UA80450C2 - Continuous process for the preparation of fructopyranose sulfamate derivatives - Google Patents

Abstract

The present invention is directed to a continuous process for the preparation of fructopyranose sulfamate derivatives of the general formula (I) wherein Rl, R3, R4, R5, R6 and X are as herein defined. The present invention is further directed to a continuous process for the preparation of topiramate.

Description

Description of the invention

This application claims the benefit of |Previous US Application 60/422,558, filed Oct. 31, 2002|, which is incorporated herein by reference in its entirety.

The present invention relates to a continuous process for obtaining sulfamate derivatives of fructopyranose of the general formula (1). then o M-e t vod o ro ro ro ( ) where B", 83, 27, 2", B and X are defined below.

Sulfamates of formula (I) p

N o

X Z o v o r u k o y

In o h in F d) to c. () where X is O or CH. and KK", KZ, vk", KZ and KE? defined below are known compounds that have been found to exhibit anticonvulsant activity and are therefore useful in the treatment of conditions such as epilepsy. These compounds are disclosed in US Patent No. 4,582,916 and US Patent No. 4,513,006), which also disclose the process of obtaining these compounds; and h» which are hereby incorporated by reference. "One of the processes disclosed in the above-mentioned patents is a process for obtaining compounds of the formula (I), which is the introduction into the reaction of an alcohol of the formula ESNOOH with a chlorosulfamate of the formula SIZOOMN» or SIZOOMNEA! in the presence of a base, such as potassium t-butoxide or sodium hydride, at a temperature of approximately -209C to 259C and

Co in a solvent such as toluene, tetrahydrofuran, or dimethylformamide, where K is a fragment having the formula o (I) t» X t 5 o KK n) o v v ime) vo This process has two major disadvantages, especially when it comes to large-scale synthesis. One disadvantage is that the process requires the coupling of Mann and DMF, which results in an uncontrolled release of heat and can therefore lead to an explosion. | See U. Viskieu ei aI., Spetisa! 5 Epdipeegipd Memuv, Ushu 12, 1982, rade 5; and ob. OemUMaiyi, Spetisa! 5 ЕЕпдипеегипд Memuv, Zeri. 13, 1982). The second disadvantage is that for the production of sulfamyl chloride (SISOOMN), which is not produced by industry, the highly toxic and corrosive chlorosulfonyl isocyanate (XCI) is also used in the process.

Another process for the preparation of compounds of formula (I) disclosed in the aforementioned (US Patent No. 4,513,0061,

involves the reaction of an alcohol of the formula КСНоООН with a sulfuryl chloride of the formula 5О05Си in the presence of a base such as triethylamine or pyridine at a temperature of about -402C to 25922 in diethyl ether or methylene chloride, in which chlorosulfate of the formula KSN 20505СИ is formed. The chlorosulfate of the formula KSN»OBZO»-SI can then be reacted with an amine of the formula K'MH»o at a temperature of approximately -409C to 259C. in methylene chloride or acetonitrile, in which the compound of formula (I) is formed. This process, which uses solvents such as diethyl ether, methylene chloride and acetonitrile, gives a relatively low yield of the desired end product of formula (1).

A third process, disclosed in the two aforementioned patents, involves reacting the chlorosulfate of formula 70.ASN.OBOOCI (formed by the reactions described above) with a metal azide, such as sodium azide, in a solvent such as methylene chloride or acetonitrile, in which the azidosulfate is formed formulas

KSNYOZOOM5. Then the azidosulfate is reduced to the compound of formula (1), where KE! is hydrogen, with the help of catalytic hydrogenation.

A disadvantage of this process is that an explosion can occur as a result of careless handling of the azide 72 compounds. Also, the process includes an additional chemical transformation, namely, the reduction of azide to the MH »- group.

IMaguagoi ei aI. in the United States 5,387,700) discloses a process for the preparation of compounds of the formula (I), which involves the reaction of an alcohol of the formula KSNOOH with sulfuryl chloride in the presence of a base in a solvent selected from the group consisting of toluene, t-butyl methyl ether and tetrahydrofuran, in which a chlorosulfate intermediate is formed formulas KSN»OBZO»SI. In the second stage, the chlorosulfate of the formula КСНОБЗО»ОСИ is reacted with an amine of the formula К'"МН" in a solvent selected from the group consisting of tetrahydrofuran, t-butyl methyl ether and a lower alkanol (for example, methanol or ethanol), in which a compound of the formula is formed (1).

One of the disadvantages of this process is that the compound of formula (I) is obtained in a stepwise process in which the first reaction is carried out, the solvent is removed, the product is isolated, the separated solid is dissolved again in another solvent, and then it is introduced into the reaction to obtain the final product. This c 29 leads to a process that requires isolation of the semi-stable, thermally unstable intermediate compound KVOZO-SI. Gee)

The purpose of the present invention is to provide a continuous process for the preparation of compounds of formula (I) which does not require changes in solvent systems, uses widely available materials, which can be carried out under safe conditions, which will have a relatively high yield and/or which will allow the production of larger quantities of substances per unit of time in a unit of reactor volume (that is, which will allow to produce a larger amount of substance in a smaller amount of equipment). yu

This invention is directed to the continuous process of obtaining compounds of the formula (I) « about M-v! and

ХХ IM-k so

X Z kh " ro o o - s vd 2" H 4 y v v () (ee) o de

X is selected from CH" or 0; shk Ge is selected from the group consisting of hydrogen and Si.dalkils; sia 70 BZ, 27, BZ and 29 are each independently selected from hydrogen and lower alkyls and, when X is СНо, B? and 29 can be oz alkene groups connected to form a benzene ring and, when X is O, B Z and 27 and/or 2? and KE? together can be a methylenedioxy group of the formula 7 5 K o 2 "

F) o A yu VO de

B" and 8 are the same or different and are hydrogen, lower alkyl or are alkyl and are connected to form a cyclopentyl or cyclohexyl ring; 65 comprising

50 people! i x OM X o i b Z

B Z nn cha v V i 50s v v 6 4 Z 4 to Kk Kk AK (M) (M) (A) reaction of the correspondingly substituted compound of the formula (IM) with sulfuryl chloride; in the presence of an organic or inorganic base; in the first organic solvent containing at least one solvent selected from a cyclic ether, a straight or branched chain dialkyl ether, an aromatic hydrocarbon, or a mixture of a cyclic ether, a straight or branched chain dialkyl ether and an aromatic hydrocarbon solvent; with the formation of the corresponding compound of formula (M);

Lo and 0.-M NO!

