RU2814735C1 - METHOD OF PRODUCING SUBSTITUTED PYRIDO[3',2':4,5]THIENO[3,2-d]PYRIMIDINE-2,4(1H,3H)-DIONES - Google Patents

Abstract

FIELD: chemistry; pharmacology.

SUBSTANCE: invention relates to fine organic synthesis and pharmacology, specifically to a method of producing pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones, of interest as intermediate antimicrobial compounds and agents with potential anticancer action. Method of producing pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones of general formula 1 based on use of 3-aminothieno[2,3-b]pyridine-2-carboxamides as starting compounds and is characterized by that 3-aminothieno[2,3-b]pyridine-2-carboxamides are reacted with 1,1'-carbonyldiimidazole in boiling dioxane for 3 hours.

formula 1,

where R=R²=CH₃, R¹=H, R=R¹=R²=CH₃ or R+R¹=(CH₂)₃, R²=2-furyl.

EFFECT: providing a method of producing end products using non-toxic reagents while maintaining synthesis efficiency.

1 cl, 3 ex

Description

The invention relates to a method for producing pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones of general formula 1 ,

where R = R ² = CH ₃ , R ¹ = H, R = R ¹ = R ² = CH ₃ , or R+R ¹ = (CH ₂ ) ₃ , R ² = 2-furyl, of interest as antimicrobial agents [ Paronikyan, E. G., Dashyan, Sh. Sh., Minasyan, N. S., Stepanyan, G. M., Babaev, E. V. Synthesis of 10-alkylsulfanyl-substituted derivatives of pyrano-, cyclohexano- and cyclopentanoannelated pyrido[4',3':4,5]thieno[3,2-d]pyrimidines // Chemistry of heterocyclic compounds. 2016. T. 52. No. 5. P. 337-345], inhibitors of the release of tumor necrosis factor TNFa [Reichelt Claudia; Ludwig Alexander; Schulze Alexander; Daghish Mohammed; Leistner Siegfried. Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones and -(3H)-ones, substituted thieno[2,3-d: 4,5-d']dipyrimidine-2,4(1H,3H)-diones and -4(3H)-ones, substituted pyrido[3',2':4,5]furo[3,2-d]pyrimidine -2,4(1H,3H)-diones and -4(3H). Patent WO2006010568 (A2), 2006-02-02, https://ru.espacenet.com/publicationDetails/biblio?FT=D&date=20060202&DB=&locale=ru_RU&CC=WO&NR=2006010568A2&KC=A2&ND=4], potential anti-cancer agents [Mohi El-Deen, EM, Anwar, MM, El-Gwaad, AAA, Karam, EA, El-Ashrey, MK, & Kassab, RR Novel Pyridothienopyrimidine Derivatives: Design, Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents // Molecules, 2022 , 27(3), 803. https://doi.org/10.3390/molecules27030803; Naguib, BH, El-Nassan, HB, & Abdelghany, TM Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors // J. Enzyme Inhib. Med. Chem., 2017, 32(1), 457–467. https://doi.org/10.1080/14756366.2016.1261130].

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of ethyl esters of 3-aminothieno[2,3-b]pyridine- 2-carboxylic acids with chlorosulfonylisocyanate in an argon atmosphere in boiling dichloromethane [Shuttleworth Stephen Joseph, Silva Franck Alexandre, Cecil Alexander Richard Liam, Gatland Alice Elizabeth, Finnemore Daniel John, Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors, Patent WO2017/29519, 2017 ,

https://worldwide.espacenet.com/patent/search/family/054258850/publication/WO2017029519A1?q=pn%3DWO2017029519; Shuttleworth Stephen Joseph, Silva Franck Alexandre, Cecil Alexander Richard Liam, Alexander Rikki Peter, Gatland Alice Elizabeth, Finnemore Daniel John. Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors, Patent WO2017029521A1·2017-02-23 https://worldwide.espacenet.com/patent/search/family/054258853/publication/WO2017029521A1?q=pn%3DWO2017029521; Menzer, William M.; Knobloch, Gunnar; Lieleg, Corinna; Schomburg, Adrian; Ladurner, Andreas; Sennhenn, Peter. ALC1 inhibitors and synergy with PARPI. Patent WO2022117782A1,·2022-06-09, https://worldwide.espacenet.com/patent/search/family/073792931/publication/WO2022117782A1?q=pn%3DWO2022117782]:

