Stereoselective method of obtaining compounds, methods of increasing the yield of trans-isomers, salicylates compounds

 

(57) Abstract:

The invention relates to a diastereoselective process for obtaining optically active analogues CIS-nucleosides and their derivatives. Describes the stereoselective method of obtaining compounds of General formula I, where W represents O; X represents S; R1represents hydrogen or acyl, R2is a pyrimidine base or analogue, including stage of the interaction between pre-similarvideo pyrimidine base or analogue with an intermediate reagent of General formula IVa or IVb, where R3is a substituted carbonyl or carbonyl derivative, a G is tsepliaeva group. Interactions with the pyrimidine base or analogue carried out without the addition of the Lewis acid as catalyst, and tsepliaeva group G is halogeno, cyano, or R9SO2group, where R9represents alkyl, possibly substituted by one or more than one group halogeno, or possibly substituted phenyl, followed, if necessary, additional recovery R3to group R1CH2. Describes ways of improving output < / BR>

The invention relates to a diastereoselective process for obtaining optically active analogues CIS-nucleosides and their derivatives

Nucleosides and their analogues and derivatives belong to an important class of therapeutic agents. For example, many nucleoside analogues showed antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis b virus (UGB) and human T-lymphotropic virus (CTLV) (PCT publication WO 89/04662 and Europatent 0349242 A2).

In particular 4-Amino-1-(2R - hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H-pyrimidine-2-it is according to the formula:

< / BR>
(also known as 3TCTMor lamivudine) and its pharmaceutically acceptable derivatives proposed in International application PCT/GB91/00706, publication W91/17159, was described as having antiviral activity, in particular against retroviruses such as HIV causes AIDS (W91/17159) and VGB (Europatent, publication 0474119).

Most of nucleosides, their analogues and derivatives contain at least two chiral centres (shown as*in the formula (A)) and exist in the form of two pairs of optical isomers (i.e., two in the CIS-configuration and two in the TRANS configuration). Usually, however, only the CIS-and the CIS-nucleosides is an important task.

< / BR>
However, different antiviral activity may have different enantiomeric forms of any analogue of CIS-nucleoside M. M. Mansuri et al. "Preparation of The Geometric Isomers of DDC, DDA, D4C and D4T as Potential Anti-HIV Agents", Bioorg. Med. Chem. Lett., 1(1), pp. 65-68 (1991).

Therefore a common and economically acceptable synthesis of the enantiomers of biologically active analogs of CIS-nucleoside is an important task.

In a publication of the International application W92/20669 described diastereoselective method for obtaining optically active analogues and derivatives of CIS-nucleoside of the formula (I)

< / BR>
where W is S, S=O, SO2or;

X-S, S=O, SO2or;

R1is hydrogen or acyl and

R2the desired purine or pyrimidine base or analogue or derivative.

The method involves the reaction of a purine or pyrimidine base or analogue with an intermediate product of the formula (IIa) or (IIb).

< / BR>
< / BR>
where R3- substituted carbonyl or carbonyl derivative, and

L - tsepliaeva group;

using a Lewis acid of formula (III).

< / BR>
R5, R6and R7independently from each other selected from the group consisting of: hydrogen, C1-20of alkyl, substituted for choosing a fluorescent is the selection by halogen, C1-20-alkyl or C1-20-alkoxyl; C6-20aryl, substituted choice fluorine, bromine, chlorine, iodine, C1-20the alkyl or C1-20-alkoxyl; trialkylsilyl; fluorine; bromine; chlorine and iodine;

R8selected from the group consisting of fluorine; bromine; chlorine; iodine; C1-20- sulfonates, substituted by choice fluorine, bromine, chlorine or iodine; C1-20-alkylamino substituted by choice fluorine, bromine, chlorine or iodine-polyvalent halides; trisemester silyl groups of the General formula (R5)(R6)(R7)Si, where R5, R6and R7defined above; saturated or unsaturated C6-20-selenourea; substituted or unsubstituted C6-20- arylsulfonyl; substituted or unsubstituted C6-20-alkoxyalkyl and trialkylsilyl.

The method according to WO92/20669 allows managed stereocenters racemic analogue of CIS-nucleoside of the equimolar mixture of the reactants (IIa) and (IIb) and from this the desired enantiomer of similar CIS-nucleoside with high optical purity, if the source material is optically pure (IIa) or (IIb). However, the method according to WO92/20669 involves the use of a Lewis acid of formula (III).

The use of such acid has a number of authorized capacity. In addition, they are expensive and quite toxic. These shortcomings are particularly evident in industrial production of nucleoside analogues.

