Continuous method for preparing fructopyranose sulfamate derivatives

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a continuous method for synthesis of sulfamate derivatives of fructopyranose of the general formula (I): wherein R1, R2, R3, R4, R5, R6 and X have values given in the invention description. Invention relates to synthesis of thiopyramate with using glyme as organic solvent in both steps of the continuous process of synthesis.

EFFECT: improved method of synthesis.

17 cl, 8 tbl, 6 ex

 

The technical field

The present invention relates to a continuous method for producing a sulphamate derivatives fructopyranose General formula (I)

in which R1, R3, R4, R5, R6andX have the meanings defined here below.

Background of the invention

Sulfamate formula (I)

in which X represents O or CH2and R1, R3, R4, R5and R6have the meanings defined here below, are known compounds which have been found, showing protivogololednoy activity and is therefore useful in the treatment of conditions such as epilepsy. These compounds are described in U.S. patent No. 4582916 and 4513006, which also discloses methods of obtaining these compounds; and the contents of which are incorporated herein by reference.

One of the methods described in the above referenced patents, is a method of obtaining compounds of formula (I), including interaction of the alcohol of the formula RCH2OH with chlorsulfuron formula ClSO2NH2or ClSO2Other1in the presence of a base, such as tert-piperonyl potassium or sodium hydride, at a temperature of from about -20°to 25°and in a solvent such as toluene, tetrahydrofuran or di is malformed, where R represents a fragment of formula (II)

This method has two major drawbacks, especially for large-scale synthesis. One disadvantage is that this method requires a combination of NaH and DMF, which has uncontrolled ectothermy and therefore is potentially explosive. See J. Buckley et al., Chemical & Engineering News, July 12, 1982, page 5; and G. DeWail, Chemical & Engineering News, 13 September 1982, Another drawback is that this method uses highly toxic and corrosive chlorosulfonylisocyanate (CSI) for industrial unavailable sulphonylchloride (ClSO2NH2).

Another method of preparing compounds of formula (I)described in the aforementioned U.S. patent No. 4513006, involves the reaction of an alcohol of the formula RCH2OH with sulfurylchloride formula SO2Cl2in the presence of a base such as triethylamine or pyridine at a temperature of about -40°25°With simple diethyl ether or methylene chloride as a solvent to obtain chlorosulphate formula RCH2OSO2Cl. Chlorosulphate formula RCH2OSO2Cl can then be subjected to interaction with the amine of formula R1NH2at a temperature of from about -40°to 25°in methylenchloride or the combined acetonitrile solvent to obtain the compound form is s (I). This method, using a simple diethyl ether, methylene chloride and acetonitrile as solvent, gives a relatively low yield of the desired final product of formula (I).

The third method, described in the two patents mentioned above, involves the interaction of chlorosulphate formula RCH2OSO2Cl (generated as described previously) with a metal azide such as sodium azide, in a solvent such as methylene chloride or acetonitrile, giving acidsulfate formula RCH2OSO2N3. Acidsulfate then restored to the compound of formula (I)in which R1represents hydrogen using catalytic hydrogenation.

The disadvantage of this method is that when dealing with azide compounds explosions can occur. This method also provides for additional chemical transformation, including the restoration of the azide in NH2group.

Maryanoff and others in the U.S. patent 5387700 disclose a method of obtaining compounds of formula (I), which includes the interaction of the alcohol of the formula RCH2OH with sulfurylchloride in the presence of a base, in a solvent selected from the group consisting of toluene, tert-butyl methyl ether and tetrahydrofuran, with the formation of chlorosulphate intermediate compounds of the formula RCH2OSO2Cl. In the second stage of CHL is rsultat formula RCH 2OSO2Cl is subjected to reaction with an amine of formula R1NH2in a solvent selected from the group consisting of tetrahydrofuran, tert-butyl methyl ether and the lower alkanol (for example, methanol or ethanol)to form the compounds of formula (I).

One of the disadvantages of this method is that the compound of formula (I) is obtained by using the periodic method, in which the first reaction, the solvent is removed, the product is highlighted, selected solid is again dissolved in another solvent, and then subjected to the reaction for the formation of the final product. This results in the way that requires allocation of polystable, thermally labile ROSO2Cl intermediate connection.

The aim of the present invention is the provision of a continuous method of obtaining compounds of formula (I), which does not require changes in the solvent system, which uses readily available materials, which may be carried out in a safe environment, which gives relatively high yields and/or allows to obtain more material per time unit volume of the reactor (i.e. which gives the possibility of obtaining more material in a smaller equipment).

Summary of invention

Present from Britanie directed to a continuous method of obtaining compounds of formula (I):

in which

X is selected from CH2or;

R1selected from the group consisting of hydrogen and C1-4of alkyl;

R3, R4, R5and R6each independently selected from hydrogen or lower alkyl, and when X is CH2, R5and R6can be allenbyi groups connected with the formation of the benzene ring and, when X represents Oh, R3and R4and/or R5and R6together can be methylenedioxy group of the formula:

in which

R7and R8are the same or different and represent hydrogen, lower alkyl, or are alkilani and connected, forming cyclopentenone or tsiklogeksilnogo ring;

including

(A) interactions appropriately substituted compounds of formula (IV) with sulfurylchloride;

in the presence of organic or inorganic bases;

in the first organic solvent comprising at least one solvent selected from simple cyclic ether, simple dialkylamide ether, straight or branched chain, aromatic hydrocarbon, or a mixture of simple cyclic, dialkylamino ether, straight or branched chain and aromatic hydrocarbon solvents is I;

with the formation of the corresponding compounds of formula (V);

(C) the interaction of the compounds of formula (V) with the appropriately substituted compound of formula (VI);

in the second organic solvent comprising at least a solvent used in stage (A);

with the formation of the corresponding compounds of formula (I).

The present invention is further directed to a continuous method of obtaining the compounds of formula (III)

also known as topiramate, the compounds of formula (I)in which X represents Oh, R1is hydrogen, R3and R4and R5and R6each taken together to form

including

(AA) the reaction of compounds of formula (IVa) with sulfurylchloride;

in the presence of organic or inorganic bases;

in the first organic solvent comprising at least one solvent selected from simple cyclic ether, simple dialkylamide ether, straight or branched chain, aromatic hydrocarbon, or a mixture of simple cyclic, dialkylamino ether, straight or branched chain and aromatic hydrocarbon solvent;

with the formation of the corresponding connected the I of the formula (Va);

(VA) the reaction of compounds of formula (Va) with ammonia;

in the second organic solvent comprising at least a solvent used in stage (A);

with the formation of the corresponding compounds of formula (III).

