The method of obtaining 5-substituted pyrrolo (2,3-)pyrimidine

 

(57) Abstract:

Offers a way to generate new 5-substituted pyrrolo (2,3-a)pyrimidine, which can be used as intermediates for obtaining pyrrolo (2,3-a)pyrimidine anticancer agents themselves or antitumor agents. The method of obtaining the above-mentioned compounds of General formula (I) where R1is hydrogen or the same or different carboxyamide group; an asterisk ( * ) marked L-configuration at the carbon atom; n=0 or 1; and aryl group which may be substituted, or salts, is that includes: (a)the interaction of 2,4-diamino-6-oxopyrimidine with guidalberto formula (II), where Y is an atom of bromine, chlorine or iodine, as defined above; and C) optional salt formation reaction of the reaction product from stage a). Described another method of obtaining the compounds of formula (I). The method is carried out in the same vessel. 2 C. and 8 C.p. f-crystals.

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This patent application is partially continuing patent application serial number 07/951515, filed September 25, 1992

The present invention relates to the field of pharmaceutical and organic chemistry, and accordingly proposed specpromtechnik products upon receipt therapeutically active antifolates based pyrrolo[2,3-d]pyrimidines.

Compounds that are known for their antifolate action, is widely recognized as chemotherapeutically agents used in the treatment of cancer. One of these agents, methotrexate, and now is widespread anti-cancer drug; have already been synthesized, tested and discussions in the chemical and medical literature, many other compounds from the family of derivatives of folic acid. Such compounds exhibit different effects on the enzymatic level. Thus, in particular, they inhibit the action of enzymes such as dihydrotetrazolo, balatonakarattya, glacialinterglacial and timedilation.

Recently opened a number of derivatives of 4-oxopyrrolo-[2,3-d] pyrimidine-L-glutamic acid, and it was shown that they with singular success can be used as antifolate drugs [see, e.g., Akimoto and others, the description of European patent publication 0434426].

5-substituted pyrrolo[2,3-d]pyrimidine compounds of the formula I

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where R is-NHC*H/COOR1/CH2CH2COOR1or or1;

each of RIis hydrogen or identical or different carboxyamide g which may be substituted, can be used for various therapeutic agents on the basis of 5-substituted pyrrolo[2,3-d]pyrimidine derivative or, when

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where each R1indicated hydrogen atom, or a salt, can be used as therapeutic agents.

In accordance with the present invention offers regiospecificity methods of obtaining 5-substituted pyrrolo[2,3-d]pyrimidine, which can be used as intermediates in obtaining, in addition to other pharmaceutically active pyrrolo[2,3-d] pyrimidine compounds or as pharmaceutically active compounds.

In addition, in accordance with the present invention serves regiospecificity way to obtain 5-substituted pyrrolo[2,3-d]pyrimidine compounds, and the specified method is carried out in the same vessel.

In accordance with the present invention offers a method of obtaining a 5-substituted pyrrolo[2,3-d]pyrimidines of the formula I

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where

each of R1hydrogen atom or these characters can be denoted by identical or different carboxylesterase group; an asterisk ( * ) marked L-configuration at uglerodsoderzhathie

a) reaction of 2,4-diamino-6-oxopyrimidine with guidalberto formula II

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where Y is an atom of bromine, chlorine or iodine, and the values of the symbols R, RIA and * are defined above, and

b) the possible reaction of the salt formation reaction product from stage a).

