Method for synthesis of bicyclo[3,1,0]hexane derivatives and intermediate compound to this end

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of bicyclo[3.1.0]hexane derivatives, used as mGIuR agonists having formulae ,

, where R1 and R2 represent hydrogen, X is a halogen, R3 is -O-R^a , R^a is C_1-10alkyl, and R⁴ is (1) hydrogen or (2) Si-(R⁹)(R¹⁰)(R¹¹), where each of R⁹, R¹⁰ and R¹¹ is C_1-10alkyl, as well as intermediate compounds obtained when realising the said methods.

EFFECT: design of an efficient method for synthesis of bicyclo[3,1,0]hexane derivatives.

26 cl, 17 ex, 1 tbl

Cross-reference to related applications

In this application claims priority under 35 U.S.C. § 119(e) based on provisional application US 60/518391, filed November 7, 2003.

The technical field to which the invention relates

The present invention relates to methods of producing derivatives of bicyclo[3.1.0]hexane, which are used as modulators of metabotropic glutamate receptors. This invention relates to new intermediate compounds obtained in the course of these methods and cleaners containing hydrochloride salt of (+)-(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and its polymorphs.

The level of technology

Excitatory amino acids, including glutamate, modulate many physiological processes in the Central nervous system of mammals (CNS), such as long-term potentiation (learning and memory), the development of synaptic plasticity, regulation of motor activity, respiration, regulation of cardiovascular activity and sensory perception.

Glutamate acts through receptors, at least two different classes. The first class includes ionotropic glutamate receptors (iGlu), acting as ligand-regulated ion channels. The second class is a G protein or the second mass is ger-associated "metabotropic" glutamate (mGluR) receptor. Apparently, both classes of receptors mediate normal synaptic transmission in the ways of excitation, as well as participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert and Sladeczek,Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson,Brain Research Reviews, 15, 41 (1990).

As mGluR modulators have been known various compounds functionalized derivatives of bicyclo[3.1.0]hexanol. The mGluR modulators therapeutically applicable for the treatment or prevention of mental disorders, schizophrenia, anxiety and related disorders, depression, bipolar disorder and epilepsy, and neurological diseases such as drug dependence, impaired cognitive function, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia, accompanied by muscle stiffness, cerebral ischemia, cerebral failure, myelopathy and head injuries. For example, in U.S. patent No. 6333428, issued December 25, 2001, describes some of mGluR agonists, which are derivatives of 2-amino-6-formello[3.1.0]hexane of the following formula:

in which each of R¹and R²choose from a group that includes

(1) hydrogen,

(2)_1-10alkyl,

(3) (C_3-8cycloalkyl and

(4)_{3-8 cycloalkyl-C1-5alkyl,}

and their pharmaceutically acceptable salts. In patent '428 stated that these compounds may be in the form of a racemate or can be in the form of enantiomers. In patent '428 also described some new intermediate compounds of the following formula:

in which R¹defined above.

In U.S. patent No. 6160009, issued December 12, 2000, disclosed class of functionalized derivatives of bicyclo[3.1.0]hexane of the following formula, which is therapeutically applicable as mGluR agonists:

in which R¹and R²together may represent a =O.

In U.S. patent No. 5750566, issued may 12, 1998, described mGluR agonist to the following formula:

known as LY 354740.

Getting described above mGluR modulators and intermediates described in the above-mentioned patents, Nakazato et al.,J. Med. Chem., 2000, 43, 4893-4909 and in WO 02/00595 (published in English as EP 1295862). However, the described syntheses have drawbacks that make them unsuitable for large-scale production. For example, in the syntheses described in the patent '428 and Nakazato, requires the racemic intermediates, which then need to be complicated methods under the Oia, including HPLC, resulting in poor performance. Usually known synthesis methods also require the use of expensive and hazardous reagents, such as Pd(OAc)₂and (PhSe)₂that should be present in stoichiometric quantities, and CH₂N₂. In addition, in the method of synthesis Nakazato as the last stage of the synthesis of the required hard hydrolysis using H₂SO₄at high temperature (145°C) for five days, resulting in low output and time-consuming selection of the final product of the previous derivative as.

It is clear that the mGluR modulators described in U.S. patent No. 6333428, 6160009 and 5570566 applicable as therapeutic agents. Essentially, there is a need to develop a method of producing these compounds, easily scalable, which are cost effective and relatively safe reagents and which, therefore, can be used in practice in large-scale production.

Currently, applicants have developed a new method of synthesis of a class of mGluR modulators on the basis of enantiomerically pure functionalized derivatives of bicyclo[3.1.0]hexane and enantiomerically pure intermediates.

The invention

The present invention relates to a new method C the importance of the class of mGluR modulators on the basis of enantiomerically pure functionalized derivatives of bicyclo[3.1.0]hexane of the formula (I)

in which R¹and R²independently selected from the group comprising

(1) hydrogen,

(2)_1-10alkyl,

(3) (C_3-8cycloalkyl and

(4) -(CH₂)_n-phenyl

where n is 1 or 2, and the above alkyl, cycloalkyl and phenyl is not substituted or substituted by one or more halogen, hydroxy, C_1-6the alkyl or C_1-6alkoxy,

X is chosen from the group comprising

(1) halogen and

(2) hydrogen, and

Q represents-CH₂- or-C(=O),

and their pharmaceutically acceptable salts.

In addition, the invention relates to new methods for producing compounds of the formula (II)

in which R³choose from a group that includes

(1) HE,

(2) -O-R^aand

(3) -NR^bR^c,

where R^achoose from a group that includes

(a)_1-10alkyl and

(b) (C_3-8cycloalkyl,

and R^anot substituted or substituted by one or more

(i)_1-10alkoxy,

(ii) hydroxy,

(iii) halogen,

(iv) SR^d,

(v) aryl, not substituted or substituted by one or more hydroxy, C_1-10alkoxy, C_1-10by alkyl or halogen,

(vi) heteroaryl, not substituted or substituted by one or more hydroxy, C_1-10alkoxy, C_1-10by alkyl or halogen, and

(vii) NR^eR^f;

R^b, R , R^eand R^fchoose from a group that includes

(a) hydrogen,

(b) (C_1-10alkyl and

(c)_3-8cycloalkyl,

and when R^b, R^c, R^eor R^frepresent_1-10alkyl or C_3-8cycloalkyl specified With_1-10alkyl or C_3-8cycloalkyl not substituted or substituted by one or more

(i) hydroxy,

(ii)_1-10alkoxy,

(iii) SR^d,

(iv) aryl, not substituted or substituted by one or more hydroxy, C_1-10alkoxy, C_1-10by alkyl or halogen, and

(v) heteroaryl, not substituted or substituted by one or more hydroxy, C_1-10alkoxy, C_1-10by alkyl or halogen, and

(vi) NR^gR^h;

where R^gor R^hrepresent hydrogen, C_1-10alkyl or C_3-8cycloalkyl,

or R^bor R^ctogether with the N atom to which they are attached, form a group

in which r is 1 or 2 and the group NR^bR^cmay be unsubstituted or substituted on the carbon atoms of the cycle one or more

(i) hydroxy,

(ii)_1-10alkoxy,

(iii) SR^d,

(iv) aryl, not substituted or substituted by one or more hydroxy, C_1-10alkoxy, C_1-10by alkyl or halogen, and

(v) heteroaryl, not substituted or substituted by one or more hydroxy, C_1-10alkoxy, C_{1-10/sub> by alkyl or halogen, and}

_{(vi) NR^gR^h;}

_{R^drepresents hydrogen or C1-10alkyl;}

X is chosen from the group comprising

(1) halogen and

(2) hydrogen, and

R⁴choose from a group that includes

(1) hydrogen,

(2)_1-10alkyl,

(3) Si-(R⁹)(R¹⁰)(R¹¹),

(4) C(=O)-R¹²,

(5) CH₂-phenyl, where the specified phenyl is not substituted or substituted by one or more substituents selected from the group comprising nitro, halogen, C_1-10alkyl and C_1-10alkoxy,

(6) (CH₂)_p-O-(CH₂)_q-X'-R¹⁴,

(7) tetrahydropyranyl,

where each of R⁹, R¹⁰and R¹¹represents a C_1-10alkyl or phenyl, and R¹⁴choose from a group that includes

(a) hydrogen,

(b) (C_1-10alkyl,

p is 1 or 2,

q is an integer from 1-10, and

X' represents O or communication,

and their salts.

The invention relates also to new ways of producing compounds of the formula (XII)

or their enantiomers (XII')

in which R³and X is defined above, and their salts.

Compounds of formula (II), (XII) and (XII') are intermediate compounds obtained in the synthesis process of mGluR modulators of formula (I). Methods of using the compound (XII) or (XII) to obtain mGluR modulators of formula (I) described in the aforementioned patents '566, '428 and '009 and Nakazato et al.,J. Med. Chem., 2000, 43, 4893-4909. The invention relates also to a number of new intermediate compounds obtained in the synthesis process in accordance with this invention.

Brief description of drawings

The invention is described in connection with the accompanying drawings, where:

Figure 1 is a powder x-ray (XPRD) crystalline forms of cleaners containing hydrochloride salt of (+)-(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and

in Fig. 2 shows the curve of differential scanning calorimetry for the crystalline forms of cleaners containing hydrochloride salt of (+)-(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

Detailed description of the invention

The present invention is directed to methods of obtaining functionalized derivatives of bicyclo[3.1.0]hexane of the formula (I)

in which R¹and R²independently selected from the group comprising

(1) hydrogen,

(2)_1-10alkyl,

(3) (C_3-8cycloalkyl and

(4) (CH₂)_n-phenyl,

where n is 1 or 2, and the above alkyl, cycloalkyl and phenyl is not substituted or substituted by one or more halogen, hydroxy, C_1-6the alkyl or C_1-6alkoxy,

X is chosen from the group comprising

(1) halogen and

(2) hydrogen, and

Q represents-CH - or-C(=O),

and their pharmaceutically acceptable salts.