The present invention is further directed to a compound obtained according to any of the methods described in this specification.

The illustration of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound obtained in accordance with any of the methods described above.

The illustration of the invention is a pharmaceutical composition made by mixing a pharmaceutically acceptable carrier and the compound obtained in accordance with any of the methods described above.

The illustration of the invention is a method of obtaining a pharmaceutical composition, comprising a mixture of pharmaceutically acceptable carrier and the compound obtained in accordance with any of the methods described above.

Another example of the invention is the use of compounds obtained in accordance with any of the methods described herein, upon receipt of a medicinal product for the treatment of epilepsy.

Detailed description of the invention

According to the embodiment of the present invention the second the content of inorganic fillers solvent used in stage (C)) is the same as the first organic solvent used in stage (A)). According to another embodiment of the present invention, the first organic solvent used in stage (A)), and the second organic solvent used in stage (C)) is a glyme.

Used herein, the term "reactor" means a reactor of a continuous action, for example, a flow reactor with a stirrer (CSTR)reactor ideal displacement, the reactor tower type and similar. Preferably the reactor is a continuous action is a flow reactor with a stirrer.

Used herein, the term "residence time" refers to the average amount of time that the particles of the reagent or reagents remain in the reactor.

Used herein, the term "alkyl" whether used alone or as part of a group of substituent includes alkyl straight or branched chain. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and similar. If not noted otherwise, the term "lower"when used with alkyl, denotes the composition of the carbon chain of 1-4 carbon atoms.

With reference to substituents, the term "independently" means that when more than one of such substituents, such substituents may be the same or different from each other.

When there is because a particular group is "substituted" (e.g., alkyl, phenyl, aryl, aralkyl, heteroaryl), this group may have one or more substituents, preferably from one to three substituents, more preferably one to two substituents independently selected from the specified list of alternates.

The term "subject"used herein refers to an animal, preferably a mammal, most preferably to a person who is or has been the object of treatment, examination or observation or experiment.

The term "therapeutically effective amount", as used here, means the amount of active compound or pharmaceutical agent that causes the biological or medical response in a tissue system, animal or human, which seeks a researcher, veterinarian or doctor or other Clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

Have in mind that when used herein, the term "composition" includes a product containing the described ingredients in the above quantities, as well as any product which results, directly or indirectly, from combinations of the described ingredients in the described amounts.

Abbreviations used in the description, particularly the Schemes and Examples, are as follows:

CS or charsleft = Chloro that diacetone-β -D-fructose

CSTR = continuous-flow reactor with a stirrer

DAF = Diacetone-β-D-fructose

DIPEA = Diisopropylethylamine

DMF = N,N-Dimethylformamide

GC = Gas chromatography

Glyme = Etilenglikolevye ether

HPLC = Liquid chromatography high pressure

MTBE = Methyl tert-butyl ether

SC = Sulfurylchloride

TEA = Triethylamine

THF = Tetrahydrofuran

TPM = topiramate

The present invention is directed to a continuous method of obtaining the compounds of formula (I)

in which

X is selected from CH2or;

R1selected from the group consisting of hydrogen and C1-4of alkyl;

R3, R4, R5and R6each independently selected from hydrogen or lower alkyl, and when X is CH2, R5and R6can be allenbyi groups connected with the formation of the benzene ring and, when X represents Oh, R3and R4and/or R5and R6together can be methylenedioxy group of the formula:

in which

R7and R8are the same or different and represent hydrogen, lower alkyl, or are alkilani and connected, forming cyclopentenone or tsiklogeksilnogo ring.

More specifically, the present invention is directed to a continuous method of obtaining the soedineniya formula (I), shown in Scheme 1.

Stage (A):

Stage (In):

Scheme 1

Accordingly, at the stage of (A) suitably substituted compound of formula (IV), a known compound or compound that is obtained by the known methods, and the base is dissolved in the first organic solvent, and subjected to reaction with sulfurylchloride;

where the base is an inorganic base, such as Na2CO3, K2CO3, NaHCO3and the like, or an organic base such as a tertiary amine, such as pyridine, a derivative of pyridine, TEA, DIPEA, and the like; preferably an organic tertiary amine base, preferably, pyridine;

where the base is preferably does not react with the compound of the formula (IV) or sulfurylchloride;

on which the first organic solvent includes at least one solvent selected from simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a mixture of simple cyclic, dialkylamino ether, straight or branched chain of the aromatic hydrocarbon solvent; preferably, the first organic solvent includes at least one solvent selected from simple cyclic ether or a simple dialkylamide ether, straight or branched chain, such as THF, Piran, glyme, MTBE and similar; more preferably, the first organic solvent includes at least glyme;

where sulfurylchloride preferably present in amounts greater than about 0.9 mole per mole of the compounds of formula (IV), more preferably the molar ratio of compounds of formula (IV) to sulfurylchloride is in the range from about 1:0.9 to 1:1.5 and even more preferably the molar ratio of compounds of formula (IV) to sulfurylchloride is in the range from about 1:1.0 to 1:1,05;

where the base is preferably present in amounts greater than about 1 molar equivalent of compound of formula (IV); more preferably, the molar ratio of compounds of formula (IV) to the base is greater than or equal to about 1:1,05; even more preferably the molar ratio of compounds of formula (IV) to the base is in the range from about 1:of 1.05 to 1:1,20; even more preferably the molar ratio of compounds of formula (IV) to the base is about 1:1,05;

where the reaction temperature is preferably maintained at less than, h is m about 50° C, more preferably at about 0°With up to about 20°S, more preferably at about 0°C;

with the formation of a solution containing the appropriate compound of formula (V), and sediment cleaners containing hydrochloride salt of the base.

According to one embodiments of the present invention, the first organic solvent used in stage (A), selected from the group consisting of simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a simple mixture of cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent. Preferably, the first organic solvent used in stage (A)) select from simple cyclic ether or a simple dialkylamide ether, straight or branched chain, such as THF, Piran, glyme, MTBE and similar; more preferably, the first organic solvent used in stage (A)) is glyme.

According to the embodiment of the present invention, the first organic solvent used in stage (A), selected from the group consisting of simple cyclic ether, question the CSOs dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent; in which the first organic solvent is other than tetrahydrofuran or tert-butyl methyl ether.