According to the present invention it is also proposed a method of obtaining a 5-substituted pyrrolo[2,3-d]pyrimidines of the formula I

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where the symbols R, R1n and * are defined above,

or their salts, in the exercise of which is provided

a) reaction halogenous agent with the compound of the formula III

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where the symbols R, R1n and * are defined above, and R2- Deputy of the formula IV, V or VI

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where R3-OR4where R4- oxirlarida group; OCOR5where R5- alkyl, C1-C6, phenyl, benzyl or cycloalkyl C3-C6; NR6R7where each of the symbols R6and R7independently of each other may be marked alkyl, C1-C6cycloalkyl C3-C6or together with the nitrogen atom and possibly an oxygen atom, they may form a 5 - or 6-membered saturated monocyclic group which may be substituted by one or more of the B> each or R8and R9- alkyl, C1-C4or together with the oxygen atoms they can form a 5 - or 6-membered saturated monocyclic group which may be substituted by one or two substituents selected from a class which includes hydroxyl, alkyl (C1-C4and alkoxygroup C1-C4;

b) reaction of the reaction product from step a) with 2,4-diamino-6-oxopyrimidine and

c) the possible reaction of the salt formation reaction product from step (b).

Throughout the text of this specification temperature in all cases expressed in degrees Celsius, the proportions of all materials, percentages and the like are expressed in weight units in all cases, except those that relate to solvents or their mixtures, the number of which is expressed in volumetric units.

The term "alkyl (C1-C4" used to denote a linear or branched aliphatic chains of 1 to 4 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, Deut.-butyl and tert.-butyl.

The term "alkyl (C1-C6" used to denote Akilov C2-C4plus linear and branched aliphatics is, 3-methylpentyl, 2,3-dimethylbutyl and the like.

The term "aryl" is used to denote a cyclic structure, which in formulas I, II, III and VII identified as and is used to denote a 5 - or 6-membered aromatic residues, including heterocyclic groups containing up to three heteroatoms (e.g. nitrogen, oxygen and sulfur), such as phenyl, in particular 1,4-phenylene, thienyl, pyridyl, furyl and the like. Such aryl group possibly substituted, in addition to COR-a group of one or more substituting groups selected from halogen atoms, hydroxyl, alkyl (C1-C4and alkoxygroup C1-C4. With the exception of unsubstituted 1,4-phenylene, preferably only the substitution group in the 2nd position 1st position COR.

The term "alkoxygroup C1-C4" is used to denote alkyl groups with 1 to 4 carbon atoms attached through an oxygen bridge, in particular methoxy, ethoxy-, n-propoxy-, isopropoxy and the like.

The term "halogen atoms" is used to denote the atoms of bromine, chlorine, fluorine and iodine.

The term "cycloalkyl C3-C6is used to denoted the R, cyclopentyl and cyclohexyl.

Used in this description the expression "carboxylesterase group for R1where R1cannot denote a hydrogen atom and oxirlarida group for R4" denote groups which generally are not contained in the molecules of the final therapeutic compounds, but which are intentionally introduced at a certain stage of the implementation process of synthesis to protect the group, otherwise, able to react in conducting various chemical manipulations, with subsequent removal. As compounds whose molecules contain one or more protective groups, have value primarily as a chemical intermediate products (although some blocked derivatives also exhibit biological activity), their exact structure is not critical. Numerous reactions for the formation and removal of such protective groups are described in a number of normal work, including, for example, Protective Groups in Organic Chemistry, Chapter 3 (published by Makami, Plenum Press, 1973); Greene, Protective Groups in Organic Synthesis, Chapter 2 (John Willy, 1981), Shroeder and lyubts, The Peptides, volume 1 (Academic press, 1965).

The carboxyl group can be protected in the form of ether groups to which olekuly. The class of esters suitable for use in the protection of the carboxyl group, branched covers alkalemia (C1-C6) esters, in particular tert.-butylene, and esters, substituted (I) alkoxygroup C1-C4such as methoxymethyl, 1-methoxyethyl, ethoxyethyl and the like;

(II) alkylthiophene C1-C6such as methylthiomethyl, 1-ethylthiomethyl and the like; (III) haloesters group, such as 2,2,2-trichloroethyl, 2-bromacil, 2-iodoxybenzoic and the like; (IV) from 1 to 3 phenyl groups, each of which may be unsubstituted, or one-, two - or trehzameshchenny alkilani C1-C6, alkoxygroup C1-C4, hydroxyl, halogen atoms and nitro groups, such as nitrobenzyl; or (V) aryl, such as Fenella. If more than one carboxyl group carboxylesterase groups can be both identical and different. In a preferred embodiment, such a group must be identical. Preferred blocking groups are C1-C6essential, in particular methylamine and etilefrine.