In one of the embodiments the invention is directed to a method of obtaining compounds of formula (IA):

in which X, R¹and R²defined above.

In this embodiment, the invention involves the oxidation of the intermediate compounds of formula (II):

in which X, R³and R⁴defined above,

obtaining the compounds of formula (IV):

removing protection from a hydroxyl group of the compounds of formula (IV) with a compound of the formula (V):

and the interaction of the compounds of formula (V) with the compound of the formula (VI)

in which each of R⁵and R⁶independently selected from the group comprising

(1) hydrogen,

(2)_1-10alkyl,

(3) (C_3-8cycloalkyl and

(4) (CH₂)_m-phenyl,

where m is 0, 1 or 2, and

R⁷choose from a group that includes

(1) hydrogen, and

(2) Si-(R⁹)(R¹⁰)(R¹¹), where each of R⁹, R¹⁰and R¹¹represents a C_1-10alkyl or phenyl,

obtaining the compounds of formula (VII):

After that, the connection of the formula (VII) is oxidised to produce a connection form is s (VIII):

which is converted into a compound of formula (IX):

Then the compound of formula (IX) is converted into the desired compound of formula (IA):

in which X, R¹and R²defined above.

In preferred embodiments of the method of obtaining the compounds of formula (IA) X is a fluorine. In other preferred embodiments, implementation of the X represents hydrogen.

In preferred embodiments of the method of obtaining the compounds of formula (IA) R¹and R²represent hydrogen.

In preferred embodiments of the method of obtaining the compounds of formula (IA) R³is methoxy, ethoxy or benzyloxy.

In the method of obtaining compounds of formula (IA) are preferred groups R⁴are TBS, TMS and TES. A preferred group R⁷is TMS.

In preferred embodiments of the method of obtaining the compounds of formula (IA) R⁵and R⁶selected from the group comprising methyl and phenyl. It is preferable that R⁵=R⁶.

In preferred embodiments of the method of obtaining the compounds of formula (IA) phase transformation of the compound (IX) into the compound (I) includes the hydrolysis of the compound (IX).

The invention n is purposed to new intermediate compounds of formula (VII), (VIII) and (IX):

and

which are formed during the synthesis of mGluR modulators of formula (I)and their salts. In the compounds of formula (VII), (VIII) and (IX) R³, R⁴, R⁵and X is defined above.

The present invention is also directed towards methods of obtaining the intermediate compounds of formula (II):

in which R³, H and R⁴defined above, and their salts. In this method the compound of formula (X):

in which X is hydrogen, and R³defined above, is subjected to epoxydecane, for example, by reaction with a peroxide, such as tert-butyl hydroperoxide, or other oxidants (including nagkalat, such as natantia acid and peracetic acid), preferably in the presence of a metal catalyst, such as VO(acac)₂. After that, the hydroxyl group of compound (X) can be protected, for example, using TBS or TMS, resulting in the compound of formula (XI):

in which X is hydrogen, and R⁴defined above. After that, the connection can be fluoridate (where X is fluorine). Alternatively, the compound (X) can be first to fluoridate (where X is F). Then fluorinated with the Association can be subjected to the above epoxydecane.

An alternative way of obtaining the epoxy derivative can be accomplished through gelegenheden reaction with a source of halogen. For example, the compound of formula (X) can be administered during the interaction with N-bromosuccinimide followed by treatment with a base, and then to allocate epoxy product.

Then protected with epoxy derivative (XI) being in communication with a suitable base in the presence of a Lewis acid receiving compound of formula (II):

in which X, R³and R⁴defined above. Then the compound of formula (II) can be oxidized to obtain the compound (IV):

which can then oxidize in accordance with the above-described stages of the process, obtaining the compounds of formula (IA).

Alternatively, the compounds of formula (IV) can be converted to compounds of formula (IA) using the methods described in the prior art. For example, Nakazato,J. Med. Chem.2000, 43, 4893-4909 described the use of the compounds of formula (IV) to obtain the compounds of formula (IA) in scheme 5 page 4898. In the method proposed Nakazato, want to get dithioketal, and then derived as.

In U.S. patent No. 6160009 in columns 8-13 describes the use of compounds of formula (IV) to obtain the compounds of formula (IA). This reaction produced flows through the water as well.

In preferred embodiments of the method of obtaining the compounds of formula (II) R³is methoxy, ethoxy or benzyloxy.

In preferred embodiments of the method of obtaining the compounds of formula (II) X is fluorine. In other preferred embodiments, implementation of the X represents hydrogen.

In the method of producing compounds of the formula (II) is preferred groups R⁴are TBS, TMS and TES.

In other preferred embodiments, the implementation of this method, the oxidation of compound (II) comprises contacting the compound (II) with RuCl₃and oxidant. The preferred oxidants are bleach. Preferred bleach is NaClO.

The invention is directed to new intermediate compounds of formula (XA), (XI), (IVA) and (II)shown below:

In compounds (XA), (XI), (IVA) and (II) R³, H and R⁴defined above.

The invention is directed also to a method of obtaining intermediate anonovich compounds of the formula (XII):

and their enantiomers (XII'):

in which R³and X is defined above, and their salts.

In one of the embodiments of this method of obtaining compounds of formula (XII), the compound of formula (II)

in which X, R³and R⁴defined above, is introduced into the reaction for obtaining the compounds of formula (XIII), containing the following a leaving group, R⁸:

where R⁸choose from a group that includes

(1) halogen and

(2) O-SO₂-R¹²where R¹²choose from a group that includes

(a)_1-10alkyl,

(b) (C_1-10perfluoroalkyl,

(C) phenyl substituted or not substituted with one or more substituents selected from the group comprising nitro, halogen, C_1-10alkyl or C_1-10alkoxy.

After that, the group R⁴remove, getting below hydroxyl ester derivative (XIV):

which is then oxidised to produce the desired [3.1.0]bicyclic α,β-unsaturated ketone of formula (XII):

In one embodiment, the implementation of this method for obtaining compounds of formula (XII') a compound of the formula (II) is oxidised to produce a compound of formula (IV):

in which X, R³and R⁴defined above. Then the compound (IV) is injected into the reaction elimination, for example by reaction with a base, such as DBU, receiving the compound of formula (XII')

representing the corresponding enantiomer of the compounds is of formula (XII).

Ananova compound of formula (XII) or (XII') can be converted to the compound of formula (I) using methods known in the art. For example, Nakazato,J. Med. Chem. 2000, 43, 4893-4909 described the use of the compounds of formula (XII) to obtain the compounds of formula (IA) in scheme 5 page 4898.

In U.S. patent No. 5750566 described the use of the compounds of formula (XII) for compounds of formula (I), where Q is CH₂in column (12) in scheme IV.

In Dominguez et al,Tetrahedron: Asymmetry, 1997, 8, 511-514, describes the use of compounds of formula (XII) for compounds of formula (I), where Q is CH₂scheme 2 page 513. This method requires the derivative of as.

In preferred embodiments, the synthesis of compounds of formula (XII) or (XII') R³represents methoxy, ethoxy or benzyloxy.

In preferred embodiments, the synthesis of compounds of formula (XII) or (XII') X represents fluorine. In other preferred embodiments, implementation of the X represents hydrogen.

In the synthesis of compounds of formula (XII) and (XII') a preferred protective group, R⁴are TBS, TMS and TES.

In the synthesis of compounds of formula (XII) and (XII') a preferred group R⁸include On-tosyl (pair-toluensulfonyl), On-mizil and On-triplet.

The invention is also aimed at hydroch ridnyi salts of compounds of formula (I). In preferred embodiments, the implementation of this cleaners containing hydrochloride salt is a salt of the compounds of formula (I)in which X represents fluorine, and as R¹and R²are hydrogen that is designated as compound (I'):

which is a (+)-(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. The invention is also directed to a new crystalline polymorph cleaners containing hydrochloride salt of compound (I').

Definition

Used herein, the term "synthesis on Striker" refers to reactions known to experts in the field of organic synthesis, to obtain alpha aminonitriles.

Used herein, the term "essentially enantiomerically pure form" means that the desired enantiomer is present in amount of at least 50% e/e (enantiomeric excess) relative to the undesired enantiomer.

Used here, the term "Lewis acid" refers to a compound that can accept electrons.

Used here, the term "aryl" refers to a polyunsaturated, aromatic hydrocarbon Deputy, which may be a single ring or multiple rings (preferably from 1 to 3 rings), which can be condensed or covalently linked. Non-limiting examples of aryl g the SCP include phenyl, naftalina and diphenylol.

Used here, the term "heteroaryl" refers to a polyunsaturated, aromatic ring containing in a loop, at least one heteroatom (nitrogen, oxygen or sulfur). Heteroaryl group may be a single ring or multiple rings (preferably from 1 to 3 rings), which can be condensed or covalently linked. Non-limiting examples of heteroaryl groups include pyrrole, pyrazole, imidazole, pyridine, pyrazin, pyrimidine, furan, Piran, oxazol, isoxazol, purine, benzimidazole, quinoline, isoquinoline, indole, and so on.

In that case, when defined here heteroaryl group is substituted, the Deputy may be linked to a carbon atom of the cycle this heteroaryl group or a heteroatom cycle (i.e. nitrogen, oxygen or sulfur), which have valences, allowing the substitution. Preferably Deputy linked to the carbon atom of the cycle.

Used herein, the term "halogen" refers to fluorine, chlorine and bromine. The preferred halogen is fluorine.

