Diisopropyl ((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate process

FIELD: chemistry.

SUBSTANCE: invention concerns process of production of diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate represented by the formula , which is the key intermediate compound in synthesis of antiviral nucleoside analogue. The invention also concerns new intermediate compounds of formulae and , and their production of compound (2) obtained under this invention, which is an antiviral nucleoside analogue (especially against hepatitis B virus) represented by the formula .

EFFECT: high purity grade and high output.

4 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a new method of obtaining the compounds represented by the following formula (2)

which is a key intermediate compound for the synthesis of analog anti-virus (especially against hepatitis b virus) nucleoside represented by the following formula (1):

The present invention also relates to novel intermediate compounds and the method of obtaining the compounds of formula (1) [compound (1)below] of the compounds of formula (2) [compound (2), below], obtained according to the present invention.

The LEVEL of TECHNOLOGY

The compound (1) is a therapeutic agent against hepatitis B (Korean patent application No. 2002-0003051, WO 02/057288), the compound (2) can be used as an important reagent to obtain the compound (1), together with a compound of the following formula (3):

in which X represents fluorine atom, chlorine atom, bromine atom or iodine atom.

It is known that these purine derivatives as the compound (1), have anti-cancer and anti-viral activities, and ten (10) or more kinds of such derivatives, including AZT, 3TC, ACV, and so forth, are already commercially available.

The compound (2)used is as important intermediate compound to obtain the compound (1), was obtained by the method shown in the following reaction scheme 1.

The reaction scheme 1:

In the specified method of scheme 1 as the initial substance use ethylglycol the following formula (4):

In the method according to scheme 1, ethylglycol formula (4) was introduced into the reaction with tert-butyl(diphenyl)similiarites with the formation of the compounds of formula (5), which was introduced in the reaction with ethylmagnesium and tetraisopropoxide titanium according to the method known from the prior art (Syn. Lett, 07, 1053-1054, 1999), which leads to cyclopropylamino alcohol of formula (6), which was then isolated as a solid from heptane. Thus obtained compound of the formula (6) was dissolved in dimethylformamide and was introduced into the reaction with tert-piperonyl lithium and Diisopropylamine a phosphonate, receiving compound of the formula (7). This compound of formula (7) was boiled with ammonium fluoride in methanol, which led to the compound (2).

The above-mentioned method, however, has the disadvantage that a polluted form of the compound (2)as diisopropylaminoethanol applied at the stage of synthesis of the compounds of formula (7), remains in the reaction solution and thus is always contained in the final of the obtained compound (2) in the amount of 7-15%. Further, poor stability of the connection form is s (6) tert-piperonyl lithium at the stage of synthesis of the compounds of formula (7) is responsible for the volatility of output and the difficulties of the selection.

So for specialists in this field it is desirable to increase the purity of the compound (2) and to improve the stability of the compounds of formula (6) during the synthesis of the compounds of formula (7).

The INVENTION

Thus, the authors of the present invention conducted extensive research method of obtaining the compound (2) with a view to its improvement and as a result found that the above-mentioned disadvantages of the previously proposed method can be overcome by using as the reagent Fritillaria instead of tert - butyl(diphenyl)silingardi, which leads to the compound (2) high purity. The inventors have also found that the compound (1) can be obtained with high yield by applying a high-purity compound (2)thus obtained, and thereby completed the present invention.

Therefore, the aim of the present invention is to provide a new method of obtaining the compound (2). Another objective of the present invention are new intermediate compounds obtained when carrying out the method of obtaining the compound (2). A further purpose of the present invention is a method of obtaining an analogue of the nucleoside of formula (1), which can be used as an antiviral agent, with the use of the compound (2)obtained by the method according to the present invention. The present invention is SP is a way to obtain compound (2), includes stage reaction of compounds of formula (4) with Fritillaria to obtain ethyl ester trisiloxane acid of the following formula (8):

reaction of compounds of formula (8) with ethylaniline to obtain 1-trailersamerican the following formula (9):

response 1-trailersamerican formula (9) with diisopropyl-methylphosphonate in a solvent in the presence of a base to obtain diisopropyl ether (l-trisiloxane-cyclopropylmethyl-phosphonic acid of the following formula (10) in solid form:

and turning trailvoy group of compounds of formula (10) hydroxyl group.