The class a preferred oxybromide groups includes the remnants of a simple ester of silylating residues include, for example, triisopropylsilane, trimethylsilylethynyl, triethylsilane and tert. butyl dimethylsilane group (see, for example, Gavin E. U., Silicon Reagemts in Organic Synthesis (Academic press, 1988).

The compound of formula I exists in tautomeric equilibrium with the corresponding 4(3H)-exocoetidae. For illustrative purposes, below is an equilibrium state pyrrolopyrimidine cyclic system and the numbering of the positions.

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For convenience 4(3H)-oxform depicted in formula I, and throughout the text of this specification used the item. However, it is obvious that these images cover the corresponding tautomeric 4-oxypora.

The terms of the proposed method require the reaction of 2,4-diamino-6-oxopyrimidine with guidalberto formula II in a solvent, taking into account the need to promote cyclization.

Used in the implementation of the proposed method of 2,4-diamino-6-oxopyrimidine source material is technically available, while the methods of obtaining guidalberto formula II, when R OR1where R1hydrogen atom or carboxylesterase group known from the literature (see, for example, 1,4-phenylene, n is 0, R is a OR1and R1- hydrogen atom. Methods of protection of carboxyl groups and obtain the compounds of formula II in which n is 1, is well known.

Another starting material for the compounds of formula II is obtained by condensation of enol ether of formula VII

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aryl group which may be substituted; R is a OR1; R1hydrogen atom or carboxylesterase group; n is 0 or 1; R3-OR4; and R4- oxirlarida group, as it is in General described in the above work McGrew, with the compound of the formula VIII

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where each of R1which may be identical or different, denotes carboxylesterase group, and when the carbon atom marked with * has the L-configuration, using conventional technologies condensation. One of the preferred ways of condensation, when R in the formula II compounds - hydrogen atom described by Taylor and others in the description to the us patent N 4686537. In another embodiment, the compound of formula II must first be freed from the protective groups, and then to carry out the condensation.

After completion of the condensation reaction, the reaction product halodrol according to known procedures (see, for example, vysheukazanuyu material of the formula II, where Y is an atom of bromine, chlorine or iodine, and the values of the symbols R1, n and * are defined above.

The class is acceptable Ganoderma agents includes, for example, elemental bromine, chlorine and iodine, N-bromo-N-chloro - and N-jodatime, N-bromo-N-chloro - and N-odftoolkit and the like.

Thus, according to this first aspect of the present invention proposes a method of obtaining 5-substituted pyrrolo[2,3-d]pyrimidines of the formula I

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where

R1any hydrogen atoms or identical or different carboxylesterase group; an asterisk ( * ) when the carbon atom denoted by L-configuration; n is 0 or 1; and aryl group which may be substituted; or their salts, in the exercise of which is provided

a) reaction of 2,4-diamino-6-oxopyrimidine with guidalberto formula II

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where Y is an atom of bromine, chlorine or iodine, and the values of the symbols R, R1, n and * are defined above, and

b) the possible reaction of the salt formation reaction product from stage a).

The above reaction is carried out in an environment acceptable solvent, which include for example alcohols C1-C4, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, N-methylpyrrolidinone, acetonitrile and water.

The time required for completion of this reaction, can easily determine any ordinary person skilled in the art. The completion of this reaction can be determined by chromatographic analysis, for example, thin-layer chromatographic analysis or chromatographic analysis under high pressure.

The temperature generated at this stage, should be sufficient to ensure completion of this reaction. Usually the temperature is in the range from about 25 to 100opreferred, whereas the temperature in the range of from about 70 to 90oC is particularly preferred.

As for other things, the compounds of formula I, obtained by carrying out the proposed method can be easily selected according to conventional procedures, and they require no further purification for subsequent use as intermediates.