X c Y -6 v B ooo v!A-mn,.--t her v (M) c 4 v I do -z d) (U) «) (B) reaction of the compound of the formula (M) with the correspondingly substituted compound formulas (MI); in a second organic solvent containing at least the solvent used in step (A); o with the formation of the corresponding compound of formula (1). yu

This invention is further directed to the continuous process of obtaining the compound of the formula (HER) "

Ok, MN» Fo in what so / o

O sh--0 x « -

Я: я - с Ох о г" i и я 0 9 (HO) (ee) ("c) iz also known as topiramate, a compound of the formula (I), where X is O, B is hydrogen, all EI B" viv connected with the formation of c 50 o 5-9 CHnaz

ЗХ шчи то сн име) Z , which includes 60 b5

/Vozsi o ОН 0 to 5000 o oj byu, o yu (ma) (ma) (Aa) reaction of the compound of the formula (Ma) with sulfuryl chloride; in the presence of an organic or inorganic base; in a first organic solvent containing at least one solvent selected from a cyclic ether, a straight or branched chain dialkyl ether, an aromatic hydrocarbon, or a mixture of a cyclic 75 ether, a straight or branched chain dialkyl ether and an aromatic hydrocarbon solvent; with the formation of the corresponding compound of the formula (Ma); 1

Axis og MAK

IV: a- o To dme -o i МНу-- ЦО o - -i pr p z o (ma) (t) (Ba) reaction of the compound of the formula (Ma) with ammonia; in a second organic solvent containing at least the solvent used in step (A); o z o with the formation of the corresponding compound of the formula (PI).

The present invention is further directed to a compound obtained by any of the processes described herein. i am

Indicative of the invention is a pharmaceutical composition that contains a pharmaceutically acceptable carrier and a compound obtained by any of the above-described processes.

An illustrative example of the invention is a pharmaceutical composition obtained by mixing a pharmaceutically acceptable carrier and a compound obtained by any of the above-described processes. co

An example of the invention is the process of obtaining a pharmaceutical composition, in which a pharmaceutically acceptable carrier and a compound obtained by any of the above-described processes are mixed.

Another example of the invention is the use of a compound obtained by any of the processes described herein for the preparation of a medicament for the treatment of epilepsy. Detailed description of the invention "

In an embodiment of this invention, the second organic solvent (used in stage (B)) is the same as the first organic solvent (used in stage (A)). In another embodiment of the present invention, the first organic solvent (used in step (A)) and the second organic solvent (used in step (B)) are both glyme.

As used herein, the term "reactor" refers to a continuous reactor, such as a continuous stirred tank reactor (CRT), a displacement reactor, a tower reactor, and the like. The best continuous reactor is a continuous reactor with a stirrer.

As used herein, the term "reaction duration" refers to the average amount of time that a portion of the reactant or reactants spends in the reactor. as used herein, the term "alkyl", alone or as part of a substituent group, includes straight and branched alkyl chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, o-t-butyl, t-butyl, pentyl and the like. Unless otherwise noted, the term "lower" as used with o-alkyl refers to a carbon chain of 1-4 carbon atoms.

With respect to substituents, the term "independently" means that when more than one such substituent is possible, such substituents may be the same or different.

When a particular group is "substituted" (eg, alkyl, phenyl, aryl, aralkyl, heteroaryl), that group may have one or more substituents independently selected from the list of substituents.

F) As used herein, the term "subject" refers to an animal, preferably a mammal, preferably a human, which is or has been subjected to treatment, observation or experimentation.

As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that produces a biological or medical response in a tissue system, animal or human, that is sought by the investigator, veterinarian, medical practitioner or other clinician, which includes alleviation of disease symptoms or the disorder being treated.

As used herein, the term "composition" is intended to encompass a product consisting of the specified ingredients in specified amounts, as well as any product resulting, directly or indirectly, from the combination of specified ingredients in specified amounts.

In the specifications, especially the Diagrams and Examples, the following abbreviations are used:

o or t hporsupphate diazcetone-K-Sefructose kporekpphate

BA - bezharerenai reaction vperat x mishapcon dAF - odivcetone-B-C-ruktose

DIPED - diisopropylethylamine

Liqueur - MN-dimethypformatmid

GC - gas chromatography

Glyma dimetaglucoe ether ethylglycopic ether - high-performance liquid chromatography

MmtBE to metig.x butygovzhA fa shh t sulinfernpchlorid

TEA t trivpilamine tgf t tetrahydrofuran

You are a tapiramate

This invention is directed to the continuous process of obtaining the compound of formula (I)

About. M-8 is in

In o ch 7 o o o o (I) 2

IF) "

Where

X is selected from CH" or 0; at

He is selected from the group consisting of hydrogen and C-;-alkyls; c 23, c, c and K5 are each independently selected from hydrogen and lower alkyls and when X is СНо, B? and 29 can be alkene groups connected to form a benzene ring and, when X is O, B is 27 and/or 2? and KE? together can be a methylenedioxy group of the formula "

Her name is "Ko s". and "In the 0s (ee) o de

B" and 8 are the same or different and are hydrogen, lower alkyl or are alkyl and are connected to form a cyclopentyl or cyclohexyl ring; c 20 More specifically, the present invention is directed to a continuous process for the preparation of the compound of formula (I), as shown in Scheme 1 mk stadgia |Du still -k on hi ne « Vod,---k to I (F) zh I IT t yuyu NYA SHK) stvdya (Vu bo !

BOS p;-chna h y h y «i fe y VA-MTU ---- -- Zhli -

Gi t SYA v: di 1 Zh b5

Skayuya 1

Accordingly, at stage (A), the appropriately substituted compound of formula (IM), a known compound or a compound obtained by known methods, and the base are dissolved in the first organic solvent and reacted with sulfuryl chloride; wherein the base is an inorganic base such as Ma 2 CO 5 3 , K 2 CO 3 , MaHSO 3 , and the like, or an organic base such as a tertiary variable base such as pyridine, pyridine derivatives, TEA, DIPEA, and the like; preferably an organic tertiary amine base, even better pyridine; where is better, when the base does not react with the compound of the formula (IM) or sulfuryl chloride; wherein the first organic solvent contains at least one solvent selected from a cyclic ether such as 7/o Pyran, tetrahydrofuran and the like; straight or branched chain dialkyl ether such as

MTBE and similar; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent; preferably, the first organic solvent contains at least one solvent selected from a cyclic 7/5 ether or a straight or branched chain dialkyl ether such as THF, pyran, thim, MTBE and the like; even more preferably, the first organic solvent contains at least glyme; preferably, when the sulfuryl chloride is present in an amount greater than about 0.9 moles per mole of the compound of formula (IM); even better, when the molar ratio of the compound of formula (IM) to sulfuryl chloride is in the range of about 1:0.9 to about 1:1.5; even better, when the molar ratio of the compound of formula (IM) to sulfuryl chloride is in the range of about 1:1.0 to about 1:1.05; preferably, when the base is present in an amount greater than about 1 molar equivalent of a compound of formula (IM); even better, when the molar ratio of the compound of the formula (IM) to the base is greater than or equal to about 1:1.05; even more preferably, the molar ratio of the compound of formula (IM) to the base is from about 1:1.05 to about 1:1.20; even better, when the molar ratio of the compound of the formula (IM) and the base is approximately 11105; preferably, the reaction temperature is maintained below about 50°C, more preferably from about 0°C i) to about 202°C, most preferably about 09; with the formation of a solution containing the corresponding compound of formula (M) and a precipitate of the hydrochloride salt of the base.