When carrying out the method of the present invention N-organic (NMP) can be selected more preferable as a solvent for the stage of combining cyclopropylamino formula (9) with phosphonate group with the formation of compound (2) with the best yield and purity.

The method of the present invention may be depicted by the following reaction scheme 2, in which X represents fluorine atom, chlorine atom, bromine atom or iodine atom.

The reaction scheme 2:

The preferred amount of each reagent and conditions re the functions, including the reaction temperature and the method of treatment can be specifically explained below.

First, define the following abbreviations used in this description:

Tr:Trail
Et:Ethyl
EDC:1,2-Dichloroethane
THF:Tetrahydrofuran
EA:The ethyl acetate
i-Pr:Isopropyl
LTB:Tert-piperonyl lithium
NMP:N-organic
DBMP:Diisopropylaminoethanol
MTBE:Methyl tert-butyl ether
TFA:Triperoxonane acid
MDC:Methylene chloride
AN:Acetonitrile
Min:Minute

In the first stage reaction ethylglycol formula (4) with Fritillaria, 1.0 equivalent of Fritillaria (TrCl) and 1-1,3 equivalents of pyridine were added to 1.0 to 1.5 equivalent of the compounds of formula (4), and the mixture was stirred in the presence of EDC at a temperature of about 30-60°C. After stirring the acid-the main processing of the mixture was brought to the compound of formula (8), which is then processed and hexane to transfer in solid form or used in the next reaction without further purification. To the compound of formula (8) was added to 2.1-3.1 equivalent ethylaniline, preferably etimani chloride or etimani bromide, and 0.2 to 0.6 equivalent of tetraisopropoxide titanium and carried out the reaction of Kulinkovich at 5-15°C (J. Am. Chem. Soc, 1995, 117, 9919-9920). Then there was added an aqueous solution of citric acid, the reaction mixture was stirred and extracted, giving a compound of the formula (9). The compound of formula (9) was dissolved in the solvent, particularly preferably in NMP, there was added 1.3 to 1.7 equivalent DBMP and 1.5-2.0 equivalents LTB and the mixture was stirred over 6-19 hours under the condition not exceeding 45°C; and subjected to an acid-base treatment, which gave the compound of formula (10). The compound of formula (10)obtained in this way were transferred into the solid form by treatment with heptane at a low temperature. To the compound of formula (10) was added to 1.5-2.5 equivalent of TFA and 0.1-0.5 ml/g of water and the mixture was stirred at room temperature. After stirring, acid-base processing and filtering the thus obtained solid substance and extraction of the obtained compound (2). Here acid-the main processing is preferably conducted by sodium hydroxide, and extraction by methylene chloride.

The method of the present invention leads to the compound (2) high purity from 98 to 100%.

Compounds of the formulas (9) and (10)obtained as an intermediate the connection method of the present invention, themselves are also new compounds. Therefore, the present invention further introduces these new intermediate compounds.

The compound (2)obtained in the above way, is a key intermediate compound for the synthesis of nucleoside analogue of formula (1), as mentioned earlier. Specifically, compound (1) can be obtained by the method comprising a stage of introduction of the leaving group in the compound (2) to obtain a compound of the following formula (11):

in which L is a leaving group, preferably methanesulfonate-pair-toluensulfonate group, or halogen atom; combinations of the compounds of formula (11) with the compound of the formula (3) to obtain a compound of the following formula (12):

in which X is defined as before, and hydrolysis of compounds of formula (12) to obtain the compound of the following formula (13):

in which X is defined as previously, removal of the group X of the compound of formula (13) and at the same time the introduction of tert-butylcarbamoyl group in the fragment phosphonic acid. Detailed reaction conditions of the above-mentioned method described in the earlier application authors (Korean patent application No. 2002-0003051, WO 02/057288). Therefore, the present invention provides sposobnosti connection (1) from compound (2), obtained by the method presented in reaction scheme 2.

The present invention will be more specifically explained by the following examples. However, it should be clear that these examples are intended to illustrate the present invention but not to limit, in any way, the scope of the present invention.

