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-Ra , Ra is C1-10alkyl, and R4 is (1) hydrogen or (2) Si-(R9)(R10)(R11), where each of R9, R10 and R11 is C1-10alkyl, 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) (C3-8cycloalkyl 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) (C3-8cycloalkyl 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, C1-6the alkyl or C1-6alkoxy,

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-Raand

(3) -NRbRc,

where Rachoose from a group that includes

(a)1-10alkyl and

(b) (C3-8cycloalkyl,

and Ranot substituted or substituted by one or more

(i)1-10alkoxy,

(ii) hydroxy,

(iii) halogen,

(iv) SRd,

(v) aryl, not substituted or substituted by one or more hydroxy, C1-10alkoxy, C1-10by alkyl or halogen,

(vi) heteroaryl, not substituted or substituted by one or more hydroxy, C1-10alkoxy, C1-10by alkyl or halogen, and

(vii) NReRf;

Rb, R , Reand Rfchoose from a group that includes

(a) hydrogen,

(b) (C1-10alkyl and

(c)3-8cycloalkyl,

and when Rb, Rc, Reor Rfrepresent1-10alkyl or C3-8cycloalkyl specified With1-10alkyl or C3-8cycloalkyl not substituted or substituted by one or more

(i) hydroxy,

(ii)1-10alkoxy,

(iii) SRd,

(iv) aryl, not substituted or substituted by one or more hydroxy, C1-10alkoxy, C1-10by alkyl or halogen, and

(v) heteroaryl, not substituted or substituted by one or more hydroxy, C1-10alkoxy, C1-10by alkyl or halogen, and

(vi) NRgRh;

where Rgor Rhrepresent hydrogen, C1-10alkyl or C3-8cycloalkyl,

or Rbor Rctogether with the N atom to which they are attached, form a group

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

(i) hydroxy,

(ii)1-10alkoxy,

(iii) SRd,

(iv) aryl, not substituted or substituted by one or more hydroxy, C1-10alkoxy, C1-10by alkyl or halogen, and

(v) heteroaryl, not substituted or substituted by one or more hydroxy, C1-10alkoxy, C1-10/sub> by alkyl or halogen, and

(vi) NRgRh;

Rdrepresents 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, C1-10alkyl and C1-10alkoxy,

(6) (CH2)p-O-(CH2)q-X'-R14,

(7) tetrahydropyranyl,

where each of R9, R10and R11represents a C1-10alkyl or phenyl, and R14choose from a group that includes

(a) hydrogen,

(b) (C1-10alkyl,

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) (C3-8cycloalkyl 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, C1-6the alkyl or C1-6alkoxy,

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) (C3-8cycloalkyl 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 C1-10alkyl 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) (C1-10perfluoroalkyl,

(C) phenyl substituted or not substituted with one or more substituents selected from the group comprising nitro, halogen, C1-10alkyl or C1-10alkoxy.

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, C1-10alkyl 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, C3-8cycloalkyl 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).

AnalysisCalculated for C8H11FO4
C, 50,53; H, of 5.83; F, 9,99
Found:C, 50,36; H, of 5.92; F, of 10.05

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).

AnalysisCalculated for C14H25FO4Si
C, 55,23; H, 8,28; F, 6,24
Found:C, 55,27; H, 8,63; F, of 6.31

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).

AnalysisCalculated for C14H25FO4Si
C, 55,23; H, 8,28; F, 6,24
Found:C, 55,44; H, 8,46; F, 6,39

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).

AnalysisCalculated the C 14H23FO4Si
C, 55,60; H, to 7.67; F, 6,28
Found:C, 55,60; H, 7,56; F, 6,33

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).

AnalysisCalculated for C8H9FO4
C, 51,07; H, 4,82, F, 10,10
Found:C, 51,06; H, a 4.83, F, of 10.05

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).

AnalysisCalculated for C14H26O4Si
C, 58,70; H, 9,15
Found:C, 58,45; H, 9,49

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 Na2SO4.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).