In an embodiment of the present invention, the first organic solvent (used in step (A)) is selected from the group consisting of a cyclic ether such as pyran, tetrahydrofuran and the like; a straight or branched chain dialkyl ether such as glyme, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or is a mixture of a cyclic ether, a dialkyl ether with a straight or branched chain and an aromatic hydrocarbon solvent. Preferably, the first organic solvent (used in step (A)) is selected from a cyclic ether or a straight or branched dialkyl ether such as THF, pyran, glyme, MTBE and the like, even more preferably, the first organic solvent is (used in stage (A)) is glim.

In an embodiment of the present invention, the first organic solvent (used in step (A)) is selected from the group consisting of a cyclic ether, a straight or branched chain dialkyl ether, and an aromatic hydrocarbon solvent; wherein the first organic solvent is not tetrahydrofuran or t-butyl methyl ether. - c In an embodiment of this invention, stage (A) of the reaction is carried out in such a way that the compound of the formula (IM) and the base, c dissolved in the first organic solvent, react with pure sulfuryl chloride due to the fact that in "" a continuous reactor, preferably BRAM, are continuously fed two reaction streams containing a compound of formula (IM) and a base dissolved in a first organic solvent, and sulfuryl chloride.In another embodiment of the present invention, sulfuryl chloride is dissolved in the same organic solvent used to dissolve (oo) the compound of formula (IM) and base (i.e., the first organic solvent). o It is better when the solution containing the compound of formula (M) and the precipitate of the hydrochloride salt of the base are filtered using known methods to separate the precipitate. ч It is better when the solution containing the compound of formula (M) , are concentrated using known batch or continuous methods, for example, by solvent evaporation (such as liquid falling film evaporation or film evaporation) or vacuum d istilation, with the preparation of a concentrate of the compound of formula (M). In an embodiment of the present invention, the solution containing the compound of formula (M) is concentrated to an amount less than or equal to approximately half of the original mass of the solution. In another embodiment of this invention, a solution containing a compound of formula (M) is concentrated to an oil.

When the compound of formula (IM) is reacted with an amount of sulfuryl chloride greater than about 1 equivalent, the solution containing the compound of formula (M) is preferably concentrated using known batch or continuous methods to remove at least about 7095 wt% of the solvent. When the compound of formula (IM) is reacted with about 1 equivalent of sulfuryl chloride, the solution containing the compound of formula (M) is preferably concentrated by known batch or continuous methods to remove at least about 2095 wt% of the solvent.

In an embodiment of the present invention, a solution containing a compound of formula (M) is treated to remove volatile substances. Suitable treatments include, but are not limited to, vacuum distillation, concentration, distillation, passage through activated carbon or other absorbent, and the like.

The concentrate of the compound of formula (M) is dissolved in a second organic solvent containing at least 65% of the solvent used in step (A) (i.e. the first organic solvent) and preferably containing at least one solvent selected from a cyclic ether such as pyran, tetrahydrofuran and similar; a straight or branched chain dialkyl ether such as thim, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent. Preferably, the concentrate of the compound of formula (M) is dissolved in the same organic solvent used in step (A) described above.

Preferably, the concentrate of the compound of formula (M) is dissolved to a final weight ratio of solvent to compound of formula (M) ranging from about 2:11 to about 10:1, more preferably to a final weight ratio of solvent to compound of formula (M) of about 6:1, yielding the reaction stream 70 which is used in step (B), and which will be referred to hereafter as the third reaction stream containing the compound of formula (M).

In step (B), the compound of formula (M) is reacted with an appropriately substituted compound of formula (MI), a known compound or a compound obtained by known methods, in a second organic solvent containing at least the solvent used in step (A); wherein the second organic solvent contains at least one solvent selected from a cyclic ether such as pyran, tetrahydrofuran and the like; straight or branched chain dialkyl ether such as

MTBE and similar; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent; preferably, the second organic solvent contains at least one solvent selected from a cyclic ether or a dialkyl ether with a straight or branched chain, such as THF, pyran, glyme, MTBE and the like; even more preferably, the second organic solvent contains at least glyme; even better, when the second organic solvent is the same as the first organic solvent; even better, when the second organic solvent is glyme; preferably, when the compound of formula (MI) is present in an amount greater than about 1 molar equivalent of the compound of formula (M); even better, when the molar ratio of the compound of the formula (MI) to the compound of the formula (M) is greater than or equal to about 2:1; even better, when the molar ratio of the compound of the formula (MI) and the compound i) of the formula (M) is approximately 5:1; preferably, when the reaction temperature is maintained in the range of about -309C to about 502C, more preferably in the range of about 02C to about 302C, even more preferably about 202; Ha") with the formation of a solution of the compound of formula (I) and a precipitate.

When the compound of formula (MI) is ammonia, it is preferred that the ammonia is fed to the reactor at a controlled pressure or flow rate, more preferably at a pressure of less than or equal to about Zbafkd (absolute pounds per square inch, rzia), and preferably at a pressure of from about 15 afkd to about 20 afkd, more preferably at a pressure of about 19 afkd. at

In an embodiment of the present invention, the second organic solvent (used in stage (B)) is selected from the group consisting of a cyclic ether such as pyran, tetrahydrofuran and the like; a straight or branched chain dialkyl ether such as glyme, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or is a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent. It is preferable that the second organic solvent (used in step (B)) is selected from a cyclic ether or a 3.-d dialkyl ether with a straight or branched chain such as THF, pyran, glyme, MTBE and the like, even more preferably when the second The organic solvent (used in step (B)) is glyme. "» In an embodiment of the present invention, the second organic solvent (used in step (B)) is selected from the group consisting of a cyclic ether, a straight or branched chain dialkyl ether, and an aromatic hydrocarbon solvent; where the second organic solvent is not tetrahydrofuran or (oo) t-butyl methyl ether.

In another embodiment of the present invention, the second organic solvent (used in stage (B)) contains the solvent used in stage (A) (ie, the first organic solvent). It is better when the solution containing the compound of formula (I) and the precipitate is filtered using known methods, for

Separation of sediment. i-th In the embodiment of the invention, the process of obtaining the compound of formula (I) is carried out in two continuous reaction apparatuses with a stirrer (BRAMs). Preferably, stage (A) is carried out so that the duration of the reaction in the first GATE is about 1 hour. Preferably, stage (B) is carried out so that the duration of the reaction in the second GATE is approximately 3 hours. Preferably, stage (B) is carried out so that the third reaction stream and the compound of formula (MI) are introduced into the BRAM from the surface.