In the examples below, the conditions of high performance liquid chromatography (HPLC) to determine completion of the reaction are the following:

[conditions HPLC]

Column:Capcell pak C18(Type: MG 5 μm; Size: 4.6 mm (inner diameter) x 250 mm);
Wavelength (λ):254 nm;
Consumption:1.0 ml/min

Gradient (water/acetonitrile, 0.1% of TFA):At the start: 20/80, 5 min: 20/80; 7 min: 0/100; 10 min: 0/100, 12 min: 20/80.

Examples

Example 1.

Obtaining the ethyl ester trisiloxane acid (8)

Trailhead (279 g, 1.0 mol) was dissolved in EDC (680 ml, 5 ml/g relative to ethylglycol) and added to a mixture of ethylglycol (135 g, 1.3 mol). Thereto was added pyridine (99 g, 1.25 mol) and the mixture was stirred for 19 hours at 40°C. After confirmation by HPLC completion of the reaction was added 0.5 N solution of aq is th hydrochloric acid (270 ml, 2 ml/g relative to ethylglycol) in order to make the reaction solution two-phase, then was extracted. After repeated extraction EDC drove under reduced pressure. In order to obtain the compound of formula (8) in solid form, concentrated compound was added hexane (680 ml), the temperature was lowered to 0°C, the mixture was stirred for about 3 hours and was filtered.

[HPLC]

Connection:TrClCompound (8)
Retention time:5,388,58
The peak area:2,39%83,93%

1H NMR (400 MHz, CDCl3) d of 1.23 (t, 3H, J=8 Hz), of 3.78 (s, 2H), 4,14 (q, 2H, J=8 Hz), 7,26-7,22 (m, 3H), 7,33-7,29 (m, 6H), 7,50-7,47 (m, 6H);

13C NMR (400 MHz, CDCl3) d 10,8, 57,3, 59,3, 84,0, 123,9, 124,6, 125,3, 140,0, 166,7.

Example 2.

Obtaining l-trisiloxane-cyclopropanol (9)

Assuming that the output in example 1 is 100%, the compound of formula (8)obtained in example 1 was added tetrahydrofuran (1040 ml, 3 ml/g, relative to the compound of formula (8)) and the mixture was cooled to 0°C. There was added tetraisopropoxide titanium (113,8 g, 0.4 mol) and then was added dropwise ethylmagnesium (1500 ml, 3.0 mol, 1M concentration) at 5-15°C for 3-6 hours. After confirmation met the house HPLC completion of the reaction was added 20% aqueous solution of citric acid [1790 ml, 5 ml/g relative to the compound of formula (8)] to the reaction solution under the condition not exceeding 35°C, which was stirred for about 1 hour. After stirring tetrahydrofuran kept at reduced pressure and the residue was extracted twice, first time 1390 ml of ethyl acetate [4 ml/g relative to the compound of formula (8)] and the second time 690 ml of the same solvent [2 ml/g relative to the compound of formula (8)]. Thus, the obtained organic layer was washed saturated aqueous NaHCO3[690 ml, 2 ml/g relative to the compound of formula (8)] and concentrated under reduced pressure, which gave the compound of formula (9), indicated in the header.

[HPLC]

Connection:TrClConnection (9)
Retention time:of 5.406,23
The peak area:5,07%78,54%

1H NMR (400 MHz, CDCl3) d 0,45 (DD, 2H, J=8 Hz), 0,80 (DD, 2H, J=8 Hz), 2,59 (s, 1H), 3,18 (s, 2H), 7.23 percent-to 7.32 (m, 9H), 7,45-7,47 (m, 6H);

13C NMR (400 MHz, CDCl3) d 8,4, 51,9, 63,9, 83,0, 123,7, 124,6, 125,3, 140,5.

Example 3.