We found that by judicious choice of tsepliaeva group L in the intermediate compounds (IIa) and (IIb) reaction with purine or pyrimidine base or analogue can be successfully carried out without the addition of a Lewis acid as a catalyst and, in particular, without the addition of the Lewis acid of formula (III).

Accordingly, according to the invention, a method of stereoselective synthesis of analogues and derivatives of CIS-nucleoside of the formula (I).

< / BR>
where W is S, S=O, SO2or;

X-S, S=O, SO2or;

R1is hydrogen or acyl and

R2the desired purine or pyrimidine base or analogue or derivative,

based on the glycosylation of the purine or pyrimidine base or analogue or derivative intermediate reagent of the formula (IVa) or (IVb).

< / BR>
< / BR>
where R3- substituted carbonyl or carbonyl derivative,

G - halogeno, cyano, or R9SO2group, in which R9- alkyl, substituted by one or more halogen or arbitrarily substituted phenyl (

In the preferred embodiment of the invention includes a stereoselective method of obtaining analogs and derivatives of CIS - nucleoside of the formula (I) described above containing phase glycosylation purine or pyrimidine base or analogue or derivative intermediate reagent of formula (IVa) or (IVb), as defined above, characterized in that the glycosylation reaction is conducted without the addition of the Lewis acid of formula (III):

< / BR>
where R5R6and R7independently from each other selected from the group consisting of: hydrogen, C1-20-alkyl, substituted by choice fluorine, bromine, chlorine, iodine, C1-16-alkoxyl or C6-20-alloxylon; C7-20aralkyl substituted for choosing halogen, C1-20-alkyl or C1-20-alkoxyl; C6-20aryl, substituted choice fluorine, bromine, chlorine, iodine, C1-20-alkyl or C1-20-alkoxyl; trialkylsilyl; fluorine; bromine; chlorine and iodine;

R8selected from the group consisting of fluorine; bromine; chlorine; iodine; C1-20-sulfonates, substituted by choice fluorine, bromine, chlorine or iodine; C1-20-alkylamino substituted by choice fluorine, bromine, chlorine or iodine-polyvalent halides; trisemester silyl groups shared Assenova C6-20-selenourea; substituted or zameshannogo C6-20- arylsulfonyl; substituted or unsubstituted C6-20-alkoxyalkyl and trialkylsilyl.

Professionals it is clear that when the glycosylation using equimolar mixture of intermediate agents (IVa) or (IVb will be obtained racemic mixture of analogues CIS-nucleosides. However, it is preferable to glycosylate using optically pure reagent of the formula (IVa) or (lVb) to give the desired analogue of CIS-nucleoside high optical purity.

The term nucleoside refers to any compound consisting of associated with pentose purine or pyrimidine base.

The term analogue or derivative of the nucleoside denotes a compound containing 1,3-oxathiolan: 1; 3-dioxolane or 1,3-ditiolan associated with purine or pyrimidine base or an analogue, which can be modified by any of the following methods or combination thereof: a modification of a base, for example, introduction of a substituent (in particular, 5-fertilizin) or substitution of any group isothermic group (for example, 7-deazaadenosine); a modification of a sugar, such as substitution of hydroxyl groups by any Deputy or izmenenii N-1, can be attached at position N-3 or C-6, and purines, usually attached to N-9 may be, for example, is attached to N-7).

"Purine or pyrimidine base" means a purine or pyrimidine base found in naturally occurring nucleosides. Its counterpart is a base, such such natural nucleosides according to the structure (types of atoms and their arrangement), but either having additional functional properties, or not possessing some of the properties of naturally occurring nucleosides. Such analogues belong obtained by substitution of the CH group by a nitrogen atom (for example, 5-isoperimetry, such as 5-azacytosine), or Vice versa (for example, 7-deazapurine, such as 7-deazaadenosine, or 7-deazaguanine, or both (for example, 7-deaza-8-azaperone). Derivatives of these bases or analogues understand the Foundation, whose cycle is characterized either attached to, or derived substituents, or modified by well-known substituents, such as halogen, hydroxyl, amine, C1-6-alkyl. Such purine or pyrimidine base, analogs and derivatives are well known to specialists in this field.

The term halogen here e, branched or cyclic saturated hydrocarbon radicals or combinations thereof. The term arbitrarily substituted phenyl means unsubstituted phenyl or phenyl substituted by one or more C1-6-alkyl-, nitro-, amino-, halogen - or cyano-groups.

R2- preferably pyrimidine base. More preferably, when R2- cytosine or 5-fertilizin.