The present invention is further directed to a continuous process for the preparation of the compound of formula (I), also known as topiramate, as depicted in Scheme 2. ime) 60 b5

Stage (Da): o /vOssi ; yaetoN Zo ie OO 000580 -- as Yu.O: -o - y Z o U o zach 7 (ma) ma)

Stage (Vau: uva MBO MN z - MN tn Ko

C - crazy (ma; IEKI p. 29 Scheme 2 o

Accordingly, at stage (Aa), the compound of formula (Ma), a compound also known as diacetonefructose (DAF), and the base are dissolved in the first organic solvent and reacted with sulfuryl chloride; where the base is an inorganic base such as Ma 2 CO 3 , K»USO 3, ManHsCO» 3 and the like, or an organic (ab) base such as a tertiary amine base such as pyridine, pyridine derivatives, TEA, DIPEA and the like; preferably an organic tertiary amine base, even better pyridine; it is better when the base does not react with the compound of the formula (IMa) or sulfuryl chloride; And wherein the first organic solvent contains at least one solvent selected from a cyclic ether such as pyran, tetrahydrofuran and the like; dialkyl ether with a straight or branched chain, such as thim, o

MTBE and similar; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; (ee) or a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent; preferably, the first organic solvent contains at least one solvent selected from a cyclic ether or a dialkyl ether with a straight or branched chain, such as THF, pyran, thim, MTBE and the like; even more preferably, the first organic solvent contains at least tim; even better, when the first organic solvent is glyme; - c where better, when sulfuryl chloride is present in an amount greater than about 0.9 mol per mol of compound a of formula (Ma); more preferably, when the molar ratio of the compound of formula (Ma) to sulfuryl chloride is in the range "» from about 1:0.9 to about 1:1.5; even more preferably, when the molar ratio of the compound of formula (IMa) to sulfuryl chloride is in the range of about 1:1.0 to about 1:1.05; preferably, when the base is present in an amount greater than about 1 molar equivalent of the compound of formula (ee) (Ma); even more preferably, when the molar ratio of the compound of formula (Ma) and the base is greater than or equal to about 1:1.05; even more preferably, the molar ratio of the compound of formula (IMa) to the base is in the range of from about 1:1.05 to about 1:1.20; even more preferably, the molar ratio of the compound of formula (Ma) and the base is g" about 1:1.05; cl 50 preferably when the reaction temperature is maintained below about 502C, more preferably from about 0gC to about 202C, most preferably about 02; m) forming a solution containing the corresponding compound of the formula (Ma) and the precipitate of the hydrochloride salt of the base.

In an embodiment of the present invention, the first organic solvent (used in step (Aa)) is selected from the group consisting of a cyclic ether such as pyran, tetrahydrofuran and the like; dialkyl ether 22 with a straight or branched chain, such as thim, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or is a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent. Preferably, the first organic solvent (used in step (Aa)) is selected from a cyclic ether or a straight or branched dialkyl ether such as THF, pyran, thim, MTBE and the like, even more preferably, the first organic solvent (used in stage (Aa)) is glim.

In an embodiment of the present invention, the first organic solvent (used in step (Aa)) is selected from the group consisting of a cyclic ether, a straight or branched chain dialkyl ether, and an aromatic hydrocarbon solvent; wherein the first organic solvent is not tetrahydrofuran or t-butyl methyl ether. b5 In the embodiment of this invention, stage (Aa) of the reaction is carried out so that the compound of the formula (Ma) and the base, dissolved in the first organic solvent, react with pure sulfuryl chloride; due to the fact that two reaction streams containing a compound of formula (Ma) and a base dissolved in the first organic solvent (the first reaction stream) are continuously fed into a continuous reactor, preferably BRAM, Her! sulfuryl chloride (second reaction stream) In another embodiment of this invention, sulfuryl chloride is dissolved in the same organic solvent used to dissolve the compound of formula (Ma) and the base (ie, the first organic solvent).

It is better when the solution containing the compound of formula (Ma) and the precipitate of the hydrochloride salt of the base is filtered using known methods to separate the precipitate.

Preferably, the solution containing the compound of formula (Ma) is concentrated by known batch or 7/0 continuous methods, for example by evaporation of the solvent (such as falling liquid film evaporation or film evaporation) or vacuum distillation, to give a concentrate of the compound of formula (Ma). In an embodiment of this invention, the solution containing the compound of formula (Ma) is concentrated to an amount less than or equal to approximately half of the original mass of the solution. In another embodiment of this invention, a solution containing a compound of formula (Ma) is concentrated to an oil.

When the compound of formula (Ma) is reacted with an amount of sulfuryl chloride greater than about 1 equivalent, the solution containing the compound of formula (Ma) is preferably concentrated using known batch or continuous methods to remove at least about 7095 wt.% of the solvent.

Then, when the compound of formula (Ma) is reacted with about 1 equivalent of sulfuryl chloride, the solution containing the compound of formula (Ma) is preferably concentrated using known batch or continuous methods to remove at least about 2095 wt% of the solvent.

In an embodiment of the present invention, the solution containing the compound of formula (Ma) is processed to remove volatile substances. Suitable treatments include, but are not limited to, vacuum distillation, concentration, distillation, passage through activated carbon or other absorbent, and the like.

The concentrate of the compound of the formula (Ma) is dissolved in a second organic solvent containing at least one part of the SUBSTANCE used in step (Aa), preferably containing at least one solvent selected from a cyclic ether such as pyran, tetrahydrofuran and the like; dialkyl ether with a straight or branched i) chain, such as thim, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent. It is better when the concentrate of the compound of formula (Ma) (3) is dissolved in the same organic solvent that was used in step (Aa) described above.

Preferably, the concentrate of the compound of the formula (Ma) is dissolved to a final mass ratio of the solvent o to the compound of the formula (Ma) that is in the range of from about 2:1 to about 10:1, even more preferably to the mass ratio «g of the solvent to the compound of the formula ( Ma) of approximately 6:1, yielding the reaction stream used in step (Ba), and which will be referred to hereafter as the third reaction stream, containing o

With the compound of the formula (Ma). co

At stage (Ba), the compound of formula (Ma) is introduced into a reaction with ammonia, preferably gaseous ammonia; in a second organic solvent containing at least the solvent used in step (Aa); wherein the second organic solvent contains at least one solvent selected from a cyclic ether such as pyran, tetrahydrofuran and the like; of a straight or branched chain dialkyl ether such as thim, "

MTBE and similar; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; with c or a mixture of a cyclic ether, a dialkyl ether with a straight or branched chain and an aromatic hydrocarbon solvent; preferably, when the second organic solvent contains at least one solvent, ;" selected from a cyclic ether or a straight or branched dialkyl ether such as THF, pyran, thim, MTBE and the like; even more preferably, the second organic solvent contains at least tim; even better, when the second organic solvent is the same as the first organic solvent; even better, when the second organic solvent is glyom; preferably, when the ammonia is present in an amount greater than about 1 molar equivalent of a compound of formula o (Ma); even better, when the molar ratio of ammonia to the compound of formula (Ma) is greater than or equal to approximately 2:1; they are even better when the molar ratio of ammonia and the compound of the formula (Ma) is approximately 5:1; preferably, when the reaction temperature is maintained in the range of about -309C to about 502C, still more preferably in the range of about 02C to about 302C, even more preferably about 202; with the formation of a solution of the compound of the formula (HER) and a precipitate.