Getting diisopropyl ether (l-trisiloxane-cyclopropylmethyl-phosphonic acid (10)

To the compound of formula (9) (261,25 g of 0.79 mol)obtained by concentration under reduced Yes the tion, example 2 (assuming that the compound of the formula (9) was obtained with the yield 79%, from example 1, since the value of the peak in the HPLC was 78,54%)was added NMP [1050 ml, 4 ml/g relative to the compound of formula (9)] and DBMP (307 g, 1.2 mol). To the reaction mixture were added LTB (107 g, 1.3 mol), which was then stirred under the condition not exceeding 45°C. After about 6-19 hours of the completion of the reaction was confirmed by HPLC and added 14% aqueous solution of NH4Cl [1830 ml, 7 ml/g relative to the compound of formula (9)] to stop the reaction. There was added twice MTBE [first time: 1050 ml, 4 ml/g relative to the compound of formula (9); second time: 520 ml, 2 ml/g relative to the compound of formula (9)] for separation of the phases. The thus obtained organic layers were combined and washed 21% aqueous NaCl solution [1650 ml, 6.3 ml/g relative to the compound of formula (9)]. The remaining organic layer was concentrated under reduced pressure and there was added heptane [1300 ml, 5 ml/g relative to the compound of formula (8)]. The mixture was cooled to -10°C and was filtered after about 3 hours, which gave the compound of formula (10), indicated in the header of the example (586 g, purity 96,23%, the yield of 71.3 per cent) in the form of solids.

[HPLC]

Connection:TrOHConnection (9)The is a group of (10)
Retention time:5,246,029,26
The peak area:0,10%0,09%96,23%

NMR: Not watched the other peaks, in addition to the peaks of the compounds of formula (10).

1H NMR (400 MHz, CDCl3) d 0,54 (DD, 2H, J=8 Hz), 0,80 (DD, 2H, J=8 Hz), 1,33-of 1.29 (m, 12H), up 3.22 (s, 2H), 3,92 (d, 2H, J=8 Hz), 4,67 was 4.76 (m, 2H), 7,21-7,31 (m, 9H), 7,43-7,46 (m, 6H)

13C NMR (400 MHz, CDCl3) d 11,9, 24,4, 24,4, 24,5, 24,6, 63,5, 63,8, 64,0, 65,1, 67,3, 71,3, 71,4, 86,9, 127,4, 128,3, 129,1, 144,3

Example 4.

Getting aminobutiramida {[l-(hydroxymethyl)-cyclopropyl] oxy}methylphosphonate (2)

The compound of formula (10)obtained in example 3 (59,15 g, 116,3 mmol), was dissolved in acetone [59,2 ml, 1 ml/g relative to the compound of formula (10)], was added water (5,9 ml, 327,8 mmol) and TFA (26,52g, 232,6 mmol) and the mixture was stirred at room temperature. After the HPLC method was established that the content of the compounds of formula (10) was 7% or less, there was added 3N aqueous NaOH solution [75 ml of 2.6 ml/g relative to the compound of formula (10)], and the acetone was removed from the mixture by distillation at reduced pressure. Was filtered, the solid obtained in the course of the reaction, and the filtrate was extracted twice with methylene chloride [118.3 ml ×2; 2 ml/g relative to the compound of formula (10)]. Thus, the obtained organic layer was concentrated at reduced pressure gave compound, indicated in the header of the example (2) [31,71 g, purity 98%, relative to the compound of formula (10) 102,4%].

[HPLC]

Connection:TrOHThe compound (10)
Retention time:5,149,20
The peak area:93,58%5,07%

[NMR] in Addition to the peak for compound (2) was only observed peak of methylene chloride (a solvent).

1H NMR (400 MHz, DMSO) d of 0.55 (DD, 2H, J=8 Hz), 0,72 (DD, 2H, J=8 Hz), 1,22-of 1.24 (m, 12H), of 3.32 (s, 2H), 3,53 (d, 2H, J=4 Hz), 3,81 (d, 2H, J=8 Hz), 4.53-in-4,72 (m, 2H), 4,73 (t, 1H)

13C NMR (400 MHz, DMSO) d 7,44, 20,7, 20,75, 20,85, 20,88, 58,81, 60,47, 60,69, 61,62, 61,77, 67,12, 67,18

As explained above, when Fritillaria used according to the present invention, the intermediate compound of formula (10) can be obtained as a solid substance that solves the problem of the prior art, consisting in the fact that diisopropylaminoethanol is not removed, but remains in the compound (2), which reduces its purity. Especially, if N is the organic was chosen instead of dimethylformamide as a solvent to obtain compounds of formula (10), the stability of the compounds of formula (9) to tert-piperonyl lithium significantly increased, which acts favorably on the purity and yield of the compound (2). In addition, compound (), which can be used as an antiviral agent, can be obtained, mainly high yield, using high-purity compound (2)obtained according to the present invention.