According to the embodiment of the present invention stage (A) the reaction is carried out so that the compound of formula (IV) and the base are dissolved in the first organic solvent, is subjected to reaction with pure sulfurylchloride, using continuous feed one reaction stream containing the compound of the formula (IV) and the base are dissolved in the first organic solvent, and a second reaction stream containing sulfurylchloride, in the reactor of continuous operation, preferably CSTR. According to another embodiment of the present invention sulfurylchloride dissolved in the same organic solvent as that used for dissolving the compounds of formula (IV) and the base (i.e. in the first organic solvent).

Preferably, the solution containing the compound of the formula (V) and the precipitate cleaners containing hydrochloride salt of the base, is filtered according to known methods to remove the sediment.

Preferably, the solution containing the compound of the formula (V), concentrated using a known batch or continuous methods, for example by evaporation of the solvent (such as evaporation with a falling film or film evaporator), or vacuum distillation, obtaining a concentrate of the connection is ormula (V). According to the embodiment of the present invention, the solution containing the compound of the formula (V), concentrated to less than or equal to about half the original mass of the solution. According to another embodiment of the present invention, the solution containing the compound of the formula (V), concentrated to oil.

When the compound of the formula (IV) is subjected to reaction with more than about 1 equivalent of sulfurylchloride, the solution containing the compound of the formula (V), preferably concentrate according to the known batch or continuous method for removing at least about 70% by weight of solvent.

When the compound of the formula (IV) is subjected to reaction with about 1 equivalent of sulfurylchloride, the solution containing the compound of the formula (V), preferably concentrate according to the known batch or continuous method for removing at least 20% by weight of solvent.

According to the embodiment of the present invention, the solution containing the compound of the formula (V), is treated to remove volatile substances. Suitable processing methods include, but are not limited to, vacuum distillation, concentration, evaporation, passing through activated charcoal or other absorbent, and similar.

Concentrate the compounds of formula (V) is dissolved in a second organic solvent, enabling the m at least, the solvent used in stage (A) (i.e., the first organic solvent), preferably comprising at least one solvent selected from simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a simple mixture of cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent. Preferably, the concentrate of the compound of formula (V) is dissolved in the same organic solvent that is used in stage (a) above.

Preferably, the concentrate of the compound of formula (V) is dissolved to a final mass relationship of the solvent to the compound of formula (V) in the range of from about 2:1 to 10:1, more preferably up to mass relationship of the solvent to the compound of formula (V) to about 6:1, receiving the reaction stream for use in stage (C), hereinafter referred to as the third reaction stream containing the compound of the formula (V).

At the stage (C) the compound of formula (V) is subjected to reaction with a suitable substituted compound of formula (VI), a known compound or compound derived known methods is AMI.

In the second organic solvent comprising at least a solvent used in stage (A);

on which the second organic solvent includes at least one solvent selected from simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a simple mixture of cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent; preferably, the second organic solvent includes at least one solvent selected from simple or cyclic simple dialkylamide ether, straight or branched chain, such as THF, Piran, glyme, MTBE, and the like; more preferably, the second organic solvent includes at least glyme; even more preferably, the second organic solvent is the same as the first organic solvent; more preferably, the second organic solvent is a glyme;

which compound of formula (VI) is preferably present in amounts greater than about 1 molar equivalent to preprogram the Oia of the formula (V); more preferably, the molar ratio of compounds of formula (VI) to the compound of formula (V) is greater than or equal to about 2:1; even more preferably the molar ratio of compounds of formula (VI) to the compound of formula (V) is about 5:1;

where the reaction temperature is preferably maintained within the range from about -30°C to 50°S, more preferably in the range from approximately 0°With 30°S, even more preferably at about 20°C;

with the formation of a solution of the compounds of formula (I) and sediment.

When the compound of the formula (VI) is ammonia gas, the ammonia gas is preferably fed into the reactor at a controlled pressure or flow rate, more preferably, at a pressure in the range of less than or approximately equal to the absolute pressure of 30 lb/sq inch (2,109 kg/cm), more preferably at a pressure in the range from about 15 psi (1,055 kg/sq.cm) to 20 psi (1,406 kg/cm), more preferably at a pressure of about 19 psi (1,336 kg/sq.cm).

According to one embodiments of the present invention, the second organic solvent used in stage (B)) selected from the group consisting of simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such to the to glyme, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a simple mixture of cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent. Preferably, the second organic solvent used in stage (B)) selected from simple cyclic ether or a simple dialkylamide ether, straight or branched chain, such as THF, Piran, glyme, MTBE and similar; more preferably, the second organic solvent used in stage (C)) is glyme.

According to the embodiment of the present invention, the second organic solvent used in stage (B), selected from the group consisting of simple cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent; in which the second organic solvent is other than tetrahydrofuran or tert-butyl methyl ether.

According to one embodiments of the present invention, the second organic solvent used in stage (C)) includes the solvent used in stage (A) (i.e., the first organic solvent).

Preferably, the solution containing the compound of formula (I) and the precipitate, filtered using known IU the W for sludge removal.

According to the embodiment of the invention is a method of obtaining the compounds of formula (I) is carried out in two flow reactors with agitators (CSTRs). Preferably, stage (A) is conducted so that the residence time in the first CSTR was approximately 1 hour. Preferably, stage (B) is conducted so that the residence time in the second CSTR was approximately 3 hours. Preferably, stage (B) is conducted so that the third reaction stream and the compound of formula (VI) enter into CSTR above the surface.

The present invention is further directed to a continuous method of obtaining the compounds of formula (III), also known as topiramate, as shown in Diagram 2.

Stage (AA):

Stage (VA):

Scheme 2

Accordingly, at the stage of (AA) the compound of formula (IVa), the connection, also known as deaconfrost (DAF), and the base is dissolved in the first organic solvent, and subjected to reaction with sulfurylchloride;

where the base is an inorganic base, such as Na2CO3, K2CO3, NaHCO3and the like, or an organic base such as a tertiary amine base, such as pyridine, a derivative of pyridine, TEA, DIPEA, and the like; preferably an organic tertiary amine base, preferably, pyridine;

where the base is preferably does not react with the compound of the formula (IVa) or sulfurylchloride;

on which the first organic solvent includes at least one solvent selected from simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a simple mixture of cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent; preferably, the first organic solvent includes at least one solvent selected from simple cyclic ether or a simple dialkylamide ether, straight or branched chain, such as THF, Piran, glyme, MTBE and similar; more preferably, the first organic solvent includes at least glyme; even more preferably, the first organic solvent is glyme;

where sulfurylchloride preferably present in amounts greater than about 0.9 mole per mole of the compounds of formula (IVa); more preferably the molar ratio of compounds of formula (IVa) to sulfurylchloride is in the range from about 1:0.9 to 1:1.5 and even more preferably the molar ratio of compounds of formula (IVa) to sulfurylchloride nah which is in the range of from about 1:1.0 to 1:1,05;

where the base is preferably present in amounts greater than about 1 molar equivalent relative to the compound of formula (IVa); more preferably, the molar ratio of compounds of formula (IVa) to the base is greater than or equal to about 1:1,05; even more preferably the molar ratio of compounds of formula (IVa) to the base is in the range of from about 1:of 1.05 to 1:1,20; even more preferably the molar ratio of compounds of formula (IVa) to the base is about 1:1,05;

where the reaction temperature is preferably supported at less than about 50°S, more preferably at about 0°With up to about 20°S, more preferably at about 0°C;

with the formation of a solution containing the appropriate compound of formula (Va), and sediment cleaners containing hydrochloride salt of the base.