R3the carbonyl associated with hydrogen, hydroxyl, trialkylsilyl, trialkylsilyl, C1-30-alkyl, C7-30-aralkyl, C1-30-alkoxyl, secondary or tertiary C1-30-alkylamino, C1-30-thioalkyl, C6-20-aryl, C2-20-alkenyl, C2-20-quinil; or

R3- 1,2-dicarbonyl, such as

< / BR>
arbitrarily substituted C1-16-alkyl or C6-20-aryl; or

R3- anhydride, such as

< / BR>
arbitrarily substituted C1-6-alkyl or C6-20-aryl; or

R3- somethin in which the nitrogen is associated with hydrogen, C1-10-alkoxyl or C1-20-dialkylamino and carbon - hydrogen, C1-20-alkyl or C1-20-alkoxyl; or

R3- thiocarbonyl (C= S), substituted by hydroxyl, C1-20-alkoxyl or C1-20-thiol.

4was chiral addition.

The term chiral addition means asymmetric molecule used for chemical separation of racemic mixtures. Such chiral additions can have one chiral center, such as --methylbenzylamine, or more chiral centers, such as menthol. After chiral addition built in the source material, its function is simple separation of the mixture of diastereoisomers (see, for example, J. Jacques et al., Enantiomers, Racemates and Resolution, pp. 251-369, John Wiley & Sons, New York (1981)).

Chiral addition R4preferably selected from (d)-mantila, (I)-mantila, (d)-8-phenylmenthyl, (I)-8-phenylmenthyl, (+)-norephedrine and (-)-norephedrine. More preferred (I)-Menthyl or (d) of mantel and the most preferred (I)-Menthyl.

Preferably, when W is Oh, and X is S.

Preferably, when G is a halogen, such as Cl, Br or I, more preferably Cl.

Intermediate reagents of the formulae (IVa) and (IVb) can be isolated or, if it is convenient, obtained in situ.

Intermediate reagents of the formulae (IVa) and (IVb) conveniently be obtained from the respective TRANS-alcohols of the formulae (Va) and (Vb):

< / BR>
< / BR>
where R3, W, and X determine the m for the introduction of a group G.

Suitable reagents for the introduction of a group G is well known to specialists in this field and include, for example such halogenation agents, as oxalipatin. The preferred halogenation are the reagents of Vilsmeier, which is convenient to obtain the in situ reaction of such N,N - disubstituted amide as dimethylformamide (DMF), so halogenation as oxaliplatin (for example, oxalicacid), thionylchloride (e.g., thionyl chloride), postorganic (for example, trichloride or phosphorus oxychloride), alkyl - or phenylsulfonylacetate, or anhydride. The halogenation reaction can be performed under normal conditions.

Intermediate reagents of the formulae (IVa) and (IVb) may be convenient to enter into reaction with similarbank purine or pyrimidine base in such a suitable organic solvent, as a hydrocarbon (e.g. toluene) or a halogenated hydrocarbon like dichloromethane, or a nitrile as acetonitrile, or an amide such as dimethylformamide, or such esters as ethyl acetate, or a simple ester, as tetrahydrofuran, or a ketone such as acetone, or a mixture, preferably at an elevated temperature such as the temperature of the selected solvent at the reflux.

Suitable methods are described in detail in the accompanying examples.

Analogues of CIS-nucleosides obtained by reaction of compounds of formula (I) with a purine or pyrimidine base or analogue, can then be restored to obtain a particular stereoisomer of formula (I). Suitable reducing agents are well known to specialists in this field and include, for example, hydride reducing agents, as socialogical, literalized or detribalized. We found that stereospecificity support use as a reductant of detribalized in the presence of a phosphate or borate buffer, such as dinitrigenoxide.

In accordance with the method according to the invention and the method according to WO92/20669 target product is usually obtained in the form of a solution in such polar solvents as water solvent.

In practice, this is due to the high rustboro the compounds of formula (I) can be successfully isolated from the solution in the polar solvent, the formation of poorly soluble salts. If desired, water-insoluble salt can then be converted by conventional methods into the free base or another salt. Further, we found that the most suitable salt is a salicylate.

Thus, according to the invention proposed techniques described above, additionally providing for the allocation of the compounds of formula (I) in the form of water-insoluble salts, in particular musk.

Salicylates compounds of formula (I) are among the pharmaceutically acceptable derivatives, described and claimed in Eurosafe 00382526 and publication WO91/17159, but not disclosed here sufficiently. Therefore, these salts are novel and constitute a further object of the invention.

In addition, according to the invention proposed salicylates compounds of formula (I) or their hydrates.

In particular, we found that the formation of salicylate 4-amino-1-(2R-hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H - pyrimidine-2-it (lamivudine, 3TCTM) brings significant benefits in the selection of this compound from polar solvents.

In the preferred embodiment, therefore, the invention provides a salicylate 4-amino-1-(2R-hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H-p is th salt, and as such she and her hydrates can be used as an antiviral drug, as described in the application WO91/17159 and incorporated here by reference.