C, 58,55; H, 9,34
AnalysisCalculated for C14H26O4Si
C, 58,70; H, 9,15
Found:

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 Na2SO4.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 scan settings
The measurement date/time:7/18/2003 10:6
Source of raw data:PHILIPSbinary (scan) (.RD)
Axis scanning:Gonio
Starting position [°2θ]:3,0080
End position [°2θ]:39,9830
Step length [°2θ]:0,0170
The duration of the scan [c]:10,1500
Scan type:CONTINUOUS
Offset [°2θ]:0,0000
The material of the anode:Cu
Install the generator:40 kV, 50 mA
Rotation:

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

The list of peaks
Position [°2θ]Height [cts]The full width at the level of half-maximum (FWHM) [°2θ]d-the distance [E]Relates. the intensity.[%]
16,5056 260,270,11715,3708628,52
19,6239261,890,16734,52388increased by 28.70
21,9330189,450,13384,0525520,76
23,1656535,890,11713,8396458,72
26,4349912,560,11713,37172100,00
30,2118242,150,20072,9582726,54
32,8470633,430,20072,7267169,41
33,5963108,100,20072,6675911,85
34,639670,310,4015 2,589607,70
37,200987,950,26762,41698for 9.64

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 Randrepresents a C1-10alkyl, and
R4represents a
(1) hydrogen or
(2) Si-(R9)(R10)(Rll),
where each R9, R10and R11represent1-10alkyl,
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) C1-10the alkyl and
(2) phenyl,
R7represents a
(1) hydrogen or
(2) Si-(R9)(R10)(R11), where each of R9, R10and R11represent1-10alkyl,
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) C1-10the 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-Ra,
where Rarepresents a C1-10alkyl,
X represents halogen;
R4is a Si-(R9)(R10)(R11),
where R9, R10and R11represent1-10alkyl,
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-Ra,
where Rarepresents a C1-10alkyl, and
R4is a Si-(R9)(R10)(R11),
where R9, R10and R11represent1-10alkyl,
X represents halogen;
includes:
(A) the conversion of compounds of formula (II)
,
in which R4is a Si-(R9)(R10)(R11),
where R9, R10and R1 represent1-10alkyl,
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 From1-10alkyl,
(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-Ra,
where Rarepresents a C1-10alkyl,
X represents halogen,
R4represents Si(R9)(R10)(R11),
where R9, R10and R11represent1-10alkyl,
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-Ra,
where Rarepresents a C1-10alkyl,
each of R5and R6independently selected from
(1) C1-10the alkyl and
(2) phenyl,
X represents Soboh is halogen;
and their salts.

20. The compound of formula (VIII):
,
in which R3represents-O-Ra,
where Rarepresents a C1-10alkyl,
each of R5and R6independently selected from
(1) C1-10the 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) C1-10the alkyl and
(4) phenyl,
X represents halogen;
and its salts.

22. The compound of formula (HA):
,
in which R3represents-O-Ra,
where Rarepresents a C1-10alkyl,
and its salts.

23. The compound of formula (XI):
,
in which R3represents-O-Ra,
where Rarepresents a C1-10alkyl,
R4represents a
(1) hydrogen,
(2) Si-(R9)(R10)(R11),
where R9, R10and R11represent1-10alkyl,
X represents halogen;
and its salts.

24. The compound of formula (II):
,
in which R3represents-O-Ra,
where Rarepresents a C1-10alkyl,
and R4represents a
(1)hydrogen,
(2) Si-(R9)(R10)(R11/sup> ),
where R9, R10and R11represent1-10alkyl, and
X represents halogen;
and its salts.

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

where R3represents-ORa,
where Rarepresents a C1-10alkyl,
X represents halogen;
R4is a Si-(R9)(R10)(R11),
where R9, R10and R11represent1-10alkyl,
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.