In accordance with another aspect of the present invention proposes a method of obtaining 5-substituted pyrrolo[2,3-d] pyrimidines of the formula I, in the exercise of which is provided

a) reaction halogenous agent with the compound of the formula III

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where the values of R3-OR4where R4- oxirlarida group; OCOR5where R5- alkyl, C1-C6, phenyl, benzyl or cycloalkyl C3-C6; NR6R7where each R6and R7independently - alkyl (C1-C6cycloalkyl C3-C6or together with the nitrogen atom and possibly an oxygen atom form a 5 - or 6-membered saturated monocyclic group which may be substituted by one or two substituents selected from class, which covers alkyl, C1-C4and alkyloxyalkyl C1-C4; each of R8and R9independently - alkyl (C1-C4or together with the oxygen atom, they form a 5 - or 6-membered saturated monocyclic radical, which is possibly substituted by one or two substituents selected from a class which includes hydroxyl, alkyl (C1-C4and alkoxygroup;

b) reaction of the reaction product from stage a) of 2,4-diamino-6-oxopyrimidine and

c) the possible reaction of the salt formation reaction product from step (b).

In the technique known procedures to obtain the aldehyde of formula III [where R2Deputy formula IV] (see, for example, Taylor and others J. Med. Chem., 55, 3222 - 3227, 1990)� 1, well-known, and R2- Deputy of the formula IV. The aldehyde of formula III can be further modified with getting enamines, enol ethers, enol ethers [where R2Deputy formula V] and acetals [where R2Deputy formula VI] in accordance with methods which are well known in organic chemistry. Thus, the starting material according to this aspect of the present invention includes compounds of formula III in the form of aldehydes, enol ethers, enol ethers, enamines and acetals.

The preferred source compounds of formula III are enol ethers of the formula III, where R is a OR1, R1- carboxylesterase group; R2- Deputy of the formula V, R3-OR4and R4-oxirlarida group (especially methyl).

Alternatively simple enol ether as a starting material of formula III can be obtained by condensation of the above-mentioned preferred simple enol ether of formula III with the compound of the formula VIII according to the above. Before the condensation reaction of compounds of formula III, where R is a OR1and R1- carboxylesterase group, it is preferable to remove b is evershine this process.

After you select the source of the compounds of formula III and its introduction in the appropriate solvent first by reaction of this compound with palodiruyut agent, followed by reaction of the reaction product from the first stage with 2,4-diamino-6-oxopyrimidine. The possible reaction of the salt formation reaction product of this first stage according to conventional procedures.

Appropriate and preferred solvents, temperature, duration of reaction and f allocation for the implementation of this method is identical to that described above for the cyclization of compounds of formula II to obtain compounds of formula I.

During the process of producing compounds of the formula I according to the proposed method each stage can be managed independently, and the reaction product from each stage is isolated and purified, or, what is preferable? leave at the place of receipt in the process, when each of the stages of the method sequentially carried out in the same reaction vessel.

The compounds of formula I, where R is a OR1and R1hydrogen atom or carboxylesterase group, or where R1identical or different carboxylesterase group, made the Eski active pyrrolo [2,3-d] pyrimidine antifolate agents.

When R OR1and R1hydrogen atom or after the preferred stage of removal of the protective groups, when R1- carboxylesterase group, you must first carry out the condensation reaction of compounds of formula I with a compound of the above formula VIII. In that case, if after condensation of R1- hydrogen atom, the product is obtained in final form, ready for pharmaceutical applications. In that case, if R1- carboxylesterase group, such blocking group can be removed after getting the product, which is a therapeutically active antifolate.

Similarly, in the case where the compound of the formula I and R1hydrogen atom, it is therapeutically active as the reaction product of the implementation of the methods of the present invention. Incidentally, when R1- carboxylesterase group, the specified connection should also be selected according to standard methods, getting a therapeutically active agent.

