained (47,2 g, GC: area 87%) can be used directly in the next stage.

GC: retention time: 13,7 minutes

MS (E.I. 70 eV): 173 (16%, M-OⁱPr); 159 (22%, M-CO₂Et); 155 (100%, 173-H₂O); 71 (98%, 173-CHOCO₂Et).

MS (C.I., ammonia): (M+H)⁺: 233,1353 (theory: 233,1389); (M+NH₄)⁺: 250,1593 (theory: 250,1654).

Example 5

Acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate

In a round bottom flask loaded TiCl(OiPr)₃(0.1 mol, 1 M in hexane) and 300 ml of DCM is added dropwise at room temperature was added acylglycerol without toluene (22,6 g, 0.11 mol, 1.1 EQ.), dissolved in 25 ml DCM. After a period of stirring 0.5 h at room temperature dropwise at room temperature over 30 min was added 2,3-dihydrofuran (7 g, 0.1 mol, 1 EQ.), dissolved in 50 ml of DCM, and the mixture was stirred for 5 h at room temperature. Then at room temperature was added dropwise isopropanol (76 ml, 1 mol, 10 EQ.) and the mixture was stirred over night. Finally, dropwise at room temperature was added to the basic aqueous mixture of Rochelle salt (50 g in 500 ml of water, 5 g of K₂CO₃) and the mixture was stirred over night. Two layers were separated, the organic layer was dried Na₂SO₄, was filtered and was evaporated in vacuum. According to the scientists the oil (18.2 g, GC: the area of 85%) can be used directly in the next stage.

MS (E.I. 70 eV): 173 (16%, M-OⁱPr); 159 (22%, M-CO₂Et); 155 (100%, 173-H₂O); 71 (98%, 173-CHOCO₂Et).

MS (C.I., ammonia): (M+H)⁺: 233,1353 (theory: 233,1389); (M+NH₄)⁺: 250,1593 (theory: 250,1654).

Example 6

Acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate

In a round bottom flask loaded with 400 ml of DCM and Ti(OiPr)₄(28.4 g, 0.1 mol)dropwise at room temperature over 30 min was added TiCl₄(11 ml, 0.1 mol), dissolved in 400 ml of DCM. After a period of 17 h stirring dropwise at room temperature over 30 min was added acylglycerol without toluene (90 g, 0.44 mmol, 1.1 equiv.) dissolved in 150 ml of DCM. After 15 min dropwise during 30 min at room temperature was added 2,3-dihydrofuran (28 g, 0.4 mol, 1 EQ.), dissolved in 150 ml of DCM, and the mixture was stirred for 5 hours Then added dropwise at room temperature was added isopropanol (306 ml, 4 mol, 10 EQ.) and the mixture was stirred for 3 hours Finally, dropwise at room temperature was added to the basic aqueous mixture of Rochelle salt (100 g in 1000 ml of water, 10 g of K₂CO₃) and the mixture was stirred over night. Two layers were separated, the organic layer was dried Na₂SO₄, was filtered and was evaporated in vacuum. The oil obtained (81,5 g, GC: PL is under 70%) can be used directly in the next stage.

GC: retention time: 13,7 minutes

MS (E.I. 70 eV): 173 (16%, M-OⁱPr); 159 (22%, M-CO₂Et); 155 (100%, 173-H₂O); 71 (98%, 173-CHOCO₂Et).

MS (C.I., ammonia): (M+H)⁺: 233,1353 (theory: 233,1389); (M+NH₄)⁺: 250,1593 (theory: 250,1654).

Example 7

a) 1-(2-Isopropoxypyridine-3-furanyl)-1,2-ethanediol

A 2-liter round bottom flask loaded with 600 ml of ethanol and NaBH₄(12,55 g, 0.33 mol, 1.1 EQ.) at 0°C dropwise over 1 h at 0°C was added acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate (70 g, 0.3 mol, 1 EQ.), dissolved in 400 ml of ethanol. The mixture was allowed to warm at room temperature and was stirred for 19 hours After cooling at 0°C was added over 10 min diethanolamine hydrochloride (46,7 g, 0.33 mol, 1.1 equiv.) dissolved in 100 ml of water, and the mixture was stirred for 8 hours, the Solvent is evaporated under reduced pressure, thus obtaining a light yellow solid. After dilution with 300 ml of ethyl acetate heterogeneous mixture was filtered through dicalite. The mixture was used directly in the next stage.

b) 1-(2-Isopropoxypyridine-3-furanyl)-1,2-ethanediol

In a round-bottom flask is loaded with ethanol (50 ml) and NaBH₄(1,066 g, 28,19 mmol, 1.1 EQ.) at 0°C dropwise over 1 h at 0°C was added acylhydrolase-(2-from the propoxymethyl-3-furanyl)acetate (7,44 g, 25,62 mmol, 1.000 equiv.) dissolved in ethanol (30 ml). The mixture was allowed to warm to room temperature and was stirred for two days. Then to the reaction mixture at 0°C was added ammonium chloride (2,056 g, 38,44 mmol, 1.5 equiv.) dissolved in water (18 ml). The reaction mixture was stirred for 4 h at room temperature and the solvent evaporated under reduced pressure, thus obtaining a brown solid. Then the crude mixture was added ethyl acetate (40 ml) and the mixture was heated at 40°C for 30 minutes. After filtration through dicalite homogeneous mixture was evaporated to dryness under reduced pressure, thus obtaining the desired product (4,39 g, 19,61 mmol, 0,7655 EQ., output 76,55%).