Preferably, the ammonia gas is fed to the reactor at a controlled pressure or flow rate, more preferably at a pressure ranging from less than or equal to about Zbafkd (absolute pounds per square inch, rzia), even more preferably at a pressure ranging from about 15afkd to about 20afkd, even better, at a pressure of about 19afkd. o In an embodiment of the present invention, the second organic solvent (used in stage (Ba)) is selected from the group consisting of a cyclic ether such as pyran, tetrahydrofuran and the like; a straight or branched chain dialkyl ether such as thim, MTBE and the like; an aromatic hydrocarbon solvent such as toluene, benzene, xylene and the like; or is a mixture of a cyclic ether, a straight or branched dialkyl ether and an aromatic hydrocarbon solvent. Preferably, the second organic solvent (used in step (Ba)) is selected from a cyclic ether or straight or branched chain dialkyl ether such as THF, pyran, thim, MTBE and the like, even more preferably, the second organic solvent (used in at stage (Ba)) is a glioma. 65 In an embodiment of the present invention, the second organic solvent (used in step (Ba)) is selected from the group consisting of a cyclic ether, a dialkyl ether with a straight or branched chain and an aromatic hydrocarbon solvent; wherein the second organic solvent is not tetrahydrofuran or t-butyl methyl ether.

In another embodiment of this invention, the second organic solvent (used in stage (Ba)) contains

TWO FACTOR used in step (Aa) (i.e. first organic solvent).

It is better when the solution containing the compound of formula (III) and the precipitate is filtered using known methods to separate the precipitate.

In the embodiment of the invention, the process of obtaining the compound of formula (II) is carried out in two continuous reaction apparatuses with a stirrer (BRAMs). Preferably, step (Aa) is carried out so that the reaction time in the first 7/0 GATE is about 1 hour. It is better when the stage (Ba) is carried out so that the duration of the reaction is in the second

BRAMI is about 3 hours. It is better when the stage (Ba) is carried out so that the third reaction stream and ammonia are introduced into the BRAM from the surface.

One skilled in the art will appreciate that any of the processes of the present invention can be used to prepare racemic mixtures of a compound of formula (I) or any of the stereoisomers of a compound of formula (I) by 7/5 Selection and Substitution corresponding racemic mixtures or stereoisomers of reagents.

If the compounds of the present invention have at least one chiral center, they may accordingly exist as enantiomers. If compounds have two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and their mixtures are encompassed within the scope of this invention. In addition, some of the crystalline forms of the compounds may exist as polymorphic modifications and are intended to be included in the present invention as such. Additionally, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and it is believed that such solvates are also within the scope of the present invention.

If the processes for obtaining compounds according to the invention lead to the formation of a mixture of stereoisomers, these isomers can be separated using conventional techniques, such as preparative chromatography. Compounds can be obtained in racemic form, or individual enantiomers can be obtained either by enantiospecific synthesis or resolution. Compounds can be, for example, i) resolved into their constituent enantiomers by standard techniques such as the formation of diastereomeric pairs via salt formation with an optically active acid such as (-)-di-p-toluyl-O-tartaric acid and/or ()-di-p-toluyl-Y-tartaric acid, followed by fractional crystallization and regeneration of the free base. Compounds can also be separated by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary group. Alternatively, compounds o can be separated using a chiral HHT column. "Mr

During any of the processes of obtaining the compounds of this invention, it may be necessary and/or desirable to protect sensitive or reactive groups of any of the molecules involved in them. This can be achieved by Fr

With the help of ordinary protective groups, for example, (described in Rgoyesiime Sgotsrz ip Ogdapis Spetisvigu, ey. U.E MU. so

MsOptie, Riepyt Rgezv, 1973; and T.M. Sgeepe "5 R.S.M. MUtsiv, Rgoyesiime sgoyMirz ip Ogdapis Zupipeviv, dopp UMieu Kk

Zopz, 1991). Protecting groups can be removed at an appropriate subsequent stage using techniques known in the art.

The following examples describe the invention in more detail and are intended to illustrate the invention, but not to limit it. in c Example 1

Production of diacetone-p-HO-fructose chlorosulfate (HO);" Continuous process

DAF stock solution was prepared by weighing diacetone-D-fructose (DAF) (911.0g) into a one-gallon glass bottle. Glyme (2113.5g, 245O0ml) and pyridine (290.7g, 297ml) were added to the solid substance, (oo) the solution was stirred until DAF was completely dissolved. If necessary, additional mother liquor was prepared.

An Erlenmeyer flask with a volume of 1 liter was filled with DAF mother solution (936.8 g, 987.2 ml) and placed on a top-loading scale. A piston pump was connected to supply the solution to the reactor. Sulfuryl chloride (СХ) (172.2 g, 103.vml) was weighed into a separate flat-bottomed boiling flask and the flask was immediately stoppered. Then the flask with CH was placed on the top-loading scales and a second piston pump was connected to feed CH into the reactor. c The reactor was a continuous glass reactor with a stirrer and four necks and a lateral overflow opening at a level of approximately 1 liter. A nitrogen cushion with a pressure bubbler was connected to the reactor. It was determined that the substance that remained in the reactor from the previous synthesis consisted of 0.395 DAF, 99.790 5 ХС and 0.089 of another unidentified substance.

The reciprocating pump for the SC was started at a reactor feed intensity of 2.2 g per minute. When the SC reached the reactor, the piston pump for the DAF mother liquor was started at a reactor feed rate of 15.2 g per minute.

The reactor cooling system was set at -1592C to try to keep the reaction temperature around 02C during the course of the reaction; a temperature ranging from 4.02 to 5.020 was reached. The contents of the reactor were stirred at a speed of 4000 rpm.

The reactor was operated continuously for seven (7) hours, when necessary, the reservoirs from which the CH and DAF mother liquor were supplied were replenished. Scale readings were used to monitor the feed rate and pumps were adjusted to maintain the required reactor feed rate. 65 The reaction time in the reactor was calculated to be approximately one (1) hour.

The receiving flask was replaced every hour, the product stream was filtered, and then evaporated to oil on a rotary evaporator, maintaining the water bath temperature at about 402C. Each aliquot part of the concentrated oil was transferred to a glass bottle and placed in a freezer at -202С for storage.

Samples were also taken from the product flow from the reactor every hour and analyzed by GC, the results are presented below in Table 1: o dove ov. from here 04 iv

Example 2

Topiramate continuous process (TPM)

The nutrient solution of CS was prepared from the oil obtained according to Example 1, by dissolving it in lyme to a final concentration of 1 g of lye per 5.8 g of lyme, using the following method. The CS oil (376.1g) was removed from the freezer (where it was stored between reactions to avoid decomposition) and allowed to warm to room temperature. CH was washed into a 4-liter Erlenmeyer flask with portions of glyme. The desired amount of glim was added, the total amount of glim added was 2181.33g. The solution was mixed well and filtered through a 934-AN glass fiber filter pad using low vacuum to give a mother liquor (25232 g). A 2-liter stainless steel reactor with an overflow hole at the level of approximately 1.5 liters was isolated from a 20-liter stainless steel product receiver. The product receiver was pumped down to a vacuum of 3 mm Hg using a water jet pump.