 

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21 cl, 3 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing ethylene oxide by bringing a mixture fed into an epoxidation reactor, which may contain ethylene, oxygen, carbon dioxide and water in a defined concentration, into contact with a highly selective epoxidation catalyst containing a promoter amount of rhenium. Contacting the mixture fed into the epoxidation reactor is done under epoxidation reaction conditions at reaction temperature below 260°C. The said mixture contains carbon dioxide in concentration less than 2 mol % of the entire mixture and concentration of water in the mixture of at most 1.5 mol % of the entire mixture. Observation of the combination of the said conditions for carrying out the epoxidation process improves operational properties of the epoxidation catalyst, for example increased stability, selectivity and activity of the catalyst.

EFFECT: invention also relates to a method of producing 1,2-ethanediol or 1,2-diol ether, which involves production of ethylene oxide using the method described above and its conversion to 1,2-ethanediol or 1,2-diol ether.

10 cl, 5 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: claimed is water solution of hydrogen peroxide, suitable for olefine epoxidation, which includes: I) in total less than 50 wt fraction/mln of alkaline metals, alkaline-earth metals or their combinations irrespective of whether said alkaline or alkaline-earth metals are in catione-active or complex form; II) in total at least 50 wt fraction/mln of amines, which have pkb value less than 4.5, or respective protonated compounds; and III) in total at least 100 wt fraction/mln anions or compounds, which are able to dissociate with anion formation, according to which values in wt fraction/mln are given in terms of hydrogen peroxide weight. Claimed is method of obtaining hydrogen peroxide solution. Claimed is application of water solution of hydrogen peroxide.

EFFECT: economically efficient production of water solution of hydrogen peroxide and improved long-term activity and selectivity of catalyst.

18 cl, 5 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: according to the present invention, ethylene is oxidised in contact with mix of heterogeneous catalyst in particles and solid inert substance in particles, treated with alkali metal, in oxidation conditions.

EFFECT: improved efficiency.

3 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to ethylene oxide and to the method of obtaining 1,2-ethanediol or a simple ether of 1,2-ethanediol, from ethylene oxide, obtained using the proposed method. The process of producing ethylene oxide involves an epoxidation reactor system, containing a volume of a high octane epoxidation catalyst. The method involves replacing part of the volume of the high octane epoxidation catalyst with a volume of highly selective catalyst and modification of the process system so as to provide for initial raw materials of the reactor of the epoxidation system, with low concentration of carbon dioxide.

EFFECT: considerable improvement in the effectiveness of the system of producing ethylene oxide due to perfection of the process and operation of the existing production system.

13 cl, 5 dwg, 5 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: method involves a stage of interaction of one or more α-halogenketones with general formula I , where each of "X" independently represents a halogen atom, except fluorine, a hydrogen atom and "Z" represents a halogen atom, except fluorine; with molecular hydrogen in the presence of heterogeneous catalyst, containing a transition metal, where the catalyst is a metallic salt, which is saturated with the catalyst carrier, where the metal consist of iridium, ruthenium or their mixture. The metal catalyses hydrogenation of all carbonyl groups of α-halogenketons to alcohol groups, at temperature from 1° to 200°C and pressure of at least 14 abs. pound/square inch with formation of one or more α-halogenspirits with general formula II . The invention also relates to the method of obtaining epoxides (alternatives), to the method of obtaining epi-halogenhydrine (alternatives) and to the method of obtaining propylene oxide (alternatives).

EFFECT: improved activity of the catalyst.

3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention covers production of mixture of stereoisomers of limonene diepoxides (1.2-8.9-diepoxide-p-terpanes) used as resin components or composites for technical purposes, in fine organic synthesis and in perfumes. The method includes epoxidation of double bonds in limonene with diluted hydrogen peroxide in water solution of acetonitrile, N,N-dimethylformamide or methanol at ambient temperature under catalytic action of manganese sulphate mixed with sodium bicarbonate and salicylic acid. Further reaction products are extracted from the reaction mixture with organic solvent, extractant is distilled. Crude epoxide thus obtained undergoes purification by established methods (vacuum distillation or absorption). The method allows to obtain diepoxides mixture with 93-97% purity and yield up to 85%.