Mixture of diastereomers:

¹H NMR (CDCl₃, 400 MHz): to 5.85 (d, J=8 Hz, 0,11H); 5,11-a 4.86 (m, 2H); from 4.3 to 3.6 (m, 7,7H); 3,8-3,5 (m, 3H); to 3.45 (m, 3,7H); 2,49-2,0 (m, 3,4H); 1,95-1,5 (m, 2,34); of 1.28 (m, 1,1H); 1,20-of 1.12 (m, 6H).

¹³C NMR (CDCl₃; 100 MHz): (main peaks) 109,0; 108,2; 105,8; 105,5; 72,6; 69,6; 69,4; 67,8; 66,9; 63,3; 63,1; 63,0; 49,0; 48,7; 32,4; 28,9; 27,6; 26,4; 23,6; 21,8; 21,8; 15,2; 14,2.

GC: peaks of different isomers @ 5,7 min 17%; 6,07 min 8,29%; 6,32 min 15,7%; 6,7 min 20,29%; 6,9 min 11,0%; 10,6 min to 7.6%; min 10,8 5%.

Example 8

Hexahydrofuro[2,3-b]furan-3-ol

In a 50-ml round-bottom flask 1-(2-isopropoxypyridine-3-furanyl)-1,2-ethanediol (2,21 g; 8,89 mmol, 1 EQ.) was dissolved in tetrahydrofuran (9 ml). After about what ladenia at 0°C. to the mixture was added methanesulfonyl acid (65 mg; 676,33 Microm). The reaction mixture then was heated at 45°C for 30 min After cooling at room temperature, to the mixture was added triethylamine (0.3 g; 2,96 mmol). The solvent was evaporated and to the mixture at room temperature was added ethyl acetate (9 ml; 91,98 mmol). The mixture is then filtered through dicalite and the solvent was evaporated under reduced pressure, thus obtaining endo/Exo-bis-THF (1,562 g; GC: area 71%) when diastereomerism the ratio of endo/Exo-diastereoisomer 15/85.

Two diastereoisomers were separated by chromatography on silica gel, eluent: 9/1 mixture AcOEt/hexane.

GC: Exo-hexahydrofuro[2,3-b]furan-3-ol: retention time 11,36 min; endo-hexahydrofuro[2,3-b]furan-3-ol: retention time 11,57 minutes

¹H NMR:

Exo-hexahydrofuro[2,3-b]furan-3-ol: to 1.67 (m, 1H); 2.13 in (m, 1H); 2,31 (user. s, 1H); and 2.79 (m, 1H); 3,8-3,9 (m, 3H); 2,95 (DD, 1H, J=3.2 Hz, J=10.3 Hz); 4,2 (d, 1H, J=3.1 Hz); at 5.9 (DD, 1H, J=4,9 Hz);

endo-hexahydrofuro[2,3-b]furan-3-ol: to 1.85 (m, 1H); 1,94 (user. s, 1H); and 2.27 (m, 1H); 2,84 (m, 1H); 3,6 (DD, 1H, J=7,1 Hz, J=9,2 Hz); the 3.89 (m, 1H); of 3.97 (m, 1H); 4,43 (DD, 1H, J=6,8 Hz, J=14,5 Hz); of 5.68 (d, 1H, J=5,2 Hz).

Example 9

a) Tetrahydrofuro[2,3-b]furan-3(2H)-he

In a 250-ml round-bottom flask NaOCl (x 6.15 g, 14% wt./mass.) was diluted in 100 ml of water. the pH of the solution was adjusted to 9.5 using 1 M aqueous solution of NaHCO₃. In a separate 250-ml round-bottom flask is hexahydrofuro[2,3-b]furan-3-ol (1 g, 7.7 mmol, 1 EQ.) was dissolved in 15 ml of AcOEt at 0°C. Then was added KBr (91 mg, 0.77 mmol, 0.1 EQ.), dissolved in 1 ml of water, followed by addition of TEMRO (12 mg, 0.08 mmol, 0.01 EQ.). Finally, dropwise to the mixture was added NaOCl. After 15 min stirring at 0°C. the mixture was extracted with 3 times 100 ml of AcOEt. The collected organic layers were dried over Na₂SO₄and the solvent evaporated under reduced pressure, thus obtaining 950 mg of a white solid, yield: 96%. Formed tetrahydrofuro[2,3-b]furan-3(2H)-it was used in the next stage without additional purification.