Used here, the term "alkyl", by itself or as part of another substituent, means a hydrocarbon radical with a linear or branched chain, containing the indicated number of carbon atoms (for example, C_1-10alkyl means alkylen the th group, containing from one to ten carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, hexyl and so on.

Used here, the term "alkoxy"by itself or as part of another substituent means a group O-alkyl in which alkyl is defined above, including linear or branched alkyl groups.

Used here, the term "cycloalkyl"by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical, containing the indicated number of carbon atoms (for example, C_3-8cycloalkyl means cycloalkyl group containing from three to eight carbon atoms).

Used here, the term "pharmaceutically acceptable" refers to molecular objects and compositions, which are generally regarded as safe", for example, which are physiologically tolerated when administered to man, as a rule, do not cause allergic or similar adverse reactions such as stomach upset, dizziness and so on. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by the regulatory authority of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally accepted the th Pharmacopoeia for use in animals and in particular, for the people.

In one embodiment, the implementation of the method of the invention are represented in the diagram below, 1.

Scheme 1

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸and X is defined above.

Optically active TRANS-hydroxy ester 1 can be obtained in accordance with the instructions of Partridge et al.,Org. Synth., 1985, 83, 44. See also Tolstikov et. al,J. Org. Chem.USSR, 1989, 25(1.2) and 1990, 26(7.1, 1274). TRANS-hydroxy ester 1 preferably has more than 90% of the e/s, more preferably more than 95% of the e/e and even more preferably more than 96% e/E.

TRANS-hydroxy ester 1 can be fluoridate, not protecting the secondary alcohol group receiving compound 2.

One way to achieve the desired fluorination involves reaction with a fluorinating agent such as N-forbindelseshastighed (NFSI) with a strong base in a suitable solvent, such as tetrahydrofuran. Preferably, this reaction proceeded at the temperature below -65°C., preferably below -75°C., most preferably below -78°C. Suitable strong bases include diisopropylamide lithium (LDA), tetramethylpiperidine lithium hexamethyldisilazide lithium (LHMDS) or the corresponding potassium salts or sodium.

You can then implement stereoselective epoxidation 2 reaction in toluene with an oxidant, such as a derived peroxide (for example, Gidropress tert-butyl), and a catalyst (e.g., a catalytic amount of acetylacetonate of vanadyl (VO(acac)₂). Preferably, the reaction proceeded at a temperature of about from about 0°to about 40°C.

Alternative oxidants include meta-chloroperoxybenzoic acid (mCPBA). The final epoxide 3 get the form of the TRANS-isomer.

Alternatively, TRANS-hydroxy ester 1 can first be subjected to a stereoselective epoxydecane, and the resulting epoxide 2' to fluoridate, receiving the connection 3.

Epoxidation can also be as a result of processing 1 (or fluorinated compounds 2) halogenation agent such as NBS or NIS, in a suitable solvent (for example, in a mixture of DMSO and water). After that, the connection 1 forms derived gelegenheden, which is subjected to cyclization under the action of a base (such as DBU) with the formation of epoxide.

When the protection of the hydroxyl group of 3 protective agent R⁴for example silyl protective agent such as tert-butyldimethylsilyl (TBSCl) in suitable conditions, for example, imidazole, DMF, get protected epoxy compound 4 below:

Then protect the military epoxide 4 can be maintained in an intramolecular reaction cyclopropylamine with opening of the epoxide. This reaction proceeds by adding the base in the presence of a Lewis acid such as Et₃Al. Preferably the reaction proceeds at about -50°C.

In a preferred embodiment, the connection 4 is first treated with Et₃Al, and then added dropwise LiHMDS. This reaction can occur over a period of from 0.5 to 6 hours at temperatures from -20°C to -80°C. the Preferred time is about 1 hour. The preferred temperature is about -60°C. Alternative Lewis acid, which can be used in this reaction include RTi(OR)₃, R₂Ti(OR)₂, RAlX₂or R₂AlX, where X is a halogen or inorganic radical, and each R represents a hydrocarbon group. Examples of Lewis acids include Al(OiPr)₃, Ti(OiPr)₄apirat BF₃Et₂Zn, Et₃Al and Sc(OTf)₃. Compound 5 obtained as desired stereoisomeric forms.

Oxidation obtained free of alcohol and removing the protective group leads to the bicyclic ketone 7 (compound II). Preferred oxidants include chemically pure sodium hypochlorite solution or industrial bleach. The reaction may proceed in the presence of catalytic amounts RuCl₃and in the presence of acetic acid (1.5 equivalent is allentow) at 0°C in acetonitrile. Then an excess of sodium hypochlorite should be removed (for example, by blanking isopropyl alcohol). Adding any acid (for example, 20 mol.% 1M HCl) to a solution of acetonitrile leads to the removal of the protective group R⁴.

Compound 7 can be secured in the form of ketala 8 by reaction with a diol derivatives. A preferred group R⁷is TMS.

The reaction proceeds in the presence of acid (e.g., 0.1 equivalent) at a temperature of from about 0°to about -10°C. the Preferred acid is TfOH or TfOTMS.

As a result of oxidation of the secondary alcohol 8 receive ketone 9.

The oxidation reaction can proceed at any oxidizing conditions, such as conditions Swarna. Alternatively, oxidation may occur in the presence of RuCl₃(0,5 mol%) of NaClO in acetonitrile and acetic acid at a temperature of from 0°C. to room.

Then the connection 9 is introduced into the reaction Striker with ammonia. This reaction may proceed in an alcohol solvent (e.g. methanol) with ammonia at room temperature.

You can then add TMSCN at a temperature of from -10°C. to 0°C. TMSCN can be replaced by KCN/NaCN in the presence of acids. The reaction leads to the desired aminonitriles 10 with high diastereomeric what ewnetu.

Then the connection 10 is subjected to hydrolysis, getting the desired 2-amino-6-formello[3.1.0]hexane (compound 11).

The hydrolysis reaction can proceed for 5 hours using a 1:3 mixture of acetic acid and 8 M HCl at 75°C. alternatively, the reaction may proceed in the presence of 60% H₂SO₄approximately at 100°C for about 2 hours, or alternatively, when processing a mixture of acetic acid/H₂SO₄at 60°C for approximately 2 hours.

After that, the desired compound 11 can be isolated in the form of cleaners containing hydrochloride salts using methods known to experts in this field of technology.

In another embodiment, the method of the invention are represented in the diagram below 2.

Scheme 2

where X, R³, R⁴and R⁸defined above.

Figure 2 optically active TRANS-hydroxy ester 12 was obtained according to the instructions above in the description of scheme 1. Epoxidation 12 flows diastereoselective, leading to epoxide 13, protection of the hydroxyl group in 13 leads to 14, while processing 14 Lewis acid, followed by treatment with a base get bicyclo[3.1.0]connection 15. Application enantiomer 12, described by Partridge et al.,Org. Synth., 1985, 83, 44, will lead to enantio the ' 13, 14 and 15.

Monogamistic [3.1.0]bicyclic diol 15 (which is identical to the 5 of scheme 1) was transferred to [3.1.0]bicyclic α,β-unsaturated ketone. In this diagram, the hydroxyl group in the alcohol 15 is transformed into a leaving group, R⁸and the protective group R⁴remove, receiving hydroxyl ester 17. Suitable leaving group, R⁸include sulfonate (for example, para-toluensulfonate) and halides. Oxidation of 17 cause the elimination of the leaving group R⁸getting in the [3.1.0]bicyclic α,β-unsaturated ketone 18, which can be used for the synthesis of mGluR agonists 19 (which is identical to 11 of scheme 1) and 20, in accordance with guidance issued by the U.S. patent nos 5750566, 6333428 and 6160009 and Nakazato et al.,J. Med. Chem.,2000, 43, 4893-4909.

In another embodiment, the method of the invention is depicted in the following scheme 3:

where X, R³and R⁴defined above. Scheme 3 shows the synthesis of the enantiomer may 18 (scheme 2).

The above-described chemical structure include each enantiomer or in an enantiomerically pure form or in the form of a mixture.

Source materials and reagents for the method described here are either commercially available or known from the literature or can be obtained according to literature methods described for analogous compounds. Skills, neo is required for carrying out reactions and purification of the obtained reaction products, well-known specialists in this field of technology. Cleaning methods include crystallization, distillation, chromatography, normal phase or reversed phase.

The following examples are given only for illustration and do not constitute limitations of the described invention. Examples 1-10 illustrate a method according to scheme 1. Examples 11-15 illustrate a method according to scheme 2. Examples 16 and 17 illustrate a method according to scheme 3.

EXAMPLE 1

Metalfor[(1R,5R)-5-hydroxycyclopent-2-EN-1-yl]acetate 2

To a solution of Diisopropylamine (10,8 ml of 76.8 mmol) in THF (28 ml) was added a solution of utility (28,2 ml of 70.4 mmol, 2.5 M in hexane) over 40 minutes, maintaining the temperature of the reaction mass in the range from 0 to 5°C. the resulting solution was stirred at 0°C for 3 min before cooled down to -78°C in a bath of dry ice and acetone. To a solution of LDA was added dropwise a solution of ester 1 (of 5.00 g of 32.0 mmol) in THF (41,3 ml) over 45 min, keeping the temperature of the reaction mass below -73°C, and the resulting solution was stirred at -78°C for 20 min getting the solution dianion orange or dark orange) color. In a separate flask was loaded N-forbindelseshastighed (14.1 g, with 44.8 mmol) and THF (62 ml) and the resulting solution was cooled to -96°C in a bath of liquid nitrogen-acetone. To a suspension ferrous what about the reagent was added from a dropping funnel a solution of dianion for 1 h, maintaining the temperature of the reaction mass at about -95°C. the Funnel and the flask was rinsed with 2.5 ml of THF and poured it into the reaction mixture. The resulting mixture was stirred at -96°C for 1 h before being heated to -80°C for 30 min for 7 min was slowly added acetic acid (11 ml) in THF (5 ml). The mixture was allowed to warm to ambient temperature after addition of MTBE (100 ml). The precipitate was removed by filtration and thoroughly washed with MTBE (70 ml × 6). The combined filtrate and wash fractions were again filtered and analyzed by HPLC. The chemical yield was 86%. The filtrate was passed through a small layer of silica gel (30 g) and washed this layer MTBE (200 ml). The combined solution MTBE was concentrated under reduced pressure. The residue was dissolved in EtOAc (250 ml) and washed with saturated solution of NaHCO₃(170 ml). The aqueous layer was again extracted with EtOAc (60 ml × 2). The combined organic solutions were washed with saturated salt solution (60 ml) and dried over Na₂SO₄. In the process of evaporation of the solvent was obtained the crude ester, which was subjected to distilled from a flask into the flask (1.6 mm RT. Art.), obtaining the ester as a yellow oil.