According to one embodiments of the present invention, the first organic solvent used in stage (AA), which are selected from the group consisting of simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a simple mixture of cyclic ether, simple dialkylamide the Fira with a straight or branched chain and aromatic hydrocarbon solvent. Preferably, the first organic solvent used in stage (AA)) are selected from simple cyclic ether or a simple dialkylamide ether, straight or branched chain, such as THF, Piran, glyme, MTBE and similar; more preferably, the first organic solvent used in stage (AA)) is glyme.

According to the embodiment of the present invention, the first organic solvent used in stage (AA), which are selected from the group consisting of simple cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent; in which the first organic solvent is other than tetrahydrofuran or tert-butyl methyl ether.

According to the embodiment of the present invention stage (AA) the reaction is conducted so that the compound of formula (IVa) and the base are dissolved in the first system of an organic solvent, is subjected to reaction with pure sulfurylchloride, using continuous feed one reaction stream containing the compound of the formula (IVa) and the base are dissolved in the first system of an organic solvent and a reaction stream containing sulfurylchloride, in the reactor of continuous operation, preferably CSTR. According to another embodiment of the present invention sulfury the chloride dissolved in the same organic solvent, as that used for dissolving the compounds of formula (IVa) and substrate (i.e. in the first organic solvent).

Preferably the solution containing the compound of the formula (Va) and the precipitate cleaners containing hydrochloride salt of the base, is filtered according to known methods to remove the sediment.

Preferably, the solution containing the compound of the formula (Va), concentrated using a known batch or continuous methods, for example by evaporation of the solvent (such as evaporation with a falling liquid film or film evaporation, or vacuum distillation, obtaining a concentrate of the compound of formula (Va). According to the embodiment of the present invention, the solution containing the compound of the formula (Va), concentrated to less than or equal to about half the original mass of the solution. According to another embodiment of the present invention, the solution containing the compound of the formula (Va), concentrated to oil.

When the compound of the formula (IVa) are subjected to reaction with more than about 1 equivalent of sulfurylchloride, the solution containing the compound of the formula (Va), preferably concentrate according to the known batch or continuous method for removing at least about 70% by weight of solvent.

When the compound of the formula (IVa) is subjected to reaction with about 1 equivalent of sulfurylchloride is a, the solution containing the compound of the formula (Va), preferably concentrate according to the known batch or continuous method for removing at least 20% by weight of solvent.

According to the embodiment of the present invention, the solution containing the compound of the formula (Va), is treated to remove volatile substances. Suitable processing methods include, but are not limited to, vacuum distillation, concentration, evaporation, passing through activated charcoal or other absorbent, and similar.

Concentrate the compounds of formula (Va) is dissolved in a second organic solvent that includes at least the solvent used in stage (AA), preferably comprising at least one solvent selected from simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a mixture of simple cyclic, dialkylamino ether, straight or branched chain and aromatic hydrocarbon solvent. Preferably, the concentrate of the compound of formula (Va) dissolved in the same organic solvent that is used at the stage of (AA) above.

Preferred is entrusted, concentrate the compounds of formula (Va) is dissolved to a final mass relationship of the solvent to the compound of formula (Va) in the range of from about 2:1 to 10:1, more preferably up to mass relationship of the solvent to the compound of formula (Va) is about 6:1, receiving the reaction stream for use on stage (VA), hereinafter referred to as the third reaction stream containing the compound of the formula (Va).

On stage (Ia), the compound of formula (Va) is subjected to reaction with ammonia, preferably ammonia gas.

In the second organic solvent comprising at least a solvent used in stage (AA);

on which the second organic solvent includes at least one solvent selected from simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a mixture of simple cyclic, dialkylamino ether, straight or branched chain and aromatic hydrocarbon solvent; preferably, the second organic solvent includes at least one solvent selected from simple cyclic or dialkylamino ether straight or branched chain, is such as THF, Piran, glyme, MTBE, and the like; more preferably, the second organic solvent includes at least glyme; even more preferably, the second organic solvent is the same as the first organic solvent; more preferably, the second organic solvent is a glyme;

where ammonia is preferably present in amounts greater than about 1 molar equivalent of compound of formula (Va); more preferably, the molar ratio of ammonia to the compound of formula (Va) is greater than or equal to about 2:1; even more preferably the molar ratio of ammonia to the compound of formula (Va) is about 5:1;

where the reaction temperature is preferably maintained within the range from about -30°C to 50°S, more preferably in the range from approximately 0°With 30°S, even more preferably at about 20°C;

with the formation of a solution of the compounds of formula (III) and sediment.

Preferably, the ammonia gas is fed into the reactor at a controlled pressure or flow rate, more preferably at an absolute pressure in the range of less than or equal to about 30 lb./sq inch (2,109 kg/cm), more preferably at a pressure in the range from about 15 psi (1,055 kg/sq.cm) to 20 psi (1,406 kg/sq.cm), even more before occhialino at a pressure of about 19 psi (1,336 kg/sq.cm).

According to one embodiments of the present invention, the second organic solvent used in stage (VA), which are selected from the group consisting of simple cyclic ether, such as Piran, tetrahydrofuran and the like; simple dialkylamide ether, straight or branched chain, such as glyme, MTBE, and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and similar; or a mixture of simple cyclic, dialkylamino ether, straight or branched chain and aromatic hydrocarbon solvent. Preferably, the second organic solvent used in stage (VA)) choose from simple cyclic or dialkylamino ether, straight or branched chain, such as THF, Piran, glyme, MTBE and similar; more preferably, the second organic solvent used in stage (VA)) is glyme.