EFFECT: development of technological method of production of resin component and composite material for fine organic synthesis.

7 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to a method for continuous epoxidation of olefins with hydrogen peroxide in the presence of a heterogeneous catalyst accelerating the epoxidation reaction. Aqueous reaction mixture comprises the following components: (1) olefin; (2) hydrogen peroxide; (3) less 100 ppm of alkaline metals, alkaline-earth metals in ionogenic, complex or covalently bound form, as bases or base cations possessing pH value pkB less 4.5, or their combination, and at least 100 ppm of bases or base cations possessing pH value pkB at least 4.5, or their combination. Values in ppm are given as measure for the total mass of hydrogen peroxide in the reaction mixture.

EFFECT: improved method of reaction.

20 cl, 2 tbl, 14 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of styrene. At the first step the method involves interaction of ethylbenzene hydroperoxide with propene in the presence of catalyst to yield propylene oxide and 1-phenylethanol followed by separate treatment of reaction flow and removing propylene oxide. At the second step the method involves interaction of 1-phenylethanol-containing distillate with a heterogenous dehydration catalyst at temperature 150-320°C to obtain styrene. Distillate contains 0.30 wt.-%, not above, compounds of molecular mass at least 195 Da. Invention provides decreasing the content of by-side compounds in styrene and to enhance it's the conversion degree.

EFFECT: improved method of synthesis.

3 cl, 3 tbl

FIELD: industrial organic synthesis.

SUBSTANCE: invention relates to technology of epoxidation of unsaturated compounds with hydrogen peroxide, in particular to production of propylene oxide and propylene glycol. Epoxidation is conducted in presence of organic solvent and catalytically active compound including zeolite catalyst. Product mixture contains propylene oxide, unreacted propylene, and α-hydroperoxypropanols, which are reduced with hydrogen into corresponding propylene glycols. As organic solvent, alcohols, preferably methanol, or their mixtures with water are used. Propylene oxide as well as unreacted propylene and solvent are separated by distillation at column vat temperature below 80°C and residence time less than 4 h. Hydrogenation catalyst is selected from group comprising heterogeneous catalysts containing as active metal Ru, Ni, Co, Pd, and Pt, individually or as two- or more-component mixture on suitable carrier.

EFFECT: enabled processing of hydroxyperoxyalcohol, epoxidation reaction by-product, into glycols so improving economical characteristics of the process.

15 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the field of organic chemistry, in particular, to method for production of methyl ethers of 2-thiophen carbonic acid intended for use in synthesis of optical whiteners, dyes for cotton, wool, artificial fibers, medical preparations, and also as additive to oils or hydraulic liquids. Substance of the method consists in thiophen interaction with methanol in presence of carbon tetrachloride under action of catalysts - oxo-bis-(2,4-pentanodionato)vanadium VO(acac)2 or tris (2,4-pentanodionato)iron Fe(acac)3, or molybdenum hexacarbonyl Mo(CO)6 at the temperature of 130-170°C for 3-6 hours at the following mole ratio - catalyst:thiophen:CCl4:methanol equal to 1:100:200-300:200-300.

EFFECT: suggested method makes it possible to produce target product with yield of 63-85%, using simplified technology.

1 tbl, 14 ex

The invention relates to new derivatives of esters of carboxylic acids of General formula I, where R1represents an alkyl group branched or non-branched chain having 1-4 carbon atoms; R2represents a group of formula IV, in which R4represents a hydrogen atom or etinilnoy group; R5and R6are the same or different selected from the group consisting of a hydrogen atom or a methyl group; R7represents a hydrogen atom; R8selected from propargyl, methoxymethyl or methylthio
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