Salicylate lamivudine or its hydrates can be used to obtain pharmaceutical compositions described in WO91/17159.

Salicylates compounds of formula (I) can be prepared by treatment salicylic acid solution containing the compound of formula (I). Suitable solvents can be, for example, water and such polar organic solvents, such as ethers, for example tetrahydrofuran or dioxane, and alcohols, such as methanol and ethanol, or a mixture of solvents, in particular mixtures of organic solvents with water.

If desired, the salicylates conveniently be converted into the corresponding free base by treatment with a base; for this purpose a suitable tertiary amine such as triethylamine.

Specialists in this field can easily find other water-insoluble salts, methods for their preparation and conversion into the free base.

The intermediate alcohol (Va) and (Vb) and epimeria CIS-alcohols (Vc) and (Vd) can be prepared by methods described in WO92/20669, such as the restoration of the respective cdigital, or mercaptoacetyltriglycine, or suitable derivatives. Other features of the receipt of such alcohols can be found in the following examples.

According to the invention compounds of formula (Va) and (Vb) is a key intermediate reagents in obtaining enantiomerically pure analogs or derivatives of CIS-nucleosides. In the resulting analogs or derivatives of CIS-nucleoside of the formula (I) is the absolute stereochemistry of the groups R3, W and X in (Va) or (Vb).

As a result of the reactions used to obtain the alcohols of formulas (Va) and (Vb) and their CIS-ephemerol (Vc) and (Vd), usually formed of a mixture of isomers. When the emission of compounds of formula (Va) or (Vb) by crystallization from mixtures containing their enantiomers and/or CIS-stereoisomers, the output can be limited by the proportional content of the desired isomer (Va) or (Vb) in solution.

We also found that the crystallization of the TRANS-isomers (Va) and (Vb) are preferred as compared with the crystallization of the corresponding CIS-isomers (Vc) and (Vd). In cases where R3- achiral group, a mixture with a ratio of TRANS-isomers (Va) and (Vb) 1:1 can be bicrystalline of a mixture of CIS - and TRANS-isomers (Va), (Vb), (Vc) and (Vd).

Accordingly, in another or alternate and TRANS-isomers (Va), (Vb), (Vc) and (Vd), which provides processing of the mixture at least partially dissolved CIS - and TRANS-isomers with a reagent capable of causing interconversion of isomers without complete suppression of crystallization of TRANS-isomers.

Further, we found that in cases where R3- chiral component of a mixture of stereoisomers can be selectively crystallize the only TRANS-enantiomer of formula (Va) or (Vb).

For example, the compounds of formula (Va), where R3-C(=0)R4and R4- l-Menthyl, can be selectively bicrystalline of a mixture of stereoisomers, in particular of a mixture containing alcohols (Va), (Vb) and epimeria CIS-alcohols (Vc) and (Vd).

Similarly, the compounds of formula (Vb), where R3-C(=0)R4, a R4- d-mental, can be selectively bicrystalline of a mixture of stereoisomers, in particular, from a mixture containing alcohols (Va), (Vb) and epimeria CIS-alcohols (Vc) and (Vd).

Therefore, in a preferred aspect of the invention, a method for improving the output of a single enantiomer of formula (Va) or (Vb) of a mixture of isomers, which includes the handling of isomers, at least partially in solution, a reagent that can cause interconversion of the isomers of the aircraft is capable to cause interconversion of isomers without complete suppression of crystallization of TRANS-isomers, include, for example, alcohols such as, in particular, methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, and organic bases, in particular tertiary amines, such as pyridine and triethylamine and the base Hunga. Preferred triethylamine.

Vzaimoperesechenie isomers can be carried out in any suitable solvent or mixture of solvents that would otherwise not react with alcohols of the formula (Va) or (Vb) or CIS-isomers at concentrations and temperatures, allowing the crystallization of the desired isomer or isomers and do not cause significant degradation of the desired isomer or isomers. Suitable solvents can, for example, include aliphatic or aromatic hydrocarbons, complex, and ethers, and chlorinated hydrocarbons. Mutual transformation is preferably carried out at a temperature of from about -20o120oC, more preferably in the range from -10oup to 80oC, for example from 0o50oC.

Specialists in this field it is clear that the choice of solvent, temperature, conversion reagent and, especially, the number of conversion reagent is best to perform as an integrated process, saveasui reagent organic bases are preferred amount is usually less than two Malevich equivalents relative to the total number of isomers (Va) and (Vb).

Further guidance regarding the preferred reaction conditions can be obtained from the given examples.

Interconversion of the isomers can be done separately from the preparation of isomeric mixtures; however, it is more convenient to do it in conjunction with the cooking.