According to the embodiment of the present invention, the second organic solvent used in stage (VA), which are selected from the group consisting of simple cyclic ether, simple dialkylamide ether, straight or branched chain and aromatic hydrocarbon solvent; in which the second organic solvent is other than tetrahydrofuran or tert-butyl methyl ether.

According to one embodied the th present invention, the second organic solvent, used on stage (VA), includes the solvent used in stage (AA) (i.e., the first organic solvent).

Preferably, the solution containing the compound of the formula (III) and the precipitate, filtered using known methods for sludge removal.

According to the embodiment of the invention is a method of obtaining the compounds of formula (III) is carried out in two flow reactors with agitators (CSTRs). Preferably, stage (AA) is conducted so that the residence time in the first CSTR was approximately 1 hour. Preferably, stage (VA) is conducted so that the residence time in the second CSTR was approximately 3 hours. Preferably, stage (VA) is conducted so that the third reaction stream and the ammonia injected into the CSTR above the surface.

A qualified person skilled in the art understands that any of the methods of the present invention can be used to obtain racemic mixtures of compounds of formula (I) or any of the stereoisomers of the compounds of formula (I) by selecting and replacing the corresponding racemic mixtures or stereoisomers of the reactants.

When the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. When the compounds possess two or more chiral centers, they may additionally exist as diastereomers to be clear, that all such isomers and mixtures of them are covered by the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and assumes that they as such are covered by the present invention. In addition, some of the compounds may form a solvate with water (i.e. hydrates) or common organic solvents, and also mean that such solvate covered by the scope of the invention.

When the means of obtaining the compounds according to the invention give a mixture of stereoisomers, these isomers may be separated using conventional techniques such as preparative chromatography. The compound can be obtained in racemic form, or can be obtained from the individual enantiomers or using enantiospecific synthesis or by separation. For example, the compounds can be separated into their enantiomeric components using standard techniques, such as the formation of diastereomeric pairs by salt formation with optically active acids, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds can also be separated by formation of diastereoisomeric ester is in or amides, followed by chromatographic separation and removal of the chiral auxiliary agent. Alternatively, compounds can be separated using chiral HPLC column.

While any method of obtaining compounds of the present invention may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved using conventional protective groups such as the groups described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed at a convenient subsequent stage using methods known in the art.

The following examples describe the invention in more detail and are intended to illustrate the invention, but in no way to limit it.

Example 1

Getting chlorosulphate (CS) diacetone-β-D-fructose

Continuous method

The original solution DAF were prepared using otoshiana diacetone-β-fructose (DAF) (911,0 g) in a glass bottle with a volume of 1 gallon (there are 3,785 l). To the solids were added glyme (2113,5 g, 2450 ml) and pyridine (290,7 g, 297 ml) and the solution was mixed until complete dissolution of the DAF. If necessary, were prepared additional source solution.

1-liter Erlenmeyer flask was filled with the initial solution DAF (936,8 g, 987,2 ml) and was placed on the scales to the top is agrusti. To discharge the solution in the reactor was connected piston pump.

In a separate flat-bottomed flask for boiling was otoshibuta sulfurylchloride (SC) (172,2 g to 103.8 ml) and the flask was immediately backed up. Then the flask containing SC, was placed on the scale with a top loading, and set the second piston pump for SC injection into the reactor.

The reactor was a glass reactor of continuous mixer with chetyrehkolkoy cover and side drain hole at approximately 1-liter level. The reactor was applied nitrogen cushion using the bubbler back pressure. The content of the material in the reactor from the previous experiment was determined as 0.3% of DAF, 99.7% of CS and 0.08% other unidentified material.

Piston pump for the SC started to work at the feed rate of 2.2 grams per minute. When SC was reached reactor, began working piston pump for initial solution DAF when the feeding speed of 15.2 g per minute.

The cooling system of the reactor was set at -15°in an attempt to maintain the reaction temperature during the course of the reaction near 0°; achieved temperature in the range from +4,0°to +5.0°C. Mixing in the reactor was carried out at 400 Rev/min

The reactor worked continuously for seven (7) hours, with tanks for filing SC and initial solution DAF replenished as necessary To regulate the speed of adding and installations, pump, adjusted to maintain flow rates were used count readings of scales. The residence time inside the reactor was calculated approximately as one (1) hour.

Receiving flask was replaced every hour, the flow of the product was filtered and then evaporated to an oil on a rotary evaporator with water bath, supported at a temperature of about 40°C. Each aliquot of concentrated oil was transferred into a glass container and placed in a freezer at -20°for storage.

Samples of the product stream from the reactor is also an hourly basis were selected and analyzed by GC and the results are presented in Table 1.

Table 1< / br>
The contents of the stream of product
Time% CS% DAF
1 h99,20,8
2 hours99,50,5
3 hours99,60,4
4 h99,70,3
5 h99,80,2
6 h99,80,2
7 h99,80,2

Example 2

A continuous method of producing topiramate (TPM)

CS power supply solution for what was otaplivalsya with reconstitution oil, obtained in Example 1, by dissolving in glyme to a final concentration of 1 g CS - 5.8 g of glima as follows. Oil CS (376,1 g) were removed from the freezer (where it was stored between cycles of the way to avoid decomposition) and was left to warmed to room temperature. CS were washed in 4-liter Erlenmeyer flask portions of glima. Glyme was added until the desired proportion so that the total addition of glima was 2181,33, the Solution was well mixed and filtered through 934-EN glass fiber filter using a weak vacuum to obtain the original solution CS (2523,2 g).

2-liter reactor made of stainless steel with a drain hole at about 1.5-liter level were isolated from 20-liter receiver product of stainless steel. The receiver of the product was pumped to vacuum 30" Hg with the use of a water suction device.

The reactor cooling system was installed by 16.5°and after that was put on production stages to the final installation on 13°to maintain the reaction temperature between 17,9°and 19.9°during the reaction. Mixing in the reactor was carried out at 700 rpm

The pressure in the entire system of the reactor was brought up to about 2 lb./square inch (0,141 kg/cm2) on the pressure gauge (absolute 17 lb./square inch (1,195 kg/cm2)) using anhydrous Ammi is CA. During reactor operation, when the control pressure is continuously added ammonia, maintaining system pressure between 2 lb./square inch (0,141 kg/cm2) on the pressure gauge (absolute 17 lb./square inch (1,195 kg/cm2)) and 3 lb./square inch (0,211 kg/cm2) on the pressure gauge (absolute 18 lb./square inch (1,266 kg/cm2)). The measured pressure of ammonia ranged from 1.5 lb./square inch (0,1055 kg/cm2) on the pressure gauge (absolute 16.2 lbs./square inch (1,139 kg/cm2)) to 2.5 lb./square inch (0,1758 kg/cm2) on the pressure gauge (absolute and 17.2 lb./square inch (1,209 kg/cm2)).