1. The method of obtaining compounds of the following formula (2):

,

includes stage reaction of compounds of the following formula (4):

,

with Fritillaria with obtaining the ethyl ester trisiloxane acid of the following formula (8):

,

the reaction of compounds of formula (8) with ethylaniline obtaining 1-trisiloxane-cyclopropanol the following formula (9):

,

the combination of 1-trisiloxane-cyclopropanol formula (9) with diisopropyl-methylphosphonate in a solvent in the presence of a base to obtain diisopropyl ether (1-trisiloxane-cyclopropylmethyl-phosphonic acid of the following formula (10) in solid form:

and turning trailvoy group of compounds of formula (10) hydroxyl group.

2. The method according to claim 1, in which the solvent is applied at the stage of reacting the compounds of formula (9) to obtain the compounds of formula (10)represents the N-metier oligon.

3. The method according to claim 1 or 2, in which the base is applied at the stage of reacting the compounds of formula (9) to obtain the compounds of formula (10)represents a tert-piperonyl lithium.

4. The method according to claim 1 or 2, in which etimani halide is etimani chloride or etimani bromide.

5. The method according to claim 1 or 2, in which the reaction etimani of the halide with the compound of the formula (8) was performed in the presence of tetraisopropoxide titanium.

6. The method according to claim 1 or 2, in which the product obtained after transformation trailvoy group in the hydroxyl group in the compound of formula (10), treated with sodium hydroxide, the resulting solid substance was filtered and the filtrate was extracted with methylene chloride, which resulted in a compound of the formula (2).

7. The compound of the following formula (9):

,

8. The compound of the following formula (10):

9. The method of obtaining compounds of the following formula (1):

includes the stage of introduction of the leaving group in the compound of the formula (2)obtained by the method according to claim 1, for obtaining compounds of the following formula (11):

in which L is a leaving group;

combinations of the compounds of formula (11) to link the m following formula (3):

in which X represents a fluorine atom, a chlorine atom, a bromine atom, or iodine atom to obtain a compound of the following formula (12):

in which X is defined as previously; hydrolysis of compounds of formula (12) to obtain the compound of the following formula (13):

in which X is defined as previously; the removal of the group X of the compound of formula (13), and at the same time the introduction of tert-butylcarbamoyl group in the fragment phosphonic acid.



 

Same patents:

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. 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EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention describes compound of the formula (I): wherein R1 means hydrogen atom (H); R2 means -SH, -S-C(O)-R8, -P(O)(OR5)2, -P(O)(OR5)R6, -P(O)(OR5)-R7-C(O)-R8, -P(O)(OR5)-R7-N(R5)-S(O)2-R9 or -P(O)(OR5)-R7-N(R5)-C(S)-N(R6)2; R3 means tetrazole, -C(O)OR6, -C(O)O-R7-OC(O)R5; R4 means optionally substituted aryl, or R4 means N-heterocyclyl. Also, invention describes compounds of the formula (II): and (III): wherein X means -CH2- or -O-, and pharmaceutical compositions comprising indicated compounds. Proposed compounds possess inhibitory effect on activity of plasma carboxypeptidase B and used as anti-thrombosis agents.

EFFECT: valuable medicinal and biochemical properties of compounds.