Analytically pure sample was obtained as colourless oil in the subsequent flash chromatography on a column of silica gel.

¹H NMR (400 MHz, CDC ₃): δ of 5.84 (m, 1H), of 5.55 (m, 1H), 4.95 points (DD, J = 48,8, and 5.5 Hz, 1H), 4,49 (dt, J = 7,2, 4.6 Hz, 1H), 3,82 (s, 3H), 3,11 (DM, J = 24,4 Hz, 1H), 2,75 (m, 1H), of 2.51 (s, 1H), 2,33 (m, 1H);¹³With NMR (101 MHz, CDCl₃): δ 170,02 (d, J = 24,1 Hz), 132,27, 126,13 (d, J = 5.0 Hz), 89,52 (d, J = 188,0 Hz), 73,92 (d, J = 4.0 Hz), 57,12 (d, J = 20,1 Hz), 52,64, 41,85;¹⁹F NMR (376 MHz, CDCl₃): -196,5; IR (film) 3409, 3059, 1744, 1439, 1288, 1209, 1153, 1099, 1048, 951, 733 cm^-1;= -123,5 (c1,02, CHCl₃).

EXAMPLE 2

Metalfor[(1R,2S,3R,5S)-3-hydroxy-6-oxabicyclo[3.1.0]Gex-2-yl]acetate 3

To a solution of olefin 2 (1,92 kg, 11.0 mol) in toluene (a 4.83 l) was added acetylacetonate of vanadyl (VO(acac)₂, 58,3 g, 0.22 mol) at 0°C. After adding to the solution a solution TNR (5,7 M in decane, and 38.6 ml) at 0°C. the resulting suspension was allowed to warm up to 14°C. To the reaction mixture was slowly added additional solution TNR (5,7 M in decane, 4,36 l) for 50 min, maintaining the temperature of the mixture in the range of 14-28°C. the resulting suspension was stirred for another 2 h, and then was heated at 40°C for 8 hours Excess TNR extinguished aqueous solution of Na₂S₂O₃(2.95 kg Na₂S₂O₃and 4,71 kg N₂About), which was slowly added at 0°C. the resulting mixture was stirred at 20°C. for 1.5 hours, the Disappearance of peroxides was confirmed using indicator paper. The aqueous layer was separated and was extracted with tOAc (9,42 l × 2). The combined organic solutions were washed with a saturated solution of salt (6,33 l). Salt layer re-extracted with EtOAc (3,42 l × 4). GC sample the combined organic solutions indicated the presence of product 3. The combined organic solutions were concentrated and the resulting residue was purified by chromatography on silica gel in the Cup filter (first was suirable a mixture of hexane/EtOAc (4/1), then pure EtOAc). Analytically pure sample was obtained by flash chromatography on a column of silica gel (hexane/MTBE) followed by recrystallization (EtOAc) as pale yellow crystals: TPL 31-33°C;¹H NMR (400 MHz, CDCl₃): δ 5,01 (DD, J = 48,3, 3,9 Hz, 1H), 4,13 (user. s, 1H), 3,86 (s, 3H), 3,71 (m, 1H)and 3.59 (m, 1H), 2,77 (DD, J = 32,8, 3,9 Hz, 1H), 2,30 (user. s, 1H), 2,11 (m, 2H);¹³With NMR (101 MHz): δ 168,4 (d, J = 24,1 Hz), at 88.1 (d, J = 186,1 Hz), and 73.2 (d, J = 1.6 Hz), 58,4, 57,1 (d, J = 5.6 Hz), 52,8, 51,6 (d, J = 19.3 Hz), 37,7 (d, J = 1.6 Hz);¹⁹F NMR (376 MHz, CDCl₃): δ -200,8 (DD, J = 48,3, 32,8 Hz); ICSDm/z191 (M+1), 189 (M-1), 172 ([M-H₂On]⁺), 59 ([SOON₃]⁺the main peak);= -56 (c1,0, CHCl₃).

EXAMPLE 2 the Sabbath.

Methyl[(1R,2S,3R,5S)-3-hydroxy-6-oxabicyclo[3.1.0]Gex-2-yl]acetate

To a solution of olefin 2' (50.0 mg, 0,320 mmol) in wet DMSO (6,4 μl of N₂About 1.2 ml DMSO) at room temperature was added NBS (68,4 mg, 0.384 mmol). After stirring the resulting solution at room temperature for 4.5 h was added 10 mg of NBS. The reaction mixture was stirred for 2 h, diluted with EtOAc and washed with H₂O. the Aqueous layer was extracted with EtOAc (twice) and dried the combined organic layers over Na₂SO₄. The solvent was removed under reduced pressure and the resulting residue was dissolved in CH₂Cl₂(1.2 ml). Was added DBU (57,4 μl, 0.384 mmol) to this solution, which was stirred at room temperature for 18 hours the Solvent is evaporated, and the obtained residue was purified flash chromatography on a column of silica gel, receiving epoxide 3' in the form of a mixture of diastereoisomers, which are not separated chromatographically. The main diastereoisomer has the following spectral data:¹H NMR (400 MHz, CDCl₃): δ of 3.80 (DD, J = 11,6, 5.6 Hz, 1H), and 3.72 (s, 3H), of 3.65 (m, 1H), 3,61 (m, 1H), 2,68 (DD, J = 8,4, 7.2 Hz, 1H), 2,36 (d, J = 11,6 Hz, 1H), and 2.26 (DD, J = 15,7, 7.2 Hz, 1H), measuring 2.20 (DD, J = 15,7, and 8.4 Hz, 1H), 2,11 (d, J = 15.3 Hz, 1H), 2,02 (DD, J = 15,3, and 5.6 Hz, 1H).

In a similar reaction conditions also received the following epoxides:

EXAMPLE 3

Methyl[(1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-oxabicyclo[3.1.0]Gex-2-yl)fluoroacetate 4

To a solution of apocopate 3 (1.60 kg, 8,40 mol) and DMF (3,40 l) were added imidazole (1,26 kg, 18.5 mol) at 10°C. To the reaction mixture was added TBSCl (1.52 kg, 10.1 mol), maintaining the temperature of the mixture below 8°C. the resulting solution was stirred at 5°C for 10 min, then was allowed to warm to 20°C for 30 min and was stirred 2 h at the same temperature. The expenditure of the original alcohol controlled method GC and diluted the reaction mixture with cold toluene (17,0 l, 5°C). The resulting mixture was washed with H₂On (5,67 l), saturated aqueous NaHCO₃(5,67 l), N₂On (5,67 l × 2) and saturated salt solution (5,67 l). Sample organic solution indicated the presence of 4. The result of concentrating the solution has received a 4 in the form of a yellow liquid, which was used in the next stage without additional purification. Analytically pure sample was obtained column flash chromatography on silica gel (hexane/MTBE) as colorless crystals: TPL 28-30°C;¹H NMR (400 MHz, CDCl₃): δ 5,00 (DD, J = 48,2, 3.5 Hz, 1H), 4,45 (m, 1H), 3,85 (s, 3H), 3,51 (m, 1H), 3,42 (m, 1H), 2,64-2,52 (DM, J = 34,5 Hz, 1H), and 2.14 (m, 1H), 1.91 a (m, 1H), 0,88 (s, N), 0,054 (s, 3H) and 0.051 (s, 3H);¹³With NMR (101 MHz, CDCl₃): δ 168, 8mm (d, J = 24,1 Hz), 88,3 (d, J = 186,1 Hz), 75,4 (d, J = 1.6 Hz), 58,3, 57,2(d, J = 7,2 Hz), 52,8 (d, J = 19.3 Hz), 52,7, 38,3, 25,9, 18,0, -4,5 and -4,7;¹⁹F NMR (376 MHz, CDCl₃): δ -199,9 (DD, J = 48,2, 34,5 Hz); ICSDm/z305 (M+1), 121 (main peak);= -27 (c1,0, CHCl₃).

EXAMPLE 4

Methyl(1R,2R,4S,5S,6R)-2-{[tert-butyl(dimethyl)silyl]oxy}-6-fluoro-4-hydroxybutyl[3.1.0]hexane-6-carboxylate 5

To a solution of epoxide TBS-ether 4 (sample weight 1.60 kg, 5,24 mol) in THF (16,1 l) was added a solution of Et₃Al (1.0 M in hexane, 6.81 in l, for 6.81 mol), maintaining the temperature of the mixture at -60°C for 1 h, and the resulting solution was stirred at -60°C for 20 minutes To the reaction mixture was added LHMDS (1.0 M solution in hexane, 7,86 l, 7,86 mol) over 1 h, maintaining the temperature of the mixture at -60°C., and the reaction mixture was stirred at -60°C. the reaction was monitored by GC method. After complete consumption of the epoxide (6 h) was added an aqueous solution of citric acid (3 M, 10.5 l) for 1 h, maintaining the temperature of the mixture at -50°C. After addition of MTBE (12,4 l) the resulting suspension was given to gradually warm to 15°C. under stirring. After you add the effect of H ₂On (4,93 l) and the mixture was turned into a two-phase solution. The organic layer was separated and washed twice with saturated solution of NaHCO₃(11,1 l, then 5.6 l). GC sample organic solution indicated the presence of compound 5. In the concentration of the organic layer were obtained crude alcohol as a yellow oil, which was used in the next reaction without further purification.