The reactor cooling system was set at 16.52C and then gradually adjusted to a final (su) value of 132 to maintain the temperature inside the reactor between 17.990 and 19.99 during the course of the reaction. The reactor contents were stirred at a rate of 7 rpm.

The entire reactor system was pressurized to approximately 2 kfqd (calibrated pounds per square inch, rzid) with (17 afqd) anhydrous ammonia. During the reaction, ammonia was continuously added, adjusting the pressure, maintaining the pressure level in the system between 2kfcd (17afkd) and Zkfcd (18afkd). The measured values of ammonia pressure were within about

L,zkfkd (16.2afkd) to 2.5kfkd (17.2afkd). co

The CH nutrient solution was weighed before and after use. The reservoir containing the nutrient solution of CH was placed on a balance with top loading and nitrogen was passed over the surface of the liquid. The CH feed solution was continuously fed into the reactor by a piston pump at a rate of approximately 7.1 g per minute. In the measure of the need for an additional amount of the nutrient solution of CS, it was prepared as described above and the tank was replenished 70 times. The reactor was operated continuously for sixteen (16) hours, and the overflow was collected in a receiving container for the product. The composition of the overflow was monitored with the help of RCVT, which included the amount of product (topiramate), the amount of DAF, the amount of CH and the amount of "Other" by-products, obtaining the results presented in

Table 2 below. co

Fgsi o yad ve be 33 03 bod 904 72 24 00 todovoye be 22 o o t zoedoomvoly 02 bo Chogodoett be 1403 zvede vvly 05 bodovoye vo 11 | oz b5

After 16 hours, the reactor was stopped and the receiving container for the product was left under ammonia pressure for approx

2kfkd (17afkd) for about 8 hours. After that, the receiving container for the product was opened, allowing most of the ammonia to escape.

The thick suspension of the product was filtered on a Buchner funnel. The solid was resuspended in a Buchner funnel and thoroughly washed with two approximately equal portions of fresh lye (total weight 172.2 g). The filtered contents of the receiving container for the product and the washing liquid weighed 6321.8g, while the wet weight of the washed solid matter weighed 194.6g.

The filtered solution was evaporated to an oil on a rotary evaporator, maintaining a water bath temperature of approximately 402C, to give crude topiramate. 70 GC analysis of the solution in the product receiver after sixteen (16) hours of reaction showed a mixture of 1.196 by area

DAF, 8.095 per area of CS, 90.695 TPM per area and 0.395 per area of unknown products.

GC analysis of the product receiver solution after sixteen (16) hours of reaction and approximately 8 hours of standing time showed a mixture of 0.996 area DAF, no CH, 98.5906 TIM area and 0.606 area unknown products.

GC analysis of the product acceptor content after filtration showed a mixture of 1.7 96 area DAF, no CH, 97.995 area TPM and 0.595 area unknown products.

Example C

Production of diacetone-p-HO-fructose chlorosulfate (HO)

Continuous process

A continuous glass reactor with a stirrer and four necks and a lateral overflow hole at the level of approximately 1 liter and a nitrogen cushion with a pressure bubbler were used. The reactor was cooled using an indirect glycol cooling system. Before starting the experiment, the substance in the reactor was analyzed by GC. The initial composition of the reactor contents for the completed runs is summarized in

Tables 3. Details of the program "(25 а|51| 617. phsoz9ozav|rye oto 595 94 596. o z zidde 1004 5421 0305 04 ethnicities, o | ooo oo | o | in "

A 1-liter Erlenmeyer flask was filled with DAF mother solution (prepared as described in

Examples 1) and placed on top-loading scales. To supply the solution to the reactor, a piston pump was connected

With the pump. Sulfuryl chloride (СХ) was weighed into a separate flat-bottomed boiling flask. The flask with sulfuryl chloride was stoppered and placed on a balance with top loading. The second piston pump was connected to supply CH to the reactor.

Stirring was started at approximately 40 rpm, the piston pump for SC was started at the desired intensity. When the CH reached the reactor, the piston pump for the DAF mother liquor was started at the desired intensity. The reactor operated continuously for a specified number of hours; when it was necessary, for 2 s the reservoirs from which CH and DAF mother solution were supplied were replenished. The reactor product continuously flowed into the product receiver, which was emptied as needed. Scale readings were used to monitor feed rates and pumps were adjusted to maintain reactor feed rates.

The operating mode, including the calculated duration of the reaction in the reactor, is summarized in Table 4 below. co

Ф prote 1111 012151 5|5|851 » Molar ratio ZO about TOB oo ot about 100 055 i.

F o

Tetereva rea 00007022 50 zo o Samples from the reactor were taken every hour and their content was analyzed by GC. The number of hours of operation in each of the modes and the resulting reactor content near the end of continuous operation are summarized in Table 5 below. 60

It will rot /2|z av v g vv 9DAF 0.7 5985 05105112 41 eznshiye of o o o o o o o)

Example 4

Topiramate Continuous Process (TPM) 9 The continuous reactor was a 2-liter high-pressure stainless steel reactor with an overflow hole at approximately 1.5 liters. The product receiver was a 20 liter high pressure stainless steel tank. The reactor was cooled using an indirect glycol cooling system to maintain the temperature during the reaction near the desired value. Before the start of the experiment, the substance in the reactor, which remained from the previous experiment, was analyzed using GC to determine the composition. The composition of the initial contents of the reactor is summarized in Table 6 below. "setpmo |ttv|vvo eto 830966 922 950. ho |o0o o o0/o0/o0/o o)

Propnme| 17 18/19/2021 22 September

At the beginning of the experiment, the product receiver was pumped out and the entire reactor system was pressurized, reaching the desired pressure value, with anhydrous gaseous ammonia. With the exception of Run Mo10, ammonia was added from the 25th surface. The tank containing the HC solution was placed on top-loading scales and covered (inert) (U) with nitrogen. For continuous supply of the HC solution to the reactor, a piston pump was connected. With the exception of Progony Mo10

Its Mo11 CS solution was added to the reactor from the surface.