34 cl, 19 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to phosphonic acid compounds used as inhibitors of serine proteinase of the general formula (I): wherein R1 is chosen from group comprising piperidinyl, pyrrolidinyl and 1,3,8-triazaspiro[4,5]dec-8-yl (wherein heterocyclic ring as added to nitrogen atom in ring) and -N(R7R80 wherein this heterocyclic ring is substituted optionally with one or two substitutes chosen independently from group comprising the following compounds: (a) C1-C8)-alkyl substituted optionally at terminal carbon atom with a substitute chosen from group comprising aryl, heteroaryl; c) phenyl and naphthalenyl; i) benzothiazolyl; R7 is chosen from group comprising hydrogen atom and (C1-C8)-alkyl; R8 is chosen from group comprising: (aa) (C1-C8)-alkyl; (ab) cycloalkyl; (ac) cycloalkenyl, and (ad) heterocyclyl (wherein R8 is added to carbon atom in ring) wherein (ab) cycloalkyl; (ac) cycloalkenyl, and (ad) heterocyclyl (wherein heterocyclyl (ad) comprises at least one cyclic nitrogen atom) substitutes and cycloalkyl moiety (aa) of a substitute is substituted optionally with substitutes chosen independently from group comprising: (ba) (C1-C8)-alkyl substituted at terminal carbon atom with a substitute chosen from group comprising amino-group (with two substitutes chosen independently from group comprising hydrogen atom and (C1-C8)-alkyl); (bb) (C1-C8)-alkoxy-group substituted at terminal carbon atom with a substitute chosen from group comprising carboxyl; (bc) carbonyl substituted with a substitute chosen from group comprising (C1-C8)-alkyl, aryl, aryl-(C2-C8)-alkenyl; (bd) aryl; (be) heteroaryl; (bf) amino-group substituted with two substitutes chosen independently from group comprising hydrogen atom and (C1-C8)-alkyl; (bh) halogen atom; (bi) hydroxy-group; (bk) heterocyclyl wherein (bd) is aryl substitute, and heteroaryl moiety (bc) comprise a substitute (halogen atom)1-3; R4 is chosen from group comprising aryl and heteroaryl wherein heteroaryl comprises halogen atom as a substitute; R2 and R3 are bound with benzene ring and represent hydrogen atom, and R2 and R3 form in common optionally at least one ring condensed with benzene ring forming polycyclic system wherein this polycyclic system is chosen from group comprising (C9-C14)-benzocondensed cycloalkenyl, (C9-C14)-benzocondensed phenyl; R5 is chosen from group comprising hydrogen atom and (C1-C8)-alkyl; R6 is chosen from group comprising (C1-C8)-alkyl and hydroxy-group; Y is absent, and X represents a single substitute that is added by a double bond and represents oxygen atom (O), and Z is chosen from group comprising a bond, hydrogen atom, and its salts. Also, invention relates to a method for synthesis of these compounds, to their composition inhibiting serine proteinase and to a method for its preparing. Proposed invention describes a method for treatment of inflammatory or serine proteinase-mediated disorder.

EFFECT: valuable biochemical and medicinal properties of compounds.

64 cl, 5 tbl, 38 ex

FIELD: chemistry of organophosphorus compounds.

SUBSTANCE: invention relates to the improved method for synthesis phosphorus-chlorine-containing methacrylates that can be used in synthesis of polymeric, among them, uncolored, optically transparent and composition materials with reduced inflammability. Invention describes a method for synthesis of phosphorus-chlorine-containing methacrylates of the general formula:

wherein R means lower alkyl, chloroalkyl, alkoxyl, phenoxyl or group of the formula:

R1 means lower alkoxyl, phenoxyl or group of the formula:

Method involves interaction of phosphoric pentavalent acid chloroanhydrides with methacrylic acid glycidyl ester at heating in the presence of hexamethylenephosphorotriamide or dimethylformamide as a catalyst wherein catalyst is taken in the amount 0.3-0.6% of reagents mass, and process is carried out at rise of temperature from 40°C to 80°C in the presence of compound chosen from the group: alkyl- or alkoxy-substituted phenols taken in the amount 0.03-0.3% of reagents mass. Method provides decreasing water absorption of (co)polymerization products of synthesized phosphorus-chlorine-containing methacrylates and reducing retention time of surface stickiness of fiber glass synthesized on their basis and at retention the level of other properties, among them transparence and colorless.

EFFECT: improved method of synthesis, improved and valuable properties of compounds.