Analytically pure sample was obtained column flash chromatography on silica gel in the form of a colorless amorphous solids:¹H NMR (400 MHz, CDCl₃): δ 4,47 (d, J = 4.4 Hz, 1H), 4,34 (m, 1H), 3,83 (s, 3H), 2,44 (d, J = 6,8 Hz, 1H), 2,37 (d, J = 11.2 Hz, 1H), 2,25 (d, J = 6,8 Hz, 1H), 2,07 (m, 1H), of 1.84 (m, 1H), 0,91 (s, N), 0,131 (s, 3H) and 0,128 (s, 3H);¹³With NMR (101 MHz, CDCl₃): δ 169,2 (d, J = 26.5 Hz), 79,7 (d, J = Hz 244,3), 74,1, 74,0, 52,9, 44,6 (d, J = 10.4 Hz), to 37.9 (d, J = 11.2 Hz), 25,8, 18,0, -4,8, -4,9;¹⁹F NMR (376 MHz, CDCl₃): δ -217,1 (m); ICSDm/z305 (M+1), 304 (M), 303 (M-1), 75 (main peak);= +7 (c1,1, CHCl₃).

EXAMPLE 5

Methyl(1R,2R,5S,6S)-2-{[tert-butyl(dimethyl)silyl]oxy}-6-fluoro-4-oxobicyclo[3.1.0]hexane-6-carboxylate 6

To a solution of bicyclic mono-TBS-diol 5 (2,08 kg; 6,83 mol) in acetonitrile (8.0 l) at -5°C. was added acetic acid (0,70 l) and water (2.5 l), then hydrate RuCl₃(14,20 g). To this mixture was added an aqueous solution of sodium hypochlorite (~13%; 7.0 l), for 2 h, keeping the temperature around 0°C. the resulting mixture was stirred at 0°C for another 1 h before until the entire bicyclic mono-TBS-diol 5 not disappeared, which was controlled by TLC and NMR. An excess of aqueous sodium hypochlorite was dissolved by addition of isopropanol (0,70 l), kept at 0°C for 15 minutes Two layers were separated and the aqueous layer is discarded. The solution used in the next stage without additional purification. Analytically pure sample was obtained column flash chromatography on silica gel (MTBE/hexane) as colorless crystals: TPL 70-71°C;¹H NMR (400 MHz, CDCl₃): δ of 4.66 (d, J = 5.4 Hz, 1H), 3,86 (s, 3H), of 3.73 (s, 3H), by 2.73 (m, 2H), 2,54 (dt, J = 19,1, 5.7 Hz, 1H), 2,22 (DD, J = 19,1, and 3.8 Hz, 1H), 0,91 (s, N), of 0.13 (s, 3H), of 0.11 (s, 3H);¹³With NMR (101 MHz, CDCl₃): δ 206,2, 167,1 (d, J = 26,1 Hz), 78,9 (d, J = 246,4 Hz), 67,6 (d, J = 2,8 Hz), 53,4, and 47.5 (d, J = 3,9 Hz), 42,0 (d, J = 11,4 Hz), 39,6 (d, J = 13.3 Hz), 25,7, 18,0, -4,76, -4,78;¹⁹F NMR (376 MHz, CDCl₃): δ -210,7 (m);= +58,2 (c0,50, CH₃OH).

EXAMPLE 6

Methyl(1R,2R,5S,6S)-6-fluoro-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate 7

The above-mentioned organic layer containing TBS-ketone 6 (6,83 mol), was heated to 22°C was added 1 M HCl (1,37 l). The mixture was stirred at 22-24°C for 3.5 h to remove all TBS groups. To this mixture was added a saturated solution of sodium bicarbonate (4.8 l). The mixture was stirred for 15 min, diluted with isopropylacetate (20 l) and separated the organic layer. The aqueous layer was again extracted with isopropylacetate (6 l). The combined organic layers were concentrated to dryness and purified compound by chromatography on silica gel in the Cup filter (first was suirable 30% MTBE in hexane, then only MTBE)to give compound 7 in the form of almost white crystals. Analytically pure sample was received additional column flash chromatography on silica gel in the form of colorless crystals: TPL 61-62°C;¹H NMR (400 MHz, CDCl₃): δ 4.92 in (user. s, 1H), 3,85 (s, 3H), of 2.86 (DD, J = 6,2, 2.1 Hz, 1H), 2,71 (d, J = 6.2 Hz, 1H), 2,61 (dt, J = 19,4, 5.7 Hz, 1H), 2,59 (user. s, 1H), 2,30 (DD, J = 19,4, and 3.7 Hz, 1H);¹³With NMR (100 MHz, CDCl₃): δ 206,9, 167,0 (d, J = 26,2 Hz), 79,0 (d, J = 246,6 Hz), 67,0 (d, J = 3.1 Hz), 53,5 and 46.8 (d, J = 4, 2 Hz), 41,6 (d, J = 11.8 Hz), 39,4 (d, J = 131 Hz); ¹⁹F NMR (376 MHz, CDCl₃): δ -210,6;= +77 (c0,50, CH₃OH).

EXAMPLE 6A

Methyl(1R,2R,5R,6R)-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate

TBS-ether 6' (150 mg, 0,528 mmol) was treated with 1M HCl (0,106 ml) in acetonitrile (0.8 ml) at room temperature for 2 hours the Reaction mixture was diluted with EtOAc, was suppressed by the addition of a small quantity of saturated aq. NaHCO₃off , washed with N₂O and saturated aqueous salt solution (twice) and dried over Na₂SO₄. The solvents were removed under reduced pressure and the obtained residue was column purified flash chromatography on silica gel, receiving the connection 7' in the form of colorless solids:¹H NMR (400 MHz, CDCl₃): δ 4,60 (d, J = 5,2 Hz, 1H), and 3.72 (s, 3H), to 2.67 (DD, J = 5,2, 3.6 Hz, 1H), 2,42 (DD, J = 5,2, 2.4 Hz, 1H), 2,34 (DD, J = 18,9, at 5.27 Hz, 1H), 2,22 (user. s, 1H), 2,08 (d, J = 18,9 Hz, 1H), 1,93 (DD, J = 3,6, and 2.4 Hz, 1H);¹³With NMR (101 MHz, CDCl₃): δ 208,8, 169,8, 68,3, 52,5, 42,7, 36,2, 34,2, 25,2.

EXAMPLE 7

Methyl(1S,4R,4'S,5R,5'S,6S)-6-fluoro-4-hydroxy-4',5'-diphenylene[bicyclo[3.1.0]hexane-2,2'-[1.3]dioxolane]-6-carbox ilat 8

To a solution of hydroxyketone 7 (1.09 kg; 5,76 mol) and CH₂Cl₂(7,7 l) was added a solution of (S,S)-bis-About-TMS-hydrobenzoin (2,01 kg analysis; the ceiling of 5.60 mol) and CH₂Cl₂(2.55 l). The solution was cooled to -20°C. Through the addition funnel was loaded TfOH (50,9 ml; 0,576 mol) for 4 min at -15 ° ~-20°C. the Solution was heated to -10°C and kept at -10°C. for 1.5 hours To the reaction mixture at -10°C was added an additional amount of solution (S,S)-bis-About-TMS-hydrobenzoin (107 g analysis; 0,298 mol) in CH₂Cl₂(188 g). The reaction was terminated after 30 minutes dopolnitelnoi holding at -10°C. the Reaction mixture was suppressed by the addition of pyridine (46,9 ml; 0,576 mol) at <-15°C. the Solution was heated to -10°C, washed in turn with 5 wt.% a cold aqueous solution of NaHCO₃(3.75 l), 1 M cold aqueous HCl (8.6 l), 5 wt.% a cold aqueous solution of NaHCO₃(3.75 l) and 10 wt.% cold water NaCl (5.0 liter), dried over Na₂SO₄(1.5 kg). The organic solvent layer was replaced with acetonitrile and used in the next reaction without further purification. Analysis of this solution by HPLC at this stage indicated the presence catalogo alcohol 8. Analytically pure sample was obtained column flash chromatography on silica gel in the form of colorless crystals: TPL 118-120°C;¹H NMR (401 MHz, CDCl₃): δ 7,38-7,21 (m, 10H), 4,89 (d, J 8,3 Hz, 1H), a 4.83 (d, J = 8,3 Hz, 1H), 4,51 (user. s, 1H), with 3.89 (s, 3H), 2,54 is 2.51 (m, 2H), 2,43-is 2.37 (m, 2H), 2,18 (user. s, 1H);¹³With NMR (101 MHz, CDCl₃): δ 168,7 (d, J = 26,2 Hz), 136,6, 135,8, 128,7, 128,6, 128,5, 128,4, 126,9, 126,3, 117,7, 86,2, 86,1, 77,6 (d, J = 247,1 Hz), 71,1, 53,0, of 45.7 (d, J = 7.8 Hz), 37,5 (d, J = 12.1 Hz), 36,7 (d, J = 11,9 Hz);¹⁹F NMR (377 MHz, CDCl₃): δ -216,3.