After receiving therapeutically active pyrrolo [2,3-d] pyrimidine of antifolates conversion into the salt form allows you to get in the pharmaceutical more acceptable connection.

Specific AC is nicely in any case.

Preparative example 1.

Methyl-4(4-trimethylsilyloxy-3-butenyl)-benzoate

In a mixture of 3.65 g (about 17.7 mmol) of 4-(4-carbomethoxybiphenyl)-butanal with 3,43 g (of 21.2 mmol) of 1,1,1,3,3,3-hexamethyldisilazane in 177 ml of methylene chloride under nitrogen atmosphere at a temperature of -15oC for 2 min was added to 3.89 g (of 19.5 mmol) trimethylsilylmethyl. The mixture was stirred for 10 min, and then allowed to warm to room temperature. After 2 h, the excess reagent "repaid" by adding 100 ml of water. The layers were separated and the organic phase is dried over sodium sulfate. Vacuum concentrating the solvent was removed, having 5.0 g methyl-4-(4-trimethylsilyloxy-3-butenyl)-benzoate with achieving 100% yield of product. Thin-layer chromatographic analysis (THA) [silica; hexane/ethyl acetate in the ratio 3 : 2] showed that the above product was almost pure, and its boiling temperature at a residual pressure of 0.12 Torr was 170oC.

1H-NMR spectrum (CDCl3, ) : 0,15 (C., 9H), 2,41 (K., 7.2 Hz, 2H), 2,69 (m, 2H), 3,89 (C., 3H), 4,47 (K., 7.2 Hz, 1H), x 6.15 (m, 1H), 7,25 (D. , 8,2 Hz, 2H), 7,93 (D., 8,2 Hz, 2H);

13C NMR spectrum (CDCl3, ) : 0,60, 25,0, 35,9, 51,8, 109,8, 128,4, 128,5, 129,6, 138,6, 148,0, 167,1; FDMS: 279 (90), 278 (M+, 100%), 280, 251, 226. Tonko sample.

The data of elementary analysis for C15H22O3Si

Calculated: C - 64,71% H - of 7.96%

Found: C - 64,90% H - 8,05%

Preparative example 2

2-bromo-4-(4-carbomethoxybiphenyl) butanal

To 4,46 g (16 mmol) of methyl-4-(4-trimethylsilyloxy-3-butenyl)-benzoate, obtained in experiment example a 1 in 26 ml of carbon tetrachloride at -20oC carefully added within 4 h of 2.56 g (16 mmol) of bromine in 16 ml of carbon tetrachloride. The mixture then allowed to warm to room temperature and subsequent decantation with a small amount of insoluble material. In vacuum using a rotary evaporator removed the solvent, having 4,60 g of 2-bromo-4-(4-carbomethoxybiphenyl)-butanal. Chromatographic purification [silica; hexane/ethyl acetate in a ratio of 7:3] of the above product was allowed to obtain 4.0 g of the substance to achieve the output of 87.8%.

1H-NMR spectrum (CDCl3, ) : 2,24 (m, 1H), a 2.36 (m, 1H), 2,81 (m , 1H), 2.91 in (m, 1H), 3,90 (C., 3H), of 4.16 (m, 1H), 7,27 (D., 8,2 Hz, 2H), 7,97 (D., 8,2 Hz, 2H), 9,46 (D., and 2.1 Hz, 1H);

13C NMR spectrum (CDCl3, ) : 32,5, 32,7, 51,7, 54,3, 128,3, 128,4, 129,8, 145,0, 166,6, 192,0.