Procedure vzaimoprevrascheny can be used to increase the purity of the selected isomers (Va) or (Vb).

Thanks to vzaimoprevrascheny output separate the desired isomer (Va) or (Vb) may be increased by more than 50% of theoretical (relative to all stereoisomers), usually in the amount of from about 60% to 90%, but does not exclude the possibility of increased yield more than 100% of theoretical.

The most preferred embodiment of the method according to the invention with the use of l-menthol as a chiral supplements are presented in figure 1 and described in detail in the examples, intended to illustrate the method, without limiting the scope of the claims.

The invention is further illustrated by examples. Temperatures are given in degrees Celsius. DMSO means dimethylsulfoxide.

Example 1.

4-amino-1-(2R-hydroxymethyl-[1,3]oxathiolan-53-yl)-1H-Piri is acid.

A mixture of 25 g l-methylglycosides and 2.5 ml of acetic acid and 125 g of toluene is stirred and heated under reflux. Distillation of the azeotrope trap Dean-stark remove the water. The resulting solution of l-methylglyoxal concentrated by distillation under reduced pressure, taking about 70 ml of distilled water, and then cooled to 20-25oC. Adding about 15 ml of toluene volume was adjusted to 75 ml, then added to 8.25 g decandiol and heat the mixture under reflux for about 1 h the Mixture is cooled to approximately 80oC and lighten. The filtrate is cooled to 0-5oC and approximately 1.25 hours at a temperature of 0-5oC add a solution of 1.5 ml of triethylamine in 150 ml of hexane. The resulting suspension is stirred for about 6 hours at a temperature of 0-5oC. Then filtered the final product, which is washed with a mixture of toluene and hexane (1:3, 2 x 50 ml) and dried in vacuum at 40-45oC to constant weight.

(b) 2S-isopropyl-5R-methyl-1R-cyclohexyloxy ester (2R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-[1,3]oxathiolan-2-carboxylic acid.

A solution of 2S-isopropyl-5R-methyl-1R-cyclohexylamino ester (2R, 5R)-5-chloro-[1,3]oxathiolan-2-carboxylic acid prepared as follows.

A solution of 300 Rotana with 0.7 ml of methansulfonate handle 85 g of dimethylformamide, cool until about 8oC for about 10 min add 80 ml of thionyl chloride. The resulting solution was stirred at 10-15oC for about 1.5 h and then concentrated by distillation at atmospheric pressure of about 1.5 h, taking approximately 2.1 l of distillate. The solution is cooled to 20-25oC.

The solution silicatein prepared as follows.

Suspension of 115.5 g of cytosine, 0.7 ml of methansulfonate and 242 ml hexamethyldisilazane in 290 ml of toluene for about 1.5 h heated under reflux to obtain a clear solution.

The solution silicatein handle 145 ml of triethylamine, add a solution of 2S-isopropyl-5R-methyl-1R-cyclohexylamino ester (2R,5R)-5-chloro-[1,3] oxathiolan-2-carboxylic acid and rinsing 300 g of dichloromethane, gently heated under reflux. The resulting mixture for 4 h continue to heat under reflux and add it to 73 ml of triethylamine and 1200 ml of water, kept at 30-35oC for about 1.5 hours, the resulting suspension is stirred for about 45 min, then at 30-35oC for about 10 min add 1200 ml of hexane. The suspension is stirred at room temperature overnight and then filtered. The solid is washed with water is :nof 0.75(3H,d); 0,89(d), and 0.9(m) of 0.91(d) 1,0-1,2 (m)(9H); (9H, m); 1,43, of 1.50(2H, m); a rate of 1.67(2H, m); 1,9-2,0 (2H, m); 3,14 (1H, dd): 3,55 (1H, dd); 4,69 (1H, dt); 5,70 (1H, s): 5,80 (1H, d), 6,36 (1H, dd), 7,28 (brs), 7,33 (brs)(2H); of 7.97 (1H, d),

(C) Monocalcium 4-amino-1-(2R-hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H-pyrimidine-2-it.

A solution of 137 g dialoginterface in 150 ml of water is stirred at about 20oC and add 100 g of 2S-isopropyl-5R-methyl-1R-cyclohexylamino ester (2R, 5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-[1,3] oxathiolan-2-carboxylic acid. Add 750 ml of IMS (industrial methylated alcohol-denatured) and the suspension is stirred 10 minutes for 70 minutes while maintaining the temperature within 15-30oC add 20 g of a solution of sodium borohydride in 200 ml of water containing 2 ml of 25% (by weight) sodium hydroxide. Funnel, through which the added components, washed with 50 ml of water, and the mixture was stirred at 15-30oC up until the completion of the reaction will not be monitored by HPLC. The mixture defend, the lower aqueous layer was removed, the pH of the remaining organic phase was adjusted to 4-4,5 27 ml of concentrated hydrochloric acid, keeping the temperature between 20 and 25oC. a Funnel, through which the added components, washed with 20 ml of water and the reaction mixture is moved to the distiller, washed with 50 ml in the nom pressure, then cooled to 20-25oC.