The product was identified by exact mass: m/z 128,0473 (theoretical mass: 128,0473).

b) Stereoselective obtain (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

In General, according to the method described by Ghosh et al. in J. Org. Chem. 2004, 69, 7822-7829, tetrahydrofuro[2,3-b]furan-3(2H)-he (950 mg, 7,42 mmol, 1 EQ.) was dissolved at 0°C in 50 ml of ethanol. In one portion to the mixture was added NaBH₄(302,4 mg, 8 mmol, of 1.07 EQ.). After a period of stirring 1 h was added cleaners containing hydrochloride salt diethanolamine (3.2 g, 8 mmol, of 1.07 EQ.) and the mixture was stirred over night at room temperature. The heterogeneous mixture was filtered through dicalite and washed with 20 ml of hot AcOEt. After evaporation of the organic solvents under reduced pressure received 1500 mg hexahydrofuro[23-b]furan-3-ol with a yield (%) 40%; maximum output: 60%, diastereoisomeric excess: Exo-(3S,3aS,6aR)/endo-(3R,3aS,6aR): 18,5/81,5.

1. The method of obtaining the compounds of formula (V), which comprises reaction of 2,3-dihydrofuran formula (II) with a derivative of glyoxylate formula (III) in the presence of a titanium salt of the formula Ti(Hal)_n(OR)_4-nin which Hal represents a halogen radical, n is 0, 1, 2 or 3 and R represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl, and the subsequent reaction of the resulting reaction product with an alcohol of the formula (IV) with the formation of the compounds of formula (V):

where R¹represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl, and R²represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl.

2. The method according to claim 1, in which the titanium salt is a compound of the formula Ti(Hal)_n(OR)_4-nin which n is 1, 2 or 3.

3. The method according to claim 1, in which R¹represents a C_1-4alkyl.

4. The method according to claim 1, in which R²represents a C_1-4alkyl.

5. The method according to any one of claims 1 to 4, in which 2,3-dihydrofuran formula (II) is subjected to reaction with a derivative of glyoxylate formula (III) in the presence of a titanium salt and then the reaction product is subjected to reaction with an alcohol of the formula (IV) with the formation of compound Faure the uly (V).

6. The method according to any one of claims 1 to 4, in which the resulting reaction mixture containing the compound of the formula (V), treated with Rochelle salt to effect the removal of residual compounds titanium.

7. The method according to claim 6, in which the processing of Rochelle salt is carried out in an alkaline medium.

8. The compounds of formula (Va):

and their stereoisomeric forms and racemic mixtures,
in which R¹represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl, and R²represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl, provided that when R²represents methyl, R¹is not the stands or ethyl.

9. Acylhydrolase-(2-isopropoxypyridine-3-furanyl)acetate.

10. The method of obtaining compounds of formula (VI), which contains the recovery of the compounds of formula (V) with the formation of the compounds of formula (VI):

in which R¹and R²have the meanings indicated in claim 1.

11. The method according to claim 10, in which the recovery is conducted borhydride regenerating agent.

12. The compounds of formula (VI):

in which R has the meanings indicated in claim 1.

13. 1-(2-Isopropoxypyridine-3-furanyl)-1,2-ethanediol.

14. The method of obtaining the compounds of formula (I)which provides the cyclization of compounds of formula (VI) with the formation of the compounds of formula (I):

15. The method according to 14, in which the cyclization of the compounds of formula (VI) carry out processing in a strong proton acid.

16. The method of obtaining hexahydrofuro[2,3-b]furan-3-ol of the formula (I), which contains the stage:
a) reaction of 2,3-dihydrofuran formula (II) with a derivative of glyoxylate formula (III) in the presence of a titanium salt of the formula Ti(Hal)_n(OR)_4-nin which n is 0, 1, 2 or 3 and R represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl, and the subsequent reaction of the resulting reaction product with an alcohol of the formula (IV) with the formation of the compounds of formula (V):

in which R¹represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl, and R²represents an alkyl or arylalkyl, where aryl represents phenyl or naphthyl; and
(b) recovering the resulting compound of formula (V) with the formation of the compounds of formula (VI):

and
(C) cyclization of compounds of formula (VI) with the formation of the compounds of formula (I):

and, if desired, then (i) chiral separation of the formed compounds of formula (I) for separation of (3R,3S,6R)-hexahydrofuro[2,3-b]furan-3-ol of the formula (Ia):

and/or
(ii) the oxidation of the formed joint is of the formula (I) with the formation of the compounds of formula (I'):

and then restore the compounds of formula (I') in the compound of formula (Ia).