Example 3

-4-(2-[2-amino-4-oxo-3,7-dihydropyrrolo (2,3-d) pyrimidine-5-yl] - ethyl)-benzoic acid, temperature 80oC for 5 min was added 3,82 g (a 13.4 mmol) of 2-bromo-4-(4-carbomethoxybiphenyl)-butanes obtained in the experiment of example getting 2 in 7 ml of methanol. The mixture is passed at a temperature of 80oC for 5 min, cooled to room temperature and mixed for 30 minutes Then the mixture was filtered, washed with water and dried for 18 hours at a temperature of 50oC and a residual pressure of 10 Torr, receiving of 3.32 g of methyl ester of 4-(2-[2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d] pyrimidine-5-yl] ethyl) -benzoic acid (melting point of over 220oC) achievement of output product 79.4 per cent. The remaining filtrate is cooled to a temperature of 5oC and was filtered, optionally having 0,069 g of the above product, allowing the product will be brought to 81%.

1H-NMR spectrogram (D-d6, ) : 2,80 (m, 2H), 2,93 (m, 2H), 3,78 (c. , 3H), 5,97 (S., 2H), 6,26 (D., 2.0 Hz, 1H), 7,28 (D., 8,2 Hz, 2H), 7,80 (D. , 8,2 Hz, 2H), 10,12 (S., 1H), of 10.58 (SD, 1H); FDMS 312 (M+); the data of elementary analysis for C16H16N4O3:

Calculated: C is 61.53% H - 5,16 N - 17,94%

Found: C - 61,79% H - 5,33 N - 17,66%.

Preparative example 4

-4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo(2,3-d) pyrimidine-5-yl)-ethyl]-benzoic acid

The mixture 3,17 (10,15 mmol) metrov is eriment of example 3, in 30 ml of 1N. an aqueous solution of hydrate of sodium oxide and 5 ml of methanol was mixed for 20 h at room temperature. Added 5 ml of tetrahydrofuran and the final mixture was mixed for 4 h, followed by neutralization with 30 ml of 1N. an aqueous solution of hydrochloric acid. Precipitated precipitated material was separated by filtration, washed with 20 ml water and dried in a vacuum drying Cabinet at a temperature of 50oC, resulting in a received 2.65 g of the above product, achieving 87% yield.

1H-NMR spectrogram (D-d6, ); : of 2.45 (m, 2H), 2.91 in (m, 2H), 5,99 (S. , 2H), 6,27 (D., 2.0 Hz, 1H), 7,27 (D., 8,2 Hz, 2H), 7,79 (D., 8,2 Hz, 2H), 10,14 (S., 1H), 10,59 (D., 2.0 Hz, 1H), 13,2 (Shir.S., 1H).

Preparative example 5

Dimethyl ether N-[4-{2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo (2,3-d) pyrimidine-5-yl)-ethyl}-benzoyl]-glutamic acid.

To 2.00 g (6,74 mmol (4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo(2,3-d)pyrimidine-5-yl) -ethyl] -benzoic acid obtained in the experiment of example 4, in 23 ml of dimethylformamide in a stream of nitrogen was added 1.40 g (to 13.8 mmol) N-methylmorpholine and 1,17 g (6,70 mmol) 4-chloro-2,6-dimethoxytoluene. Behind the formation of this activitiesthese of ester followed by results of the liquid chromatography analysis is methylmorpholine followed by the addition of 1.56 (7,37 mmol) of the dimethyl ester hydrochloride L-glutamic acid. After 30 min ghud-analysis showed almost complete consumption activitiesthese ether and the formation of dimethyl ether N-[4-{2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo (2,3-d) pyrimidine-5-yl)-ethyl}-benzoyl]-glutamic acid. The reaction mixture was filtered and the above product was concentrated, and then purified by chromatographic treatment on silica, elwira mixture of methanol with methylene chloride in a ratio of 1:4. Collected pure fractions, receiving of 1.30 g of the above product with the achievement of its output is 43%.

1H-NMR spectrogram (D-d6, ) : a 2.01 (m, 2H), 2.40 a (t, 7.4 Hz, 2H), 2,80 (m, 2H), 2,92 (m, 2H), 3,53 (C., 3H), 3,59 (C., 3H), and 4.40 (m, 1H), 5,99. (S., 2H), 6,26 (D., 1.9 Hz, 1H), 7.23 percent (doctor, 8,2 Hz, 2H), 7,73 (D., 8,2 Hz, 2H), 8,62 (D., 7.5 Hz, 1H), 10,15 (S., 1H), 10,57 (D., 1.9 Hz, 1H).