CS feed solution were weighed before and after use. The tank containing CS feed solution was placed on the scales to the top of the boot and on the surface of the liquid was maintained a stream of nitrogen. CS feed solution was continuously fed to the reactor using a piston pump at a rate of approximately 7,1 g per minute. When you had more CS feed solution, he was prepared, as described previously, and the tank was replenished.

The reactor was continuously operated for sixteen (16) hours, while flowing stream was collected in a container receiver product. Flowing the product was controlled by composition with HPLS, including the amount of product (topiramate), the number of DAF, the number of CS and the number of "other" products, the results are presented in Tab is itzá 2.

Table 2< / br>
The contents of the stream of product
Time% of topiramate% CS% DAF% other
1 h94,14,61,20,1
2 hoursa 94.24,31,40,1
3 hours91,56,22,10,2
4 hto 89.56,93,30,3
5 h89,87,13,00,1
6 h90,47,22,40,0
7 h90,96,82,20,1
8 h91,56,32,00,2
9 h91,76,31,80,2
10 hto 92.16,01,70,2
11 hto 92.16,11,60,2
12 hours91,76,61,40,3
90,97,81,30,1
14 hto 91.17,51,20,2
15 hto 91.66,81,10,5
16 h90,68,01,10,3

After 16 hours the reactor was switched off, and the capacity of the receiver of the product was left under pressure of ammonia of about 2 lb./square inch (0,141 kg/cm2) on the pressure gauge (absolute 17 lb./square inch (1,195 kg/cm2)) for about 8 hours. The receiver of the product is then ventilated in order to give the possibility to dissipate the greatest amount of ammonia.

The slurry product was filtered through a Buechner funnel.

The solids were suspendibility in a Buechner funnel and thoroughly washed two approximately equal portions of fresh glima (total weight 172,2 g). The filtered contents of the receiver of the product and rinse water weighed 6321,8 g, while the crude residue on the filter is washed solids weighed to 194.6,

The filtered solution was evaporated to an oil on a rotary evaporator with water bath, supported at the temperature of 40°giving raw topiramate.

The GC analysis of the solution in the receiver of the product after sixteen (16) hours of reaction time showed a mixture of 1.1% is about square DAF, 8.0% in the area of CS, 90.6% of area TRM and 0.3% by area of unknown substances.

The GC analysis of the solution in the receiver of the product through sixteen (16) hours of reaction time and about 8 hours of standing showed a mixture of 0.9% square DAF, no CS, 98.5% of the area TRM and 0.6% by area of unknown substances.

Analysis of the GC content of the receiver of the product after filtration showed a mixture of 1.7% by area, DAF, no CS, 97.9% of area TRM and 0.5% by area of unknown substances.

Example 3

A continuous method of producing chlorosulphate (CS) diacetone-β-D-fructose

Used reactor was a glass reactor of continuous mixer with chetyrehkolkoy cover, lateral drain hole at approximately 1-liter level and a nitrogen blanket using the bubbler back pressure. The reactor was cooled by indirect cooling with glycol. Before the experiment, the material in the reactor was analyzed by GC. Original compositions reactor for completed runs are summarized in Table 3.

Table 3< / br>
The original composition of the reactor
Run No.1234567
% CS99,099,694,697,999,699,499,6
% DAF1,00,4of 5.42,10,30,60,4
% other00000,100

1-liter Erlenmeyer flask was filled with the initial solution DAF (prepared as described in Example 1) and was placed on the scales to the top of the boot. To discharge the solution in the reactor was connected piston pump. In a separate flat-bottomed flask for boiling was otoshibuta sulfurylchloride (SC). The flask containing sulfurylchloride was backed up and then placed on the scale to the top of the boot. Connect the second piston pump for SC injection into the reactor.

Stirring was started at about 400 rpm, and a piston pump for SC started at a desired feed rate. When SC has reached the reactor at a desired speed started piston pump for initial solution DAF. The reactor was continuously operated for a specified period of hours, as necessary tanks for filing SC and initial solution DAF replenished. The product of the reactor was continuously fed into the receiver of the product, to the verge as appropriate oporozhnenija. Reading the testimony of scales was used to control the speed of adding and installations of the pump is adjusted to maintain flow rates. Working conditions, including estimated time of stay in the reactor, are summarized in Table 4.

Table 4< / br>
Conditions of reactor operation
Run No.1234567
The molar ratio< / br>
SO2Cl2:DAF
1,050,940,931,011,001,000,99
The molar ratio< / br>
Pyridine:DAF
1,051,051,051,051,051,051,05
The molar ratio< / br>
Glyme:DAF
2,322,322,322,32with 4.64with 4.64with 4.64
Pump speed (R/min)< / br>
Glyme:DAF
to 7.61a 7.6215,415,2the 13.4the 13.4the 13.4
Pump speed (R/min)
SO2Cl2:DAF
1,141,022,022,171,171,171,15
The reaction temperature (°C)-1-22401430
The residence time (hours)2,02,01,01,01,01,01,0

Hourly sampled from the reactor, and samples were analyzed for content using GC. Opening hours at each condition and received the contents of the reactor close to the completion of continuous operation are summarized in Table 5 below.

Table 5

Time and the contents of the reactor
Run No.1234567
Hours and hours of operation5555453
% CS99,394,191,599,599,598,895,9
% DAF0,75,90,50,51,24,1
% other0000000

Example 4

A continuous method of obtaining topiramate (TRM)

The continuous reactor was a 2-liter reactor made of stainless steel under pressure with drain hole at about 1.5-liter level. Receiver product was a 20-liter pressure tank stainless steel. The reactor was cooled by indirect cooling with glycol to maintain the temperature close to the set temperature during the reaction. Before the experiment, the material in the reactor from the previous experiment were analyzed by GC to determine the contents. The original composition of the contents of the reactor are summarized in Table 6.