EXAMPLE 8

Methyl(1S,4'S,5R,5'S,6S)-6-fluoro-4-oxo-4',5'-diphenylene[bicyclo[3.1.0]hexane-2,2'-[1.3]dioxolane]-6-carboxylate 9

To a solution of hydroxyketone 8 (2,04 kg analysis, 5,31 mol) in acetonitrile (36,7 l) was added to hydrate RuCl₃(8,25 g), then water (2.0 l) and acetic acid (0,41 l) at 0°C. To the reaction solution slowly over 19 min was added an aqueous solution of sodium hypochlorite (~13%; lower than the 5.37 l), maintaining the temperature of the reaction mixture below 4°C. the Solution is kept at 0-3,5°C for 2 h, the Reaction mixture was suppressed by addition of isopropanol (2.2 l) at 3.5°C. After 30 min of incubation at the same temperature, to the mixture was added to a cold aqueous NaHCO₃(5 wt.%, 10,7 l) for 12 min in the range from 0.4 to 3.3°C. the Obtained suspension was stirred for 30 min at 3°C was filtered and the product 9. The crude residue on the filter was washed with cold water (2 l × 2) and dried, receiving the first portion catalogo ketone 9. The filtrate and wash water were combined and separated layers. The organic layer was concentrated in vacuum. Received a suspension filter is Ali. The filter residue was washed with water (0,48 l × 2) and recrystallized from acetonitrile (1.8 l) and water (1.08 l), receiving the second portion of catalogo ketone 9. Analytically pure sample was obtained column flash chromatography on silica gel in the form of colorless crystals: TPL 58,5-59,5°C;¹H NMR (401 MHz, CDCl₃): δ 7,40-7,34 (m, 6N), 7,28-7,25 (m, 4H), equal to 4.97 (d, J = 8,4 Hz, 1H), 4,88 (d, J = 8,4 Hz, 1H), 3,93 (s, 3H), 3,10 (DD, J = 6,4, 2.0 Hz, 1H), 2,94 (d, J = 4.0 Hz, 2H), 2,87 (d, J = 6,4 Hz, 1H);¹³With NMR (101 MHz, CDCl₃): δ 201,6, 166,9 (d, J = 25,7 Hz), 136,1, 135,3, 129,0, 128,8, 128,72, 128,69, 126,8, 126,5, 110,8, 86,3, 85,8, 78,9 (d, J = 251,6 Hz), 53,6, 48,3 (d, J = 3.3 Hz), 42,2 (d, J = 13,2 Hz)41,7 (d, J = 12.0 Hz);¹⁹F NMR (376 MHz, CDCl₃): δ -208,5.

EXAMPLE 9

(1S,4'S,5R,5'S,6S)-4-Amino-4-cyano-6-fluoro-4',5'-diphenylene[bicyclo[3.1.0]hexane-2,2'-[1.3]dioxolane]-6-carboxamide 10

To a solution of 7M ammonia in methanol (7,4 l, of 47.8 mol) and Ti(OiPr)₄(1.77 l, to 5.93 mol) at 23°C was added kotelny ketone 9 (2.11 kg, 1,89 kg in the form of pure 9, 4,94 mol). The mixture was stirred for 4 h at 20-23°C. the Mixture was cooled to -12°C and was added TMSCN (505 g, 5,09 mol). The mixture was heated up to-4.5°C and stirred at this temperature for 16 hours the Mixture was filtered and washed crystals cold Meon (7.0 l) and dried at 20-25°C under reduced pressure, getting aminonitriles 10 in the form of a colorless solid. Analytically pure sample was obtained and a column of chromatogr is via on silica gel in the form of colorless crystals: TPL 196,9-197,4°C;¹H NMR (400 MHz, DMSO-d₆): δ of 8.04 (s, 1H), 7,78 (s, 1H), 7,38-7,25 (m, 10H), of 5.15 (d, J = 8,8 Hz, 1H), 4,81 (d, J = 8,8 Hz, 1H), 2,86 (s, 2H), 2,78 (DD, J = 14,5, 3.2 Hz, 1H), 2.63 in (d, J = 6,8 Hz, 1H), 2,46 (d, J = 6,8 Hz, 1H), 2,23 (DD, J = 14,5, 4,4 Hz, 1H);¹³With NMR (101 MHz, DMSO-d₆): δ 168,7 (d, J = 23,3 Hz), 136,5, 135,9, 128,6, 128,5, 128,5, 127,1, 126,9, 123,4, 115,1, 84,7, 84,3, 81,1 (d, J = 255,4 Hz), 54,6, 48,3 (d, J = 7,2 Hz), 36,6 (d, J = 11.2 Hz) and compared with 35.9 (d, J = 10.4 Hz);¹⁹F NMR (377 MHz, DMSO-d₆): δ -211,6.

EXAMPLE 10

(1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 11

A mixture of aminonitriles 10 (1.63 kg crude, 1,55 kg per net), SPLA (3,25 l), N₂(3,25 l) and conc. HCl (6,50 l) was heated to 75±2°C for 4 h According to NMR data¹⁹F the reaction was completed. The solution was cooled to 18°C. and was extracted with CH₂Cl₂(1 × 9 l and 2 × 5 l). The aqueous layer was concentrated at 10-25 mm RT. Art. and the temperature of the mixture at 50°C to ~l Obtained suspension was cooled to 0°C. and stirred 1 h the Cooled suspension was filtered, and the residue from the filter containing the HCl salt of the product 11, kept in conditions of filtration under vacuum for 5-10 min to remove the greatest possible quantity of filtrate. Above the rest with filter HCl salt was added to water (5.0 l) at 65°C and washed with hot water (300 ml). The solution was allowed to cool down to 17°C for 45 minutes Brought the pH up to 1.25 50%NaOH (230 ml). Suspension of ohlord is whether to 0°C and was stirred for 45 minutes The suspension was filtered, washed with N₂On (2 × 1 l) and dried in nitrogen atmosphere, receiving almost white crystalline product 11 in the form of a monohydrate. Analytically pure HCl salt 11 was received from 20%HCl: TPL 195-220°C (decomp);¹H NMR (401 MHz, DMSO-d₆): δ 8,99 (s, 2H), is 3.08 (DD, J = 6,4, and 1.6 Hz, 1H), to 3.02 (d, J = 6,4 Hz, 1H), 2,86 (DD, J = 18,5, 3.6 Hz, 1H), 2.57 m (DD, J = 18,5, 4.8 Hz, 1H);¹³With NMR (101 MHz, DMSO-d₆): δ 201,3 (d, J = 2.7 Hz), 170,4, 166,3 (d, J = 25,7 Hz), 78,9 (d, J = 247,0 Hz), 58,1 (d, J = 1.5 Hz), 40,6 (d, J = 13.1 Hz), 36,8 (d, J = 11,1 Hz);¹⁹F NMR (377 MHz, DMSO-d₆): δ -204,8; Titration of Cl 13,96% (Theory 13,98%).

EXAMPLE 11

Methyl((1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-oxabicyclo[3.1.0]Gex-2-yl)acetate

To a solution of olefin 12 (4,25 g of 27.2 mmol) in toluene (10,8 ml) was added acetylacetonate of vanadyl (VO(acac)₂, 289 mg, of 1.09 mmol, 4 mol%). For 30 min was added to the solution TNR (14,3 ml of 81.6 mmol, 5.7 M in decane), maintaining the temperature of the reaction mass below 28°C. the resulting mixture was stirred at room temperature for 5.5 hours and was suppressed by the addition of saturated aq. Na₂S₂O₃. The aqueous layer was separated and was extracted with ethyl acetate (×5). The combined organic layers were washed with saturated salt solution and dried over Na₂SO₄. The solvents are evaporated and the resulting residue was purified flash chromatography on silica gel, receiving Epoque and-alcohol 13 in the form of colorless liquid, contains detachable part of the by-products. This alcohol (3,21 g) was treated with imidazole (2,78 g of 40.9 mmol) and TBSCl (3,36 g of 22.3 mmol) in DMF (7.2 ml) at ambient temperature to convert the hydroxyl group in TBS-ether. The reaction mixture was stirred at room temperature for 2.5 h, then was treated with MTBE (36 ml) and N₂O (12 ml). The organic layer was separated, washed with saturated aq. NaHCO₃N₂O and saturated salt solution and dried over Na₂SO₄. The solvent is evaporated, and the obtained residue was purified flash chromatography on silica gel, receiving TBS-ether 14 in the form of a colorless liquid:¹H NMR (400 MHz, CDCl₃): δ 4,08 (m, 1H), and 3.72 (s, 3H), 3,49 (m, 1H), 3,37 (m, 1H), 2.49 USD (m, 1H), 2,31 (d, J = 7.2 Hz, 1H), 2,31 (m, 1H), 2,09 (m, 1H), 1.93 and (m, 1H), 0,88 (s, N), and 0.04 (s, 3H), of 0.03 (s, 3H);¹³With NMR (101 MHz, CDCl₃): δ 171,9, 77,0, 60,4, 57,4, 51,7, 46,4, 37,2, 34,6, 25,8, 18,0, -4,7; ICSDm/z287 (M+1), 286 (M), 285 (M-1), 169 (main peak).