2 tbl, 10 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to acyclic nucleoside phosphonate derivatives of the formula (1): wherein means a simple or double bond; R1 means hydrogen atom; R2 and R3 mean hydrogen atom or (C1-C7)-alkyl; R7 and R8 mean hydrogen atom or (C1-C4)-alkyl; R4 and R5 mean hydrogen atom or (C1-C4)-alkyl possibly substituted with one or more halogen atoms, or -(CH2)m-OC(=O)-R6 wherein m means a whole number from 1 to 5; R6 means (C1-C7)-alkyl or 3-6-membered heterocycle comprising 1 or 2 heteroatoms taken among the group consisting of nitrogen (N) and oxygen (O) atoms; Y means -O-, -CH(Z)-, =C(Z)-, -N(Z)- wherein Z means hydrogen atom, hydroxy-group or halogen atom, or (C1-C7)-alkyl; Q (see the claim invention); its pharmaceutically acceptable salts or stereoisomers. Also, invention proposes methods for preparing compounds of the formula (1) and their using in treatment of hepatitis B or preparing a medicinal agent designated for this aim.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

16 cl, 10 tbl, 87 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing N-phosphonomethylglycine. Method involves interaction of derivative of hexahydrotriazine of the formula (II):

wherein X represents CN, COOZ, CH2OY and others; Z and Y represent hydrogen atom and others with triacylphosphite of the formula: P(OCOR3)3 (III) wherein R3 means (C1-C18)-alkyl or aryl that can be substituted. The prepared product is hydrolyzed and (if X represents CH2OY) oxidized. The proposed method is a simple in realization, economy and provides high degree of the end product purity.

EFFECT: improved preparing method.

19 cl, 11 ex

FIELD: chemistry of organophosphorus compounds.

SUBSTANCE: invention relates to compounds with the bond C-P, namely to phosphorus-boron-containing methacrylate that can be used as inhibitor of combustion of polyvinyl alcohol-base film materials. Invention describes phosphorus-boron-containing methacrylate of the following formula: wherein n = 4-8. Polyvinyl alcohol films modified with indicated phosphorus-boron-containing methacrylate shows the enhanced refractoriness, rupture strength up to 206 kgf/cm2, water absorption up to 240% and relative elongation up to 12%.

EFFECT: valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, in particular improved method for production of phosphorinated and chlorinated methacrylates.

SUBSTANCE: invention relates to method for production of compounds having general formula , wherein R is lower alkyl and R1 is lower alkoxyl, phenoxyl, or group of formula . Claimed method includes reaction of pentavalent phosphorous acid chloroanhydride with glycydil methacrylate at 20-50°C in presence of titanium tetrachloride as catalyst in amount of 0.02-0.05 % calculated as reagent mass.

EFFECT: one-step method for production of phosphorous and chlorine containing methacrylates with improved water resistance.

2 tbl, 7 ex

The invention relates to new biologically active phosphonate derivative of acyclovir

The invention relates to the chemistry of organophosphorus compounds, and in particular to a new method of obtaining N-substituted phosphorylated of imidates having the structure zenatello group

The invention relates to derivatives of phosphinic and phosphonic acids of the formula (I)

where R1means unsubstituted or substituted phenyl, -O-(C1-C6)-alkyl, R2means hydrogen, RR3mean hydrogen, alkyl, unsubstituted or substituted phenyl, COOH group or - (CH2)2-CH(COOH)-NH-SO2-C6H4-C6H4-Cl(n), t stands for an integer of 1-4, And is a covalent bond, X is a group-CH=CH -, - group,- (CH2)about- where is 0,1,2 or 3, Y1and Y2mean-OH, -(C1-C4)-alkyl, -O-(C1-C4)-alkyl, and/or their stereoisomeric forms and/or physiologically acceptable salts

The invention relates to the field of chemicals, petrochemicals, and more specifically to a method for selection of high-octane component of motor fuel and benzene from catalization reforming of gasoline fractions

FIELD: chemistry.

SUBSTANCE: invention concerns process of production of diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate represented by the formula , which is the key intermediate compound in synthesis of antiviral nucleoside analogue. The invention also concerns new intermediate compounds of formulae and , and their production of compound (2) obtained under this invention, which is an antiviral nucleoside analogue (especially against hepatitis B virus) represented by the formula .

EFFECT: high purity grade and high output.

4 ex

FIELD: organic chemistry, in particular improved method for production of phosphorinated and chlorinated methacrylates.