Preparative example 6

-N-[4-{ 2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo (2,3-d) pyrimidine-5-yl) ethyl}-benzoyl]-glutamic acid

A mixture of 0.50 g (1.1 mmol) of dimethyl ether N-[4-{2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo(2,3-d) pyrimidine-5-yl)ethyl} -benzoyl] -glutamic acid obtained in the experiment of example, get 5, with 3.3 ml of 2n. an aqueous solution of hydrate of sodium oxide was stirred at room temperature for 48 h and neutralized to pH equal to 5, add a 6th product, achieving 59% yield.

Preparative example 7

-1-methoxy-4-(4-carboxymethyl)-1-butene

To 3.77 g (11 mmol) of ethoxymethylenemalononitrile in 10 ml of toluene at a temperature of 0oC in a stream of nitrogen for 20 min was added 11 ml (11 mmol) of 1M solution of tert.butoxide potassium in tetrahydrofuran. The resulting solution was stirred for 10 min and then for 15 min was added 1.92 g (10 mmol) 3-(4 - carboxymethyl)-propanol in 10 ml of toluene. After stirring the mixture for 20 minutes was added 40 ml of ethyl ether. The formed precipitate was filtered by passing through diatomaceous earth, collected, washed with 20 ml water, 20 ml of saturated sodium chloride solution and dried using a mixture of sodium sulfate with a saturated solution of sodium chloride in the ratio of 9: 1. In the vacuum concentration of the filtered solution and trituration of the precipitate in hexane got 1,72 g 1-methoxy-4-(4-carboxymethyl)-1-butene. Upon completion of the chromatographic treatment of the above product (silica gel; a mixture of hexane with ethyl acetate in the ratio 8: 2) received 1.0 g of a mixture of geometrical isomers of [Z/E - 6:4] with the achievement of the overall 45% yield of product having a boiling range 140oC under a residual pressure of 0.07 Torr.


13C-NMR spectrum (CDCl3, ) : 25,2, 29,3, 36,0, 37,4, 51,9, 56,0, 59,5, 101,8, 101,9, 105,5, 127,9, 128,0, 128,5, 128,6, 129,6, 129,7, 146,9, 147,5, 147,9, 148,0, 167,1, 167,2.

IR spectrum (CHCl3): 3025, 2954, 1716, 1656, 1610, 1437, 1284, 1112 cm-1; mass spectrum (FD): m/z 220 (M+).

Example 8

Methyl ester of 4-(2-[2-amino-4(1H)-oxo-4,7-dihydropyrrolo (2,3-d) pyrimidine-5-yl]-ethyl)-benzoic acid

To 1.10 g (5.0 mmol) of 1-methoxy-4-(4-carboxymethyl)-1-butene obtained in the experiment of example, receiving 7, in 10 ml of acetonitrile was added 10 ml of water. The resulting mixture is cooled to a temperature of 5oC and added it to 0.80 g (1.0 EQ.) bromine. Added to 0.63 g (5.0 mmol) of 2,4-diamino-6-oxopyrimidine and the mixture was stirred with heating to a temperature of 80oC. after 40 min the mixture was cooled to room temperature and added in 20 ml of water. The pH of the resulting slurry was brought to 6 by addition of 5N. solution of hydrate of sodium oxide. The precipitation was collected by filtration, washed with water and dried at a temperature of 50oC and a residual pressure of 10 Torr is R 4-(2-[2-amino-4(1H)-oxo-4,7-dihydropyrrolo (2,3-d) pyrimidine-5-yl]-ethyl)-benzoyl-L-glutamic acid