Table 6

The contents of the reactor at the beginning of the experiment
Run No.10111213141516
% TRM77,588,291,983,096,692,295,0
% CS 0000000
% DAF23,311,76,315,13,27,04,8
Run No.171819202122
% TRMof 89.185,485,796,089,881,7
% CS000000
% DAF10,314,514,32,69,617,8

At the beginning of the experiment, the receiver of the product was pumped and the pressure in the entire system of the reactor is brought to a specified with the help of anhydrous ammonia gas. With the exception of Run No. 10, ammonia was added above the surface. The tank containing the solution of CS, obtained as described in Example 2, were placed on the scales to the top of the boot and was filled with a layer of nitrogen. For continuous discharge of CS solution in the reactor was connected piston pump. Except for Runs 10 and 11, CS solution was added to the reactor over a surface. Piston us is for CS solution started to work at a given feed rate. To maintain a predetermined pressure controlled by the pressure continuously added ammonia. Product from the reactor is continuously flowed into the receiver of the product. When it was necessary to apply more solution CS, he was prepared as described in Example 2. Working conditions, including estimated time of stay in the reactor, are summarized in Table 7.

Table 7

Conditions of reactor operation
Run No.10111213141516
The mass ratio2,95,84,38,75,85,85,8
Glyme:CS oil
%DAF CS solution7,02,33,33,01,81,31,1
The feed rate of CS solution (g/min)7,47,07,47,37,17,27,7
The pressure of NH3in the reactor(absolute lb./psi)3028 174517
Speed stirrer(rpm)350300720715680686688
The temperature of the reactor(°)020191819019
The residence time (hours)3,03,13,13,03,03,02,8
Run No.171819202122
The mass ratio5,82,92,95,85,85,8
Glyme:CS oil
%DAF CS solution2,11,52,01,01,05-6
The feed rate of CS solution (g/min)7,27,77,74,24,24,3
The pressure of NH3 in the reactor(absolute lb./psi)30184171830
Speed stirrer (rpm)703697732690720722
The temperature of the reactor(°)19192018019
The residence time (hours)3,02,92,95,15,25,0

Hourly from the reactor was sampled and the samples analyzed for content using GC. Opening hours at each condition and received the contents of the reactor close to the completion of continuous operation are summarized in Table 8.

83,0
Table 8< / br>
Time and the contents of the reactor
Run10111213141516
Time (hours)6769958
% of topiramate72,977,982,277,084,990,6
% CS0,11,94,06,0the 17.310,05,3
% DAFto 25.315,016,29,95,14,64,0
Run171819202122
Time (hours)968151015
% of topiramate84,075,673,287,589,884,6
% CS1,77,416,73,06,31,5
% DAF14,215,49,68,93,113,1

Example 5 - Effect of solvent removal

Stage A: Getting chlorosulphate deaconfrost using stoichiometric amount SO2Cl2

5000-ml three-neck round-bottom sferic the Skye flask was fitted with a mechanical stirrer, thermometer and a funnel to add, is connected to a source of low pressure nitrogen to provide an inert atmosphere. To the flask was added (DAF 825 g, 3,17 mol), glyme (1915) and pyridine (263,5 g of 3.33 mol) and stirred at 25°up to complete dissolution. The flask was cooled in a mixture of salt and ice to a temperature within approximately 0°C. For 4 hours while maintaining the reaction temperature at 0°C, was added sulfurylchloride (427,9 g, 3,17 mol). The mixture is stirred further at 0°C for 15 minutes, after which the cooling bath was removed and the mixture was heated to room temperature. Samples were taken of the content and analyzed by GC.

Analysis: 1,19% DAF, 98,9% CS

The mixture was filtered under vacuum to remove solids hydrochloride of pyridine. CS solution (2835 g) was transferred into the bottle, were tightly sealed and stored at -20°s to use on Stage Century.

Stage b: Preparation of CS solution to become topiramate

The solution prepared in Stage a above (130 g) was evaporated under vacuum in a 250 ml round bottom flask on a rotary evaporator and a water bath at 40°With, until not removed 20% of solvent.

After concentrating the contents of the flask were diluted with fresh glimm to the original 130 g were mixed, and subjected to vacuum filtration is kept in a nitrogen atmosphere prior to use in Stage C.

Stage C: the transformation of the CS solution in topiramate

Clean, dry 300-ml Parr reactor with stirrer (316SS), was flushed with nitrogen, then was pumped and isolated. Fresh glyme (87 g) was transferred into the vessel, which again was slightly pumped. Turn on the stirrer, and the system pressure ever use ammonia to about 2 lb./square inch (0,141 kg/cm2) on a pressure gauge. Used water bath by adding ice as necessary to maintain the contents at a temperature of about 15-20°during the reaction period. The solution with CS Stage was added using a pump for about 1.25 hours, then was stirring additionally for 2 hours at about 15-20°C, under pressure of ammonia 2 lb./square inch (0,141 kg/cm2) on the gauge.

The contents of the reactor were subjected to vacuum filtration to remove NH4Cl, and clean filtrate was analyzed by GC.

Analysis: 9,5% DAF, 90,0% TRM

Example 6 - Effect of solvent removal

Stage A: Getting chlorosulphate deaconfrost using 5% excess SO2Cl2

5000-ml three-neck round-bottomed spherical flask was fitted with a mechanical stirrer, thermometer and a funnel to add, is connected to a source of low pressure nitrogen to provide an inert atmospheric flask was added (DAF 825 g 3,17 mol), glyme (1915) and pyridine (263,5 g of 3.33 mol) and stirred at 25°up to complete dissolution. The flask was cooled in a mixture of salt and ice to a temperature within approximately 0°C. For 4 hours while maintaining the reaction temperature at 0°add sulfurylchloride (449,5 g of 3.33 mol). The mixture is stirred at 0°additionally for 15 minutes, after which the bath was removed and the mixture was heated to room temperature. Was sampled content and analyzed by GC.

Analysis: 0,23% DAF, 99,72% CS

The mixture was subjected to vacuum filtration to remove the solid pyridine hydrochloride. CS solution (2859 g) was transferred into the bottle, were tightly sealed and stored at -20°s to use on Stage Century.

Stage: Getting CS solution to become topiramate

The portion of the solution prepared in Stage a above, (130 g) was evaporated under vacuum in a 250 ml round bottom flask on a rotary evaporator and a water bath at 40°With, until not removed 70% of solvent.

After concentration, the contents of the flask were diluted with fresh glimm to the original 130 g were mixed, and subjected to vacuum filtration and stored in a nitrogen atmosphere prior to use in Stage C.