EXAMPLE 12

Methyl(1S,2R,4S,5R,6S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxybutyl[3.1.0]hexane-6-carboxylate

To a solution of epoxide 14 (3,52 g 12.3 mmol) in THF (37,8 ml) at -70°C was added a solution of Et ₃Al (16.0 ml, 16.0 mmol, 1 M in hexane). After stirring the resulting solution at -70°C for 10 min slowly over 30 min, was added a solution of LHMDS (18,4 ml, 18.4 mmol, 1 M in hexane). The resulting solution was stirred at -70°C for 100 min and was suppressed by the addition of aq. citric acid (24,9 ml, 3 M). After adding toluene (24,9 ml) the mixture was allowed to warm to ambient temperature and was added N₂(11.7 ml). The aqueous layer was separated and was extracted with MTBE (20 ml). The combined organic layers were washed with saturated aq. NaHCO₃(36 ml × 2) and saturated salt solution and dried over Na₂SO_4.The solvent is evaporated, and the obtained residue was column purified flash chromatography on silica gel, receiving bicyclic alcohol 15 as a colorless oil:¹H NMR (400 MHz, CDCl₃): δ 4,34 (d, J = 4.4 Hz, 1H), 4,18 (DD, J = 11,6, 4,4 Hz, 1H), 3,68 (s, 3H), 2,46 (d, J = 11,6 Hz, 1H), and 2.26 (DD, J = 6,0, 2.8 Hz, 1H), 2,10 (DD, J = 6,0, 2.8 Hz, 1H), 1,67 (d, J = 15.3 Hz, 1H), 1,49 (dt, J = 15,3, 4,4 Hz, 1H), of 1.16 (t, J = 2,8 Hz, 1H), 0,90 (s, N), of 0.13 (s, 3H), of 0.11 (s, 3H);¹³With NMR (101 MHz, CDCl₃): δ 172,2, 73,8, 73,6, 51,9, 40,3, 33,3, 33,0, 25,7, 21,8, 17,9, -4,7, -5,0; ICSDm/z287 (M+1), 286 (M), 285 (M-1), 169 (main peak).

EXAMPLE 13

Methyl(1S,2R,4S,5R,6R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(4-were)sulfonyl]oxy}bicyclo[3.1.0]hexane-6-carboxylate

To a stirred solution of alcohol 15 (929 mg, 3,24 mmol) in CH₂Cl₂(3.8 ml) at 0°C was added pyridine (2,62 ml, 32,4 mmol) and p-toluensulfonate (1.24 g, of 6.49 mmol). The resulting mixture was allowed to warm to ambient temperature and stirred at the same temperature for 15 hours To the reaction mixture was added saturated aq. NaHCO₃(5 ml) and stirred the mixture at room temperature for 1 h Aqueous layer was separated and was extracted with MTBE (10 ml × 2). The combined organic layer washed with 1 M HCl (40 ml), saturated aq. NaHCO₃(10 ml) and saturated salt solution (10 ml) and dried over Na₂SO_4.The solvent is evaporated, and the obtained residue was column purified flash chromatography on silica gel, receiving p-toluensulfonate ester 16 as colorless solids:¹H NMR (400 MHz, CDCl₃): δ 7,81 (d, J = 8.0 Hz, 2H), 7,33 (d, J = 8.0 Hz, 2H), 5,02 (d, J = 5,2 Hz, 1H), 4,27 (d, J = 4,8 Hz, 1H), the 3.65 (s, 3H), of 2.45 (s, 3H), 2,30 (DD, J = 5,6, and 2.8 Hz, 1H), 2,15 (DD, J = 5,6, and 3.2 Hz, 1H), 1,85 (d, J = 16,5 Hz, 1H), 1,64 (DDD, J = 16.5, and to 5.2, and 4.8 Hz, 1H), 1,06 (DD, J = 3.2, and 2.8 Hz, 1H), 0,86 (s, N), of 0.07 (s, 3H), of 0.04 (s, 3H);¹³With NMR (101 MHz, CDCl₃): δ 171,4, 144,5, 134,5, 129,7, 127,6, 82,4, 72,7, 52,0, 40,0, 34,8, 31,3, 25,7, 2,6, 21,1, 17,9, -4,7, -4.

EXAMPLE 14

Methyl(1R,2R,4S,5R,6R)-2-hydroxy-4-{[(4-methylphenylsulfonyl]oxy}bicyclo[3.1.0]hexane-6-carboxylate

TBS-ether 16 (1.86 g, 4,22 mmol) was treated 0,84 ml aq. HCl (1 M) in acetonitrile (9.4 ml) at room temperature for 4 h, the Reaction mixture was suppressed by the addition of saturated aq. NaHCO₃(8,7 ml) and MTBE (20 ml). The aqueous layer was separated and was extracted with MTBE (10 ml × 2). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure. As a result of processing the obtained residue hexane was obtained crystals were filtered and recrystallized from a mixture of hexane/EtOAc, getting pure alcohol 17 in the form of colorless crystals:¹H NMR (400 MHz, CDCl₃): δ of 7.82 (d, J = 8.0 Hz, 2H), 7,38 (d, J = 8.0 Hz, 2H), free 5.01 (d, J = 5,2 Hz, 1H), 4,24 (d, J = 5,2 Hz, 1H), to 3.67 (s, 3H), 2,47 (s, 3H), 2,33-of 2.28 (m, 2H), 1,93 (d, J = 16.5 Hz, 1H), 1,67 (dt, J = 16.5, and 5.2 Hz, 1H), of 1.16 (t, J = 3.0 Hz, 1H);¹³With NMR (101 MHz, CDCl₃): δ 171,1, 145,1, 133,9, 130,1, 127,8, 83,2, 72,7, 52,2, 39,3, 33,9, 30,8, 21,8, 21,7.

EXAMPLE 15

Methyl(1R,5S,6S)-4-oxobicyclo[3.1.0]Gex-2-ene-6-carboxylate

To a solution of DMSO (0,404 ml, 5,70 mmol) in CH₂Cl₂(2.6 ml) was added a solution of triperoxonane anhydride (0,604 ml, to 4.28 mmol) in CH₂Cl₂(1.5 ml) at -78°C. the resulting solution was stirred at -78°C for 30 min and was added to dissolve the alcohol 17 (0,885 g, to 2.85 mmol) in CH₂Cl₂with 4.1 ml (flask was rinsed with 1.0 ml of CH₂Cl₂). After stirring the resulting solution at -78°C for 30 min was slowly added Et₃N (1,59 ml of 11.4 mmol). The resulting mixture was stirred at -78°C for 2.5 h and extinguished the reaction mixture by the addition of N₂O (5 ml). After adding MTBE (10 ml) the mixture was allowed to warm to room temperature and the aqueous layer was separated and was extracted with MTBE (10 ml). The combined organic layer washed with 1M HCl (15 ml), saturated aqueous NaHCO₃(10 ml), N₂About (10 ml) and saturated salt solution (10 ml) and dried over Na₂SO₄. The solvent is evaporated and purified the resulting residue column flash chromatography on silica gel, obtaining the α,β-unsaturated ketone 18 in the form of pale yellow crystals:¹H NMR (400 MHz, CDCl₃): δ to 7.61 (DDD, J = 5,6, and 2.4, 0.8 Hz, 1H), 5,74 (d, J = 5.6 Hz, 1H), 3,71 (s, 3H), 2,96 (m, 1H), 2,62, (m, 1H), and 2.27 (m, 1H);¹³With NMR (101 MHz, CDCl₃): δ 203,1, 168,4, 159,5, 129,7, 52,3, 45,4, 30,0, 28,9.

EXAMPLE 16

Methyl(1S,2R,5R,6R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-oxobicyclo[3.1.0]hexane-6-carboxylate (21)

To a solution of DMSO (0,358 ml, 5,04 mmol) in CH₂Cl₂(2.5 ml) was added dropwise a solution of triperoxonane anhydride (0,534 ml of 3.78 mmol) in CH₂Cl₂(1.3 ml), maintaining the temperature of the reaction mixture below -70°C. Polucen the th solution was stirred at -78°C for 55 minutes Was added dropwise a solution of alcohol 15 (722 mg, 2,52 mmol) in CH₂Cl₂(3,7 ml + 1.0 ml rinse), maintaining the temperature of the mixture below -75°C. After stirring at -78°C for 30 min was slowly added triethylamine (1,05 ml, 7.56 mmol) over 15 min, maintaining the temperature of the reaction mixture below -74,5°C. the resulting mixture was stirred at -78°C for 30 min and allowed to warm to -20°C for 20 minutes the Reaction mixture was stirred for another at -20°C for 30 min and was suppressed by the addition of N₂O. the Organic layer was separated, diluted with MTBE, washed with 0.5 M HCl, H₂Oh, saturated aqueous NaHCO₃and saturated salt solution and dried over Na₂SO₄. The solvent is evaporated under reduced pressure and purified the resulting residue column flash chromatography on silica gel, getting a colourless solid 21 (673 mg, yield 94%):¹H NMR (400 MHz, CDCl₃): δ to 4.52 (d, J = 5,2 Hz, 1H), and 3.72 (s, 3H), 2.57 m (DD, J = 5,2, 3.6 Hz, 1H), 2.40 a (m, 1H), 2,28 (DD, J = 18,5, and 5.2 Hz, 1H), 1,99 (d, J = 18.5 Hz, 1H), 1,87 (DD, J = 3,6, and 2.8 Hz, 1H), 0,89 (s, N), of 0.11 (s, 3H), and 0.09 (, 3H);¹³With NMR (101 MHz, CDCl₃): δ 209,2, 170,0, 68,8, 52,4, 43,2, 36,8, 34,5, 25,7, 25,0, 18,0, -4,7, -4,8.

EXAMPLE 17

Methyl(1S,5R,6R)-4-oxobicyclo[3.1.0]Gex-2-ene-6-carboxylate (22)

TBS-ether 21 (50.0 mg, 0,176 mmol) was treated with DBU (0,0789 ml, 0,528 mmol) in CH₂Cl₂(0.9 ml) at room temperature for 1 h the Reaction mixture was diluted with MTBE, washed with 1 M HCl and saturated aqueous salt solution (twice) and dried over Na₂SO₄. The solvent was removed under reduced pressure and purified the resulting residue column flash chromatography on silica gel, receiving a colorless solid substance 22:+272,2 (c1,1, CHCl₃). Other spectral data identical to the data for α,β-unsaturated ketone 18 obtained in example 15.

Characteristics of polymorph cleaners containing hydrochloride salt of (1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 11.