Menthol is extracted with toluene (500 ml 2 x 200 ml), the aqueous phase is diluted with 255 ml of water, then treated with 36 g of salicylic acid, washed with 40 ml of water. The mixture is heated to 71oC to obtain a solution, then cooled to 58oC contribute to the solution of the pure seed of salicylate lamivudine and forth for about 4 h, cooled it to 5-10oC. the Suspension is stirred at this temperature for 1 h, then filtered. The final product was washed with water (1 x 100 ml 2 x 200 ml) and dried in vacuum to constant weight.1H NMR (D6-DMSO) :nthe 3.11 (dd), of 3.45 (dd) (2H); of 3.77 (2H, m); 5,20 (1H, m); of 5.82 (1H, d); to 6.22 (1H, m); 6,91 (2H, m); of 7.48 (1H, m); a 7.62 (2H, br); 7,80 (1H, dd); a 7.92 (1H, d),

(d) 4-amino-1-(2R-hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H-pyrimidine-2-he

66,7 g Monosilicate 4-amino-1-(2R - hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H-pyrimidine-2-it is mixed with 470 ml of IMS and heated to 70-75oC to obtain a solution, which lighten the mold and washed with 170 ml of IMS. Add 26 ml of triethylamine and distillation (solvent) bring the volume of solution to 280 ml for 20 min the solution is cooled to 70oC, make the seed, then in the course of 2.25 hours add 600 ml of isopropylacetate with a temperature of 60oC, poderioC and stirred for 1 h, the Final product is filtered off (shifting on the filter with 30 ml of isopropylacetate), washed with isopropylacetate (2 x 130) and dried in vacuum at 40-45oC to constant weight.1H NMR (D6-DMSO):n3,10 (1H, dd); 3,39 (1H, dd); and 3.72 (2H, m); further 5.15 (1H, t); from 5.29 (1H, t); 5,72 (1H, d); to 6.19 (1H, dd); 7,17 (1H, brs); 7,22 (1H, brs); 7,80 (1H, d).

1. Stereoselective method of obtaining compounds of General formula I

< / BR>
where W represents O;

X represents S;

R1represents hydrogen or acyl,

R2is a pyrimidine base or analogue,

includes stage of the interaction between pre-similarvideo pyrimidine base or analogue with an intermediate reagent of General formula IVa or IVb

< / BR>
< / BR>
where R3is a substituted carbonyl or carbonyl derivative;

G is tsepliaeva group

characterized in that the interaction with the pyrimidine base or analogue carried out without the addition of the Lewis acid as catalyst, and tsepliaeva group G is halogeno, cyano, or R9SO2group, where R9represents alkyl, possibly substituted by one fact, what R3advanced restore to the group R1OCH2.

3. The method according to p. 2, characterized in that the recovery is carried out with sodium borohydride in the presence of phosphate buffer.

4. The method according to any of paragraphs.1 to 3, wherein R2is a pyrimidine base.

5. The method according to p. 4, wherein R2represents cytosine or 5-fertilizin.

6. The method according to any of paragraphs.1 to 5, characterized in that R3represents a group-C(=O)OR4where R4represents a possibly substituted alkyl group.

7. The method according to p. 6, wherein R4represents a chiral addition.

8. The method according to p. 7, wherein R4is a (d)-Menthyl or (l)-Menthyl.

9. The method according to any of paragraphs.1 to 8, wherein G represents Cl.

10. The method according to any of paragraphs.1 to 3, characterized in that the compound of formula I is isolated in the form of a water-insoluble salt.

11. The method according to any of paragraphs.1 to 10, characterized in that the compound of formula I is 4-amino-1-(2R-hydroxymethyl[1,3]oxathiolan-5S-yl)-1H-pyrimidine-2-one or its salicylate.

adequate TRANS-alcohols of formulas Va and Vb,

< / BR>
< / BR>
where R3W and X are such as defined in paragraph 1,

or epimeric CIS-alcohol interaction with suitable for introduction of the group G reagent.

13. The method according to p. 12, characterized in that the intermediate compounds of formulas IVa and IVb receive in situ.

14. The way to enhance the yield of the TRANS-isomers Va and Vb from a mixture of TRANS - and CIS-isomers, which includes processing said mixture, at least partially in solution, a reagent that can cause interconversion of isomers without complete suppression of crystallization of TRANS-isomers, for example, an organic base such as tertiary amine.