To 300 mg (0,766 mmol) diethyl ether N-4-(1-methoxy-1 - butene-4-yl)-benzoyl-L-glutamic acid, 3.0 ml of acetonitrile and 3.0 ml of water, which was stirred at room temperature, was added 122 mg (0,766 mmol) of bromine in 1 ml of acetonitrile. In the prepared solution was added 188 mg (2.3 mmol) of sodium acetate and 0.97 mg (0.77 mmol) of 2,4-diamino-6-oxopyrimidine and the final mixture is passed at a temperature of 60oC for 18 h, cooled, and then concentrated in vacuum. The obtained residue was washed with 2 portions of 5 ml of water and decantation of the solution. Added 5 ml of ethanol and 440 mg (2.3 mmol) of the monohydrate of p-toluenesulfonic acid. After boiling under reflux for 20 min the mixture was cooled to room temperature and was filtered. The precipitate was washed with 2 portions of 5 ml of ethanol and dried, obtaining p-toluensulfonate salt compounds specified in the header.

The present invention is described in detail, including the preferred options for its implementation. However, it should be borne in mind that the study of the above description, any person skilled in the art may make variations and modifications and/or improvements without departing from the scope and essence of the present from the x pyrrolo(2,3-d)pyrimidines of the formula I

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where R = -NHC*H(COOR1)CH2CH2COOR1or or1;

R1is hydrogen or the same or different carboxyamide group;

an asterisk ( * ) marked h-configuration at the carbon atom;

n = 0 or 1;

aryl group which may be substituted,

or their salts, characterized in that it includes a) the interaction of 2,4-diamino-6-oxopyrimidine with guidalberto formula II

< / BR>
where Y is an atom of bromine, chlorine or iodine,

R, R1, n and * are defined above,

in) optional salt formation reaction of the reaction product from stage a).

2. The method according to p. 1, characterized in that R = OR1, R1is hydrogen or carboxyamide group, n = 0, 1,4-phenylene.

3. The method according to p. 2, wherein Y is a chlorine atom or bromine.

4. The method according to p. 1, characterized in that R represents a fragment of NHC*H(COOR1)CH2CH2COOR1, R1is hydrogen or the same or different carboxyamide group, n = 0, 1,4-phenylene.

5. The method according to p. 4, wherein Y is a chlorine atom or bromine.

6. The method of obtaining 5-substituted pyrrolo(2,3-d)pyrimidines of the formula I

< / BR>
where R is NHC*H(COOR1)CH2CH2COOR1
n = 0 or 1;

aryl group which may be substituted,

or their salts, characterized in that it includes a) interaction halogenous agent with the compound of the formula III

R2-(CH2)n-CH2-A-COR,

where R, R1, n and * are defined above, and R2Deputy formula IV

R3-CH=Ch-CH2,

where R3-OR4,

R4- hidroxizina group; OCOR5where R5- alkyl(C1- C6), phenyl, benzyl or cycloalkyl C3- C6, NR6R7where R6and R7independently represent alkyl, C1- C6cycloalkyl C3- C6or together with the nitrogen atom, optionally with an oxygen atom form a 5 - or 6-membered saturated monocyclic radical, which is optionally substituted by one or two substituents selected from the group consisting of (C1- C4)alkyl and (C1- C4)alkoxy;

C) interaction of the reaction product from step a) with 2,4-diamino-6-oxopyrimidine and optional salt formation reaction of the reaction product from step C).

7. The method according to p. 6, characterized in that R = OR1, R1is hydrogen or carboxyamide group; R2- semester CLASS="ptx2">

8. The method according to p. 7, wherein the halogenation agent is a bromine or chlorine.

9. The method according to p. 6, characterized in that R represents a fragment of NHC*H(COOR1)CH2CH2COOR1each R1is hydrogen or the same or different carboxyamide group; R2- Deputy of the formula (IV) R3-CH=CH-CH2; R3= OR4, R4- hidroxizina group; n = 0 and 1,4 phenylene.

10. The method according to p. 9, wherein the halogenation agent is a bromine or chlorine.

Priority points:

25.09.92 - PP.1 to 5, except for Y - iodine;

24.05.93 - PP.6 - 10.

 

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