Examination by means of x-ray analysis is widely used to determine molecular structure, crystallinity, and polymorphism. Radiographs (XRPD) was obtained for the crystalline form of the sample HCl salt synthesized in example 10, using Philips diffractometer. The measurements were carried out in the interval from 3,0080 degree to 39,9830 degrees (2 Theta).

XRPD shown in figure 1. For the identification of crystalline forms you can use the following reflection:

The list of peaks in the XRPD shown in the following table.

Thus, in one embodiment, the implementation of a polymorphic form of (1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid HCl has a d-a distance determined by x-ray diffraction on the powder, CuK alpha of about angstroms lower than the 5.37. In another embodiment, the polymorphic form of (1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid HCl has at least one d-a distance determined by x-ray diffraction on the powder, CuK alpha of about 4,52, 4,05, 3,84, 3,37, 2,96, 2,73, 2,67, 2,59 or 2,42 angstroms.

Differential scanning calorimetry (DSC) HCl salt obtained in example 10, was performed on the instrument TA Instruments DSC 2910 at heating rate 10°C/min from 20 to 175°C and 2°C/min from 175 to 255°C. in a nitrogen atmosphere in an open crucible. The results are presented in figure 2. From these results there is a wide interval of the melting temperature with an initial temperature of about 184°C, followed by an exothermic decomposition above 227°C.

Thus, in one embodiment, the implementation of a polymorphic form of (1R,2S,5S,6S)-2-amino-6-fluoro-4-oxoby is yclo[3.1.0]hexane-2,6-dicarboxylic acid HCl has an initial melting temperature, extrapolated differential scanning calorimetry, more than 184°C.

The text uses the following abbreviations:

Me: methyl;

Et: ethyl;

iPr: isopropyl;

Bu: butyl;

Ac: acetyl;

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;

NBS: N-bromosuccinimide;

NIS: N-jodatime;

DMF: N,N'-dimethylformamide;

THF: tetrahydrofuran;

TBHP: Gidropress tert-butyl;

MTBE: methyl tert-butyl ether;

LDA: diisopropylamide lithium;

TBS: tert-butyldimethylsilyl;

TMS: trimethylsilyl;

TES: triethylsilyl;

DMSO: dimethyl sulfoxide;

TfOH: triftoratsetata;

LHMDS: hexamethyldisilazide lithium;

Ts: a pair of toluensulfonyl (tosyl);

HPLC: high performance liquid chromatography;

GC: gas chromatography;

NMR: nuclear magnetic resonance;

DSC: differential scanning calorimetry;

TLC: thin layer chromatography;

XRPD: x-ray diffraction on the powder;

EXT. temp.: the room temperature.

Although this invention has been described and illustrated with reference to some specific options for its implementation, specialists in this field will be clear that it is possible to make various adaptations, changes, modifications, substitutions, deletions or additions techniques, without departing from the essence and without leaving the scope of the invention. For example, can the be applied reaction conditions, different from the specific conditions described here above, due to a change in reagents or methods for producing compounds according to the above methods of the invention. Similarly the individual reactivity of the starting compounds may vary in accordance with and on the basis of specific existing deputies or production conditions, and such expected changes or differences in the results of review in accordance with the objectives and the practical implementation of the present invention. Therefore understood that the invention defined by the subsequent claims and that the claims should be interpreted as widely as possible.

In addition, it should be understood that all values are approximate and are provided for description. In this application cited patents, patent applications, publications, product descriptions, and protocols, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

1. The method of obtaining the compounds of formula (IA):
,
in which R¹and R²represent hydrogen,
X represents halogen,
and its pharmaceutically acceptable salts,
includes:
(A) oxidation of compounds of formula (II):
,
in which R³presented yet a-O-R ^a,
where R^andrepresents a C_1-10alkyl, and
R⁴represents a
(1) hydrogen or
(2) Si-(R⁹)(R¹⁰)(R^ll),
where each R⁹, R¹⁰and R¹¹represent_1-10alkyl,
obtaining the compounds of formula (IV):
,
(C) removing the protection of the hydroxyl group of the compounds of formula (IV) with a compound of the formula (V):
,
(C) carrying out the reaction of compounds of formula (V) with the compound of the formula (VI) in the presence of acid:
,
in which each of R⁵and R⁶independently selected from
(1) C_1-10the alkyl and
(2) phenyl,
R⁷represents a
(1) hydrogen or
(2) Si-(R⁹)(R¹⁰)(R¹¹), where each of R⁹, R¹⁰and R¹¹represent_1-10alkyl,
obtaining the compounds of formula (VII):
,
(D) oxidation of compounds of formula (VII) with a compound of formula (VIII):
,
(E) conducting the reaction of Striker with ammonia in an alcohol solvent the compounds of formula (VIII) into a compound of formula (IX):

and (F) hydrolysis of compounds of formula (IX) with a compound of formula (IA).

2. The method according to claim 1, where R⁵and R⁶represent methyl.

3. The method according to claim 1, where R 5and R⁶represent phenyl.

4. The method according to claim 1, where R³represents methoxy.

5. The method according to claim 1, where R⁷represents a trimethylsilyl.

6. The method according to claim 1, where X represents fluorine.

7. The method according to claim 1, where R⁴represents a tert-butyldimethylsilyl.

8. The method of obtaining the compounds of formula (IA):
,
in which R¹and R²represent hydrogen,
X represents halogen, and
its pharmaceutically acceptable salts,
including the hydrolysis of compounds of formula (IX):
,
in which R⁵and R⁶independently selected from
(1) C_1-10the alkyl and
(2) phenyl,
obtaining the compounds of formula (IA).

9. The method of claim 8, where R⁵and R⁶represent methyl.

10. The method of claim 8, where R⁵and R⁶represent phenyl.

11. The method according to claim..8, where X represents fluorine.

12. The method of obtaining the compounds of formula (II):
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
X represents halogen;
R⁴is a Si-(R⁹)(R¹⁰)(R¹¹),
where R⁹, R¹⁰and R¹¹represent_1-10alkyl,
includes:
(A) oxidation of compounds of formula (X):

followed by protection of the hydroxyl group with a protective agent R⁴obtaining the compounds of formula (XI):

and (C) conducting the reaction of the obtained protected epoxide in the presence of a Lewis acid to obtain the compounds of formula (II).

13. The method according to item 12, in which the conversion of the compounds of formula (X) in the compound of formula (XI) includes a stage epoxidation of compounds of formula (X) in the presence of a source of peroxide and a catalytic amount of VO(acac)₂.

14. The method according to item 12, in which the conversion of the compounds of formula (X) in the compound of formula (XI) includes processing the compounds of formula (X) halogenation agent, followed by treatment with a base.

15. The method according to item 12, in which X represents fluorine.

16. The method of obtaining the compounds of formula (XII)
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl, and
R⁴is a Si-(R⁹)(R¹⁰)(R¹¹),
where R⁹, R¹⁰and R¹¹represent_1-10alkyl,
X represents halogen;
includes:
(A) the conversion of compounds of formula (II)
,
in which R⁴is a Si-(R⁹)(R¹⁰)(R¹¹),
where R⁹, R¹⁰and R¹ represent_1-10alkyl,
in the compound of formula (XIII) the introduction of the leaving group R⁸
,
in which R⁸is a O-SO₂-R¹²where R¹²selected from the group comprising phenyl, substituted by one Deputy, selected from the group comprising From_1-10alkyl,
(C) removing R⁴obtaining the compounds of formula (XIV)

and (C) oxidation of compounds of formula (XIV) with a compound of formula (XII).

17. The method according to clause 16, where R³represents methoxy.

18. The method of obtaining the compounds of formula (XII')
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
X represents halogen,
R⁴represents Si(R⁹)(R¹⁰)(R¹¹),
where R⁹, R¹⁰and R¹¹represent_1-10alkyl,
which includes the processing of compounds of formula (IV) DBU in CH₂Cl₂

in the compound of formula (XII').

19. The compound of formula (VII):

in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
each of R⁵and R⁶independently selected from
(1) C_1-10the alkyl and
(2) phenyl,
X represents Soboh is halogen;
and their salts.

20. The compound of formula (VIII):
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
each of R⁵and R⁶independently selected from
(1) C_1-10the alkyl and
(2) phenyl,
X represents halogen;
and its salts.

21. The compound of formula (IX):
,
in which each of R⁵and R⁶independently selected from
(1) C_1-10the alkyl and
(4) phenyl,
X represents halogen;
and its salts.

22. The compound of formula (HA):
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
and its salts.

23. The compound of formula (XI):
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
R⁴represents a
(1) hydrogen,
(2) Si-(R⁹)(R¹⁰)(R¹¹),
where R⁹, R¹⁰and R¹¹represent_1-10alkyl,
X represents halogen;
and its salts.

24. The compound of formula (II):
,
in which R³represents-O-R^a,
where R^arepresents a C_1-10alkyl,
and R⁴represents a
(1)hydrogen,
(2) Si-(R⁹)(R¹⁰)(R^{11/sup> ),
where R9, R10and R11represent_1-10alkyl, and
X represents halogen;
and its salts.}

25. The method of obtaining the compounds of formula (IV):

where R³represents-OR^a,
where R^arepresents a C_1-10alkyl,
X represents halogen;
R⁴is a Si-(R⁹)(R¹⁰)(R¹¹),
where R⁹, R¹⁰and R¹¹represent_1-10alkyl,
includes:
(A) oxidation of compounds of formula (X):

followed by protection of the hydroxyl group with a protective agent R⁴obtaining the compounds of formula (XI):

and (B) conducting the reaction of compounds of formula (XI) with a base in the presence of a Lewis acid to obtain the compounds of formula (II):
,
and (C) oxidation of compounds of formula (II) with a compound of the formula (IV).

26. The method according A.25, in which X represents fluorine.