15. The way to increase the output of one of the TRANS-isomers Va and Vb from a mixture of TRANS-isomers or a mixture of TRANS - and CIS-isomers, which includes processing said mixture, at least partially in solution, a reagent that can cause interconversion of isomers without complete suppression of crystallization of the desired TRANS-isomers Va or Vb, for example, an organic base such as tertiary amine.

16. The method according to p. 15, characterized in that conduct selective crystallization of compounds of formula Va, where R3represents a group-C(=O)OR4where R4is (l)-m is trichosis fact, provide selective crystallization of the compounds of formula Vb, where R3represents a group-C(=O)OR4where R4is (d)-mantila, of a mixture of stereoisomers containing alcohols Va and Vb and epimeria CIS-alcohols.

18. The method according to p. 16, characterized in that conduct selective crystallization 2S-isopropyl-5R-methyl-1R-cyclohexylamino ester (2R,5R)-5-hydroxy[1,3]oxathiolan-2-carboxylic acid.

19. The method according to p. 18, characterized in that as a reagent that can cause interconversion of isomers without complete suppression of crystallization of the desired single enantiomer, using triethylamine.

20. Salicylate compounds of formula I or its hydrate.

21. Salicylate 4-amino-1-(2R-hydroxymethyl[1,3]oxathiolan-5S-yl)-1H-pyrimidine-2-it and its hydrates.

 

Same patents:

The invention relates to new nucleoside analogues of 1,3-oxathiolane and their use for treating viral infections, HIV infection, hepatitis b, more specifically to the (-)-4-amino-5-fluoro-1-(2-oxymethyl-1,3-oxathiolan-5-yl)-(1H )-pyrimidine-2-ONU (I) and its pharmaceutically acceptable derivative containing pharmaceutical compositions

The invention relates to new substituted cyclic derivatives of 1,3-oxathiolane having pharmacological activity, to processes for their preparation and intermediate compounds used for their production, to containing these derivatives, pharmaceutical compositions and to the use of these derivatives for the treatment of viral diseases in mammals

The invention relates to new substituted cyclic derivatives of 1,3-oxathiolane having pharmacological activity, to processes for their preparation and intermediate compounds used for their production, to containing these derivatives, pharmaceutical compositions and to the use of these derivatives for the treatment of viral diseases in mammals

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention is related to derivatives of nitrosulfobenzamide of formula (I) , in which R1 - alkyl with 1 - 6 carbon atoms, R2 - alkyl with 1 - 6 carbon atoms; Q - is hydrogen or cation of alkaline metal, and also to method of their preparation by interaction of amine of formula NHR1R2 or its salt, with diacid of formula (III) or its salt, where Q1 and Q2 are identical or different and stand for hydrogen or alkali metal cation.

EFFECT: compounds according to the present invention may be useful for production of sulfonylureas and their precursors, such as for instance sulfochlorides or sulfonamides.

10 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazolo-2-yl]-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl]-amine of formula (I) (versions) and novel intermediate compounds of the method. The method of producing a compound of formula (I) is carried out by reacting a) a compound of general formula (II), where X denotes halogen, reacting with a thiocyanate of an alkali metal in the presence of a phase-transfer catalyst, and b) reacting the obtained 2-thiocyanate-1-(2-chloro-4-methoxy-5-methylphenyl)-propan-1-one of formula (III) or tautomeric form thereof with 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethylamine of formula (IV). The invention relates to 2-thiocyanate-1-(2-chloro-4-methoxy-5-methylphenyl)-propan-1-one of formula (III) and a tautomer thereof. The invention also relates to a method of producing 2-thiocyanate-1-(2-chloro-4-methoxy-5-methylphenyl)-propan-1-one of formula (III) by reacting a derivative thereof of general formula (II), where X denotes halogen, with a thiocyanate of an alkali metal in the presence of a phase-transfer catalyst.

EFFECT: ecologically clean method of producing the desired compound of formula (I) due to formation of aqueous wastes only, low amount of solvents used to obtain a highly pure product with high output.