The piston pump for the CH solution was started at the desired power intensity of the reactor. Ammonia was fed continuously, adjusting the pressure, to maintain the desired pressure. The reactor product was continuously poured into the product receiver. As the additional amount of nutrient solution of CS was needed, it was prepared as described in Yuyu

Example 2. The mode of operation, including the calculated duration of the reaction in the reactor, is summarized in Table 7 below. With "c) with so "- 7 s h" Temperature rea 02079699 pn 00000000 v yuyu so Mass ratio limolakhs 00005829 29 58558 zedaouromyihs! 00000000 ao loto ve o "ntensity of supply of the solution of CS to the reactor(s) 727177 4242431 g Pressure of MneureacoriFI 00000000500180 4 l7lv in ya. vidko mishalovhe) 00000705 6977327 ii Temperetuereeesss 000000199 00000199 00000000500180 0206

Samples from the reactor were taken every hour and their content was analyzed by GC. The number of hours of operation in each mode and the resulting reactor content near the end of continuous operation are summarized in Table 8 below. i'm in

Number of robots 5 751919 58

From topramet 0729830 775(022 770 va 505 es om oledayu v tato v zdle 00000 oBalvoleg v v le 40 vv Pronzh 00007 voleyu yiv

Number of working hours. Example 5 - Effect of solvent removal

Stage A: Preparation of diacetonefructose chlorosulfate using a stoichiometric amount of CHoSi»

A mechanical stirrer, a thermometer, and a dropping funnel connected to a low-pressure nitrogen source to create an inert atmosphere were inserted into a 5000-mL three-necked round-bottomed flask. DAF (825 g, 3.17 mol), glyme (1915 g) 70 and pyridine (263.5 g, 3.3 mol) were added to the flask and stirred at 2523 until complete dissolution. The flask was cooled with a mixture of salt and ice to an internal temperature of approximately 02C. Sulfuryl chloride (427.9g, C3.17mol) was added over 4 hours, maintaining the reaction temperature at about 02. The mixture was stirred at 09C for another few minutes, after which the bath was removed and the mixture was warmed to room temperature. Samples of the contents were taken and analyzed by GC. 15 Analysis results: 1.19956 DAF, 98.7896 HO

The mixture was filtered under vacuum to separate solid pyridine hydrochloride. The XO solution (2835Hg) was transferred to a bottle, tightly stoppered and stored at -202С until use in Stage B.

Stage B: Obtaining a solution of CS for conversion into topiramate

The solution obtained in Stage A as described above (130 g) was evaporated in vacuo in a 250 mL round bottom flask on a rotary evaporator at a water bath temperature of 402 C until 2095 g of solvent was removed.

After concentration, the contents of the flask were diluted to the original 130 g with fresh lye, mixed, filtered under vacuum and stored under nitrogen until use in Stage C.

Stage C: Conversion of CH solution into topiramate

A clean, dry 300 mL Parr stirrer reactor (31655) was purged with nitrogen, then pumped and isolated. Ge

Fresh glim (87 g) was transferred to a vessel, which was pumped again for a short time. The stirrer was turned on and the system was pressurized with ammonia to about 2 kfcd. To maintain the temperature of the contents during the reaction at approximately 15-202С7, a water bath was used, in which ice was added as necessary. The supply of CS obtained in Stage B was carried out by means of a pump for about 1.25 hours, after which it was stirred for another 2 hours at a temperature of about 15-209C and an ammonia pressure of 2 kfcd. (av)

The contents of the reactor were filtered under vacuum to separate MBOSI, and the clear filtrate was analyzed by GC.

Analysis results: 9.590 DAF, 90.0956 TIPM "I

Example 6 - The effect of solvent removal o

Stage A: Production of diacetonefructose chlorosulfate using 595 excess amounts of HOoSi"

A mechanical stirrer, a thermometer, and a dropping funnel connected to a low-pressure nitrogen source to create an inert atmosphere were inserted into a 50O00-ml three-neck round-bottomed flask. DAF (825 g, 3.17 mol), glyme (1915 g) and pyridine (263.5 g, 3.3 mol) were added to the flask and stirred at 2523 until complete dissolution. The flask was cooled with a mixture of salt and ice to an internal temperature of approximately 02C. Sulfuryl chloride (449.5g, C3.3mol) was added over 4 hours, maintaining the reaction temperature at about 02. The mixture was stirred at 09C for another 15 minutes, after which the bath was removed and the mixture was warmed to room temperature. Samples of the contents were taken and analyzed by GC.

From" Analysis results: 0.2390 DAF, 99.7296 HO

The mixture was filtered under vacuum to separate solid pyridine hydrochloride. The XO solution (2859G) was transferred to a bottle, tightly stoppered and stored at -202С until use in Stage B. 15 Stage B: Preparation of XO solution for conversion to topiramate so Part of the solution obtained in Stage A as described above (130g) was evaporated in a vacuum in a 250-ml round-bottom flask (in a flask on a rotary evaporator at a temperature of a water bath of 402C until 7095 of the solvent was removed. 1) After concentration, the contents of the flask were diluted to the initial 130 g with fresh lye, mixed, filtered under vacuum and stored in a nitrogen atmosphere for use in Stage C 1 20 Stage C: Conversion of CH Solution to Topiramate o A clean, dry, 300-ml stirred Parr reactor (31655) was purged with nitrogen, then pumped and isolated.

Fresh glim (87 g) was transferred to a vessel, which was pumped again for a short time. The stirrer was turned on and the system was pressurized with ammonia to about 2 kfcd. To maintain the temperature of the contents during the reaction at approximately 15-202С7, a water bath was used, in which ice was added as necessary. The supply of CH, 59 obtained in Stage B, was carried out by means of a pump for about 1.25 hours, after which (F) was stirred for another 2 hours at a temperature of about 15-202C and an ammonia pressure of 2 kfcd.

GI The contents of the reactor were filtered under vacuum to separate the MN.SI, and the clear filtrate was analyzed by GC. in Analysis results: 8,196 DAF, 90,095 TPM

Bearing in mind that the foregoing specification sets forth the principles of the present invention and that the examples are given for purposes of illustration, it is to be understood that the practice of the invention includes all customary variations, adaptations and/or modifications within the scope of the following claims and their equivalents. for

Claims (1)