Stage C: the transformation of the CS solution in topiramate

Clean, dry 300-ml Parr reactor with smishally (316SS) was flushed with nitrogen, then he pumped and isolated. Fresh glyme (87 g) was transferred into the vessel, which again was slightly pumped. Turn on the stirrer and the pressure in the system, using ammonia had about 2 lb./square inch (0,141 kg/cm2) on a pressure gauge. Used water bath by adding ice as necessary to maintain the contents at a temperature of about 15-20°during the reaction period. The solution with CS Stage was added using a pump for about 1.25 hours, and then stirring was carried out additionally for 2 hours at 15-20°C, under pressure of ammonia 2 lb./square inch (0,141 kg/cm2).

The contents of the reactor were subjected to vacuum filtration to remove NH4Cl, and clean filtrate was analyzed by GC.

Analysis: 8.1% of DAF, 90,0% TRM

Although the preceding description discloses the principles of the present invention, and examples are presented for purpose of illustration, it is clear that the practical implementation of the invention encompasses all of the usual variations, adaptations and/or modifications that are included in the scope of the following claims and their equivalents.

1. A continuous method of obtaining the compounds of formula (I)

in which

X is selected from CH2or;

R1selected from groups who, consisting of hydrogen and C1-4of alkyl;

R3, R4, R5and R6each independently selected from hydrogen or lower alkyl and, when X is CH2, R5and R6can be allenbyi groups connected with the formation of the benzene ring and, when X represents Oh, R3and R4and/or R5and R6together can be methylendioxyphenyl formula

in which

R7and R8are the same or different and represent hydrogen, lower alkyl or are alkilani and connected, forming cyclopentenone or tsiklogeksilnogo ring,

including

(A) interactions appropriately substituted compounds of formula (IV) with sulfurylchloride in the presence of organic or inorganic bases with formation of the corresponding compounds of formula (V);

(C) the interaction of the compounds of formula (V) with the appropriately substituted compound of formula (VI)

both the stage And In the continuous process is carried out using glima as the organic solvent,

with the formation of the corresponding compounds of formula (I).

2. The method according to claim 1, in which the OS what Finance is an organic base.

3. The method according to claim 2, in which the organic base is pyridine.

4. The method according to claim 1, in which sulfurylchloride is used in a quantity greater than 0.9 mol per 1 mol of the compounds of formula (IV).

5. The method according to claim 1, wherein the base is present in a quantity greater than 1 molar equivalent of compound of formula (IV).

6. The method according to claim 1, wherein the compound of formula (VI) is used in a quantity greater than 1 molar equivalent of compound of formula (V).

7. The method according to claim 1, in which stage (a) and phase (b) are each carried out in a flow reactor with a stirrer.

8. A continuous method of obtaining the compounds of formula (III)

including

(Aa) the interaction of the compounds of formula (IVa) with sulfurylchloride in the presence of organic or inorganic bases with formation of the corresponding compounds of formula (Va)

(VA) the interaction of the compounds of formula (Va) with ammonia,

both stages of Aa and VA continuous process is carried out using glima as the organic solvent,

with the formation of the corresponding compounds of formula (III).

9. The method according to claim 8, in which the base is an organic base.

10. The method according to claim 9, in to the m organic base is pyridine.

11. The method according to claim 8, in which sulfurylchloride is used in a quantity greater than 0.9 mol per 1 mol of the compounds of formula (IVa).

12. The method according to claim 8, in which the base is present in a quantity greater than 1 molar equivalent of compound of formula (IVa).

13. The method according to claim 8, in which the reaction temperature in stage (AA) is less than 50°C.

14. The method according to claim 8, in which ammonia is used in a quantity greater than 1 molar equivalent of compound of formula (Va).

15. The method according to claim 8, in which the ammonia is fed into the reactor under an absolute pressure of 19 psi (1,336 kg/cm2).

16. The method according to claim 8, in which the reaction temperature in stage (VA) is from -30 to 50°C.

17. The method according to claim 8, in which stage (AA) and stage (VA) each carried out in a flow reactor with a stirrer.



 

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29 cl, 10 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to sulphated oligosaccharides of the general formula X-[Y]n-Z-UR1, where X, Y and Z each are the same hexose monosaccharide fragment selected out of group including glucose, mannose, altrose, allose, talose, galactose, idose and gulose, adjoining monosaccharide fragments are bound in 1→2, 1→3, 1→4, and/or 1→6 pattern by glycoside bonds, and each carbon atom not binding X, Y and Z groups is bound by single bond with UR group, with exception for carbon atom in 1 position of Z monosaccharide, to which UR1 group is bound by single bond; where n is an integer within 0 to 6; U is O atom or NH; each R is independently C2-C6-alkenyl, benzyl, SO3M or H, where M is any pharmaceutically acceptable cation of alkali metal or organic amine, or R form N3 together with U; R1 is C1-C12alkyl, benzyl, PEG monomethyl ether or its derivative, C1-C12alkylazide, , or , in the form of ester, free acid, free base or hydrate. Also invention refers to pharmaceutical or veterinary composition based on claimed compounds, for disorder prevention or treatment for mammals in case of proliferate retinopathy, solid tumour and/or metastasis result, coagulation/thrombosis and/or virus infection of organism. Additionally invention refers to application of claimed compounds in medicine production for disorder prevention or treatment for mammals in case of proliferate retinopathy, solid tumour and/or metastasis result, coagulation/thrombosis and/or virus infection of organism.

EFFECT: increased efficiency of compound application in medicine.

11 cl, 3 tbl, 1 dwg, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oligosaccharide, suitable for vaccine against meningitis A, which includes first mannose unit, which has spacer in alfa-configuration in C-1, where said spacer is able to conjugate with protein, and bound to second mannose unit by 1,6-bond, which binds C-6 of first unit with C-1 of second unit, 1,6-bond including phosphonate. Invention also relates to methods of obtaining oligosaccharide and improved methods of obtaining mannose derivative, suitable for obtaining immunogenic oligosaccharide. Invention also relates to pharmaceutical composition for induction of immune response, immunogenic composition, capable of inducing formation of protective antibodies against meningitis A and vaccine against meningitis A, which include oligosaccharide.

EFFECT: obtained glycoconjugates have C-phosphonate bond, which is much more stable than natural phosphodiester bonds, as well as higher immunologic activity.

51 cl, 4 dwg, 3 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as heparan sulphate-binding protein inhibitors. The invention also refers to a pharmaceutical or veterinary composition having heparan sulphate-binding protein inhibitory activity for preventing or treating a disorder in a mammal, and to the use of these compounds and compositions for antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic therapy in a mammal.

EFFECT: preparing the new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as the heparan sulphate binding protein inhibitors.

10 cl, 31 ex, 11 tbl, 40 dwg

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