13 cl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which have formula (1a):

, where R1 represents hydrogen, (C1-C4)alkyl or halogen; R2 represents hydrogen, halogen, amino, (C1-C4)alkyl, heterocyclyl, (C6-C10)aryl-(C1-C4)alkylheterocyclyl, (C3-C6)cycloalkylheterocyclyl, -NR11R12, NHR16; R3 represent hydrogen, NR11R12 or NHR16; R4 and R5 each are independently selected from: hydrogen, halogen, (C1-C4)alkyl; R6 and R8 are each independently selected from: hydrogen, (C1-C4)alkyl or halogen; R7 is hydroxy-(C1-C4)alkyl, formyl, -(CH2)nC(O)OR10 or CONHR16; R10 is hydrogen, (C1-C4)alkyl; R11 and R12 each are independently selected from hydrogen, (C1-C4)alkyl, hydroxy-(C1-C4)alkyl, halogen-(C1-C4)alkyl, amino-(C1-C4)alkyl; or R11 and R12, together with N atom, to which they are bound, form 6- or 7-member heterocycle, optionally having one or more additional heteroatoms N or O; R16 is formyl, (C1-C4)alkyl, halogen-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, (C1-C4)alkylcarbonyl, halogen-(C1-C4)alkylcarbonyl, hydroxy-(C1-C4)alkylcarbonyl, (C1-C4)alkylcarbonyloxy-(C1-C4)alkylcarbonyl or heterocyclyl-(C1-C4)alkylcarbonyl; n is 0, 1 or 2; where (C1-C4)alkyl is not substituted or is substituted with two similar or different groups, selected from: halogen, hydroxy-group and (C6-C10)aryl; heterocyclyl represents 6- or 7-member saturated monocyclic ring, containing one or two heteroatoms selected from nitrogen and oxygen, and which is not substituted or is substituted with one or two similar or different groups, which are selected from oxogroup, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl, hydroxy-(C1-C4)alkyl, (C6-C10)aryl-(C1-C4)alkyl, formyl, (C1-C4)alkylcarbonyl, (C6-C10)aryl-(C1-C4)alkylcarbonyl, (C6-C10)arylcarbonyl, (C3-C6)cycloalkylcarbonyl, -SH, -S-(C1-C4)alkyl and -S(O)2-(C1-C4)alkyl; (C6-C10)aryl is not substituted or is substituted with (C1-C4)alkyl; W represents S(O)m; m equals 0, 1 or 2; and to their pharmaceutically acceptable salts. Invention also relates to compounds of formula (1a'), to methods of obtaining compounds of formula (1a), to methods of obtaining compounds of formula (1a'), to method of obtaining compounds of formula E2, to pharmaceutical compositions, as well as to application of compounds.

EFFECT: obtaining novel biologically active compounds which demonstrate inhibiting effect with respect to activity of tumour necrosis factor-α.

30 cl, 46 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of splitting a racemic mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane to obtain an optically active mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane, involving the following steps: a) dissolving and heating said racemic mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane in a solvent in the presence of (1R)-(-)-10-camphorsulphonic acid and achiral acid to form a solution containing the following two diastereoisomeric salts: (-)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane• (1R)-(-)-10- camphorsulphonate and (+)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane•(1R)-(-)-10- camphorsulphonate; b) cooling the solution to facilitate crystallisation of diastereomeric salts; c) extraction of crystals of the optically active mixture of said two diastereomeric salts obtained at step b), which contains excess (-)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane• (1R)-(-)-10- camphorsulphonate over (+)-cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane•(1R)-(-)-10- camphorsulphonate, and d) treating said optically active mixture of said two diastereomeric salts to remove (1R)-(-)-10- camphorsulphonic acid in order to obtain an optically active mixture of cis-2-hydroxymethyl-4-(cytosin-1'-yl)-1,3-oxathiolane.

EFFECT: improved method.

16 cl, 3 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing 1,3-oxathiolane nucleosides, which involves reaction of (5-acetyloxy-1,3-oxathiolan-2-yl)methyl butanoate with a silylated pyrimidine or purine base in the presence of TiCl3(isopropoxide). Said reaction enables to obtain a product mainly containing β anomer.

EFFECT: efficient method of producing 1,3-oxathiolane nucleosides.

13 cl, 3 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula (II) comprising the steps: (a) forming 2,4-disubstituted 1,3-oxathiolane of formula (II) and (III) where the substitutes are as defined in the claim; (b) selective recrystallisation of the compound of general formula (II) from a C1-C6 alcohol or a mixture of C1-C6 alcohols. The invention also relates to a method of producing a compound of formula (VI) comprising the steps: (a) forming 2,4-disubstituted 1,3-oxathiolane of formula (II) and (III); (b) selective recrystallisation of the compound of formula (II) from a C1-C6 alcohol or a mixture of C1-C6 alcohols; and (c) removing protective groups in the compound of formula (II) to obtain a compound of formula (VI). The invention also relates to compounds of formulae (VIII) and (IX) where R2 is C(O)phenyl; each of R3 and R4 is independently selected from H or benzoyl under the condition that when R3 is H, R4 is not H; and when R4 is H, R3 is not H; and R5 is H, Br, Cl, F, I or CF3.

EFFECT: improved methods of producing 2,4-disubstituted 1,3-oxathiolanes and intermediate compounds for production thereof.

23 cl, 5 ex, 23 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

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