The formula of the invention 1. The continuous process of obtaining the compound of the formula (I) H ritve ee o and t e F where X is selected from CH" or 0; B" is selected from the group consisting of hydrogen and C. dalalkyls; 23, b", b and B are each independently selected from hydrogen and lower alkyls and, when X is CH", KE? and 25 can be 75 alkene groups connected to form a benzene ring and, when X is 0, B is 3 and 7 and/or B and 29 together can be a methylenedioxy group of the formula Ba and 05 where B" and 8 are the same or different and are hydrogen, lower alkyl or is alkyl and connected to form a cyclopentyl or cyclohexyl ring; ) the reaction of an appropriately substituted compound of the formula (IM) with sulfuryl chloride; t in the presence of an organic or inorganic base; av! in a first organic solvent containing at least one solvent selected from a cyclic ether, a straight- or branched-chain C-1 dialkyl ether, an aromatic hydrocarbon, or a mixture of a cyclic ether, a dialkyl ether with a straight or branched chain and an aromatic hydrocarbon solvent; with the formation of the corresponding compound of the formula (M); the reaction of a compound of formula (M) with a correspondingly substituted compound of formula (MI); in a second organic solvent containing at least the solvent used in step (A); with the formation of the corresponding compound of formula (1). t" 2. The process according to claim 1, where the organic or inorganic base is an organic base. page 50 Q. The process according to claim 2, where the organic base is pyridine. 4. The process of claim 1, wherein the first organic solvent contains at least one solvent selected from a cyclic 62 ether, a straight or branched chain dialkyl ether, an aromatic hydrocarbon solvent, and a mixture of a cyclic ether, a straight or branched chain dialkyl ether, and an aromatic hydrocarbon solvent. 5. The process according to claim 4, where the first organic solvent contains a cyclic ether or dialkyl ether with a straight or branched chain. 6. The process according to claim 5, wherein the first organic solvent is alum. eat) 7. The process of claim 1, wherein the sulfuryl chloride is present in an amount greater than about 0.9 moles per mole of the compound of formula (IM). 60 8. The process of claim 1, wherein the base is present in an amount greater than about 1 molar equivalent of the compound of formula (IM). 9. The process of claim 8, wherein the molar ratio of the compound of formula (IM) to the base is at least about 1:1.05. 10. The process of claim 1, wherein the reaction temperature in step (A) is lower than about 5090. 65 11. The process of claim 1, wherein the second organic solvent is alum. 12. The process of claim 1, wherein the compound of formula (MI) is present in an amount greater than about 1 molar equivalent of the compound of formula (M). 13. The process of claim 12, wherein the molar ratio of the compound of formula (MI) to the compound of formula (M) is at least about 2:1. 14. The process of claim 1, wherein the compound of formula (MI) is ammonia and the ammonia is fed to the reactor at a pressure of about 19 afkd. 15. The process of claim 1, wherein the reaction temperature in step (B) is in the range of about -30 to about 5020. 16. The process according to claim 1, where the compound of formula (M) is formed in a solution containing the compound of formula (M) and the first organic solvent. 70 17. The process of claim 16, wherein sulfuryl chloride is reacted in an amount equal to about 1 equivalent relative to the compound of formula (IM), followed by concentration of the solution containing the compound of formula (M) and the first organic solvent to remove at least about 2095 wt.% of the solvent . 18. The process of claim 16, wherein sulfuryl chloride is reacted in an amount greater than about 1 equivalent relative to the compound of formula (IM), followed by concentration of the solution containing the compound of formula (M) and the first 7/5 organic solvent to remove at least 7095 wt. solvent 19. The process according to claim 16, further comprising concentrating the solution containing the compound of formula (M) and the first organic solvent to an oil. 20. The process of claim 16, further comprising treating the solution containing the compound of formula (M) and the first organic solvent to remove volatiles. 21. The process according to claim 1, where both stages (stage (A) and stage (B)) are carried out in a continuous reaction apparatus with a stirrer. 22. A compound obtained by the process of claim 1. 23. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound according to claim 22. 24. The process of obtaining a pharmaceutical composition, which includes mixing a pharmaceutically acceptable CARRIER and a compound according to claim 22. 25. The continuous process of obtaining the compound of the formula (ІІІ) о ше -0770 о -Ко А т ч о which includes 80, со -- ОН - р н- : - 47 (ma (uv) h (Aa) reaction of the compound of the formula (Ma ) with sulfuryl chloride; -" in the presence of an organic or inorganic base; in a first organic solvent containing at least one solvent selected from a cyclic ether, a straight or branched dialkyl ether, an aromatic hydrocarbon, or a mixture of a cyclic (ee) ether, a dialkyl ether with a straight or branched chain and an aromatic hydrocarbon solvent; o with the formation of the corresponding compound of the formula (Ma); ren vo.-MH, ' t. -8B-5O 8B-y 1 50 me - MH and seaz "F (Ba) reaction of the compound of the formula (Ma) with ammonia; in a second organic solvent containing at least the solvent used in step (A); IF) with the formation of the corresponding compound of the formula (PI). 26. The process of claim 25, wherein the organic or inorganic base is an organic base. 27. The process of claim 26, wherein the organic base is pyridine. 60 28. The process of claim 25, wherein the first organic solvent comprises at least one solvent selected from a cyclic ether, a straight or branched chain dialkyl ether, an aromatic hydrocarbon solvent, and a mixture of a cyclic ether, a straight or branched chain dialkyl ether, and an aromatic hydrocarbon solvent. 29. The process according to claim 28, wherein the first organic solvent contains a cyclic ether or a dialkyl ether with a straight or branched chain. 30. The process of claim 29, wherein the first organic solvent is alum. 31. The process of claim 25, wherein the sulfuryl chloride is present in an amount greater than about 0.9 moles per mole of the compound of formula (Ma). 32. The process of claim 25, wherein the base is present in an amount greater than about 1 molar equivalent of the compound of formula (IMa). 33. The process of claim 32, wherein the molar ratio of the compound of formula (Ma) to the base is at least about 1:1.05. 34. The process of claim 25, wherein the reaction temperature in step (Aa) is less than about 5020. 35. The process of claim 25, wherein the second organic solvent is alum. 70 36. The process of claim 25, wherein the ammonia is present in an amount greater than about 1 molar equivalent of the compound of formula (Ma). 37. The process of claim 36, wherein the molar ratio of ammonia to the compound of formula (Ma) is at least about 2:11. 38. The process of claim 25, wherein ammonia is fed to the reactor at a pressure of about 19 afkd. 39. The process of claim 25, wherein the step reaction temperature (Ba) is in the range of about -30 to about 5020. 40. The process according to claim 25, where the compound of formula (Ma) is formed in a solution containing the compound of formula (Ma) and the first organic solvent. 41. The process of claim 40, wherein sulfuryl chloride is reacted in an amount equal to about 1 equivalent relative to the compound of formula (Ma), followed by concentration of the solution containing the compound of formula (Ma) and the first organic solvent to remove at least about 2095 wt% of the solvent. 42. The process of claim 40, wherein the sulfuryl chloride is reacted in an amount greater than about 1 equivalent relative to the compound of formula (Ma), followed by concentration of the solution containing the compound of formula (Ma) and the first organic solvent to remove at least 70905 wt% of the solvent. 43. The process according to claim 40, further comprising concentrating the solution containing the compound of formula (Ma) and the first Ha organic solvent to an oil. at 44. The process of claim 40, further comprising treating the solution containing the compound of formula (Ma) and the first organic solvent to remove volatiles. 45. The process according to claim 25, where the stage (VB) is carried out in a continuous reaction apparatus with a stirrer. 46. The process according to claim 25, where both stages (stage (Aa) and stage (Ba)) are carried out in a continuous reaction apparatus with a stirrer. 47. A compound obtained by the process of claim 25 48. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound according to claim 47. "And 49. The process of obtaining a pharmaceutical composition, which includes mixing a pharmaceutically acceptable carrier and a compound according to claim 47. o d) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 15, 25.09.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. " - with ;" (ee) («c) sh» p 50 (42) F) ime) 60 b5