SUBSTANCE: invention relates to method for production of compounds having general formula , wherein R is lower alkyl and R1 is lower alkoxyl, phenoxyl, or group of formula . Claimed method includes reaction of pentavalent phosphorous acid chloroanhydride with glycydil methacrylate at 20-50°C in presence of titanium tetrachloride as catalyst in amount of 0.02-0.05 % calculated as reagent mass.

EFFECT: one-step method for production of phosphorous and chlorine containing methacrylates with improved water resistance.

2 tbl, 7 ex

FIELD: chemistry of organophosphorus compounds.

SUBSTANCE: invention relates to compounds with the bond C-P, namely to phosphorus-boron-containing methacrylate that can be used as inhibitor of combustion of polyvinyl alcohol-base film materials. Invention describes phosphorus-boron-containing methacrylate of the following formula: wherein n = 4-8. Polyvinyl alcohol films modified with indicated phosphorus-boron-containing methacrylate shows the enhanced refractoriness, rupture strength up to 206 kgf/cm2, water absorption up to 240% and relative elongation up to 12%.

EFFECT: valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing N-phosphonomethylglycine. Method involves interaction of derivative of hexahydrotriazine of the formula (II):

wherein X represents CN, COOZ, CH2OY and others; Z and Y represent hydrogen atom and others with triacylphosphite of the formula: P(OCOR3)3 (III) wherein R3 means (C1-C18)-alkyl or aryl that can be substituted. The prepared product is hydrolyzed and (if X represents CH2OY) oxidized. The proposed method is a simple in realization, economy and provides high degree of the end product purity.

EFFECT: improved preparing method.

19 cl, 11 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to acyclic nucleoside phosphonate derivatives of the formula (1): wherein means a simple or double bond; R1 means hydrogen atom; R2 and R3 mean hydrogen atom or (C1-C7)-alkyl; R7 and R8 mean hydrogen atom or (C1-C4)-alkyl; R4 and R5 mean hydrogen atom or (C1-C4)-alkyl possibly substituted with one or more halogen atoms, or -(CH2)m-OC(=O)-R6 wherein m means a whole number from 1 to 5; R6 means (C1-C7)-alkyl or 3-6-membered heterocycle comprising 1 or 2 heteroatoms taken among the group consisting of nitrogen (N) and oxygen (O) atoms; Y means -O-, -CH(Z)-, =C(Z)-, -N(Z)- wherein Z means hydrogen atom, hydroxy-group or halogen atom, or (C1-C7)-alkyl; Q (see the claim invention); its pharmaceutically acceptable salts or stereoisomers. Also, invention proposes methods for preparing compounds of the formula (1) and their using in treatment of hepatitis B or preparing a medicinal agent designated for this aim.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

16 cl, 10 tbl, 87 ex

FIELD: chemistry of organophosphorus compounds.

SUBSTANCE: invention relates to the improved method for synthesis phosphorus-chlorine-containing methacrylates that can be used in synthesis of polymeric, among them, uncolored, optically transparent and composition materials with reduced inflammability. Invention describes a method for synthesis of phosphorus-chlorine-containing methacrylates of the general formula:

wherein R means lower alkyl, chloroalkyl, alkoxyl, phenoxyl or group of the formula:

R1 means lower alkoxyl, phenoxyl or group of the formula:

Method involves interaction of phosphoric pentavalent acid chloroanhydrides with methacrylic acid glycidyl ester at heating in the presence of hexamethylenephosphorotriamide or dimethylformamide as a catalyst wherein catalyst is taken in the amount 0.3-0.6% of reagents mass, and process is carried out at rise of temperature from 40°C to 80°C in the presence of compound chosen from the group: alkyl- or alkoxy-substituted phenols taken in the amount 0.03-0.3% of reagents mass. Method provides decreasing water absorption of (co)polymerization products of synthesized phosphorus-chlorine-containing methacrylates and reducing retention time of surface stickiness of fiber glass synthesized on their basis and at retention the level of other properties, among them transparence and colorless.

EFFECT: improved method of synthesis, improved and valuable properties of compounds.

2 tbl, 10 ex

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