The disadvantage of this method is the need to work with chlorosulfonyl isocyanate - an aggressive and toxic reagent that reacts violently with water, often containing an admixture of toxic cyanogen chloride [Graf, R. Reactions with N-Carbonylsulfamoyl Chloride // Angew. Chem., Int. Ed. – 1968. Vol. 7. N 3. P. 172; Graf, R. Chlorousulfonyl isocyanate, Org. Synth., Coll. Vol. 5, 226 (1973), DOI: 10.15227/orgsyn.046.0023]. Another disadvantage is the low (up to 45%) yields of target products.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by fusing 3-aminothieno[2,3-b]pyridine-2- carboxamides with urea at 180–190 °C for 0.5–2.5 h [Mohi El-Deen, E. M., Anwar, M. M., El-Gwaad, A. A. A., Karam, E. A., El-Ashrey, M. K., & Kassab, R. R. Novel Pyridothienopyrimidine Derivatives: Design, Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents // Molecules, 2022, 27(3), paper 803. https://doi.org/10.3390/molecules27030803; Shuttleworth, Stephen Joseph; Cecil, Alexander Richard Liam; Hill, Thomas James; Silva, Franck Alexandre. Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors. Patent WO2011021038A1/ 2011-02-24, https://worldwide.espacenet.com/patent/search/family/042756474/publication/WO2011021038A1?q=pn%3DWO2011021038; Rateb N. M. Convenient synthesis and antimicrobial evaluation of multicyclic thienopyridines //Phosphorus, Sulfur, and Silicon and the Related Elements. 2008. Vol. 182. No. 10. pp. 2393-2407. https://doi.org/10.1080/10426500701501276]:

The disadvantage of this method is the harsh synthesis conditions (180 °C) and, as a result, the limited applicability of the above approach to a certain range of stable substrates, the release of toxic gaseous products (ammonia), and often low product yields.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of 3-aminothieno[2,3-b]pyridine-2- carboxamides with urea in a high-boiling solvent (decalin) when heated for 4 hours [Ghattas, A. B., Khodairy, A., Abd-Rahman, M. A., Younes, S. Synthesis of some new pyrazolopyridines, pyrazolothienopyridines, pyrazolopyridothienopyrimidines and pyrazolopyridothienothriazines // Phosphorus, Sulfur, and Silicon and the Related Elements, 2003, 178(8), pp 1781-1794. https://doi.org/10.1080/10426500307843; Bakhite E. A., Abdel-Rahman A. E., Al-Taifi E. A. Synthesis and antimicrobial activity of some new pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives // Phosphorus, Sulfur, and Silicon. 2004. Vol. 179. No. 3. pp. 513-520. https://doi.org/10.1080/10426500490422155]:

The disadvantages of this method are the harsh synthesis conditions and the limited applicability of the above approach to a certain range of stable substrates, as well as the release of toxic gaseous products (ammonia).

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of 3-aminothieno[2,3-b]pyridine-2 esters -carboxylic acids with triphosgene and triethylamine in dichloromethane at -78 °C, followed by treatment with a solution of the primary amine in THF in the presence of DMAP for 25 hours at room temperature and purification of the product by reverse-phase chromatography [Hamamura Kazumasa; Oda Tsuneo; Kaku Tomohiro; Suzaki Tomohiko. Fused pyrimidine derivative and uses thereof. Patent EP1847541A1, 2007-10-24, https://worldwide.espacenet.com/patent/search/family/036777371/publication/EP1847541A1?q=pn%3DEP1847541]:

The disadvantages of this method are the need to work with extremely toxic triphosgene, the two-stage and duration of the process, and the need to use an expensive reverse-phase HPLC method to purify the product.

There is a known method for the preparation of substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione by the reaction of substituted 3-aminothieno[2,3-b]pyridine- 2-carboxamide with triphosgene in THF at room temperature [Abulwerdi, F. A., Shortridge, M. D., Sztuba-Solinska, J., Wilson, R., Le Grice, S. F., Varani, G., & Schneekloth, J. S., Jr. Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA // Journal of medicinal chemistry, 2016, 59(24), 11148–11160. https://doi.org/10.1021/acs.jmedchem.6b01450]:

The disadvantage of this method is the need to work with extremely toxic triphosgene.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of substituted ethyl esters 3-(phenyloxycarbonylamino)thieno[2,3- b]pyridine-2-carboxylic acids with primary amines for 6 hours in boiling ethanol [V. V. Dabaeva, M. R. Bagdasaryan, E. G. Paronikyan, Sh. Sh. Dashyan. Synthesis of New Fused Pirano[4,3-b]pyridine Derivatives // Russ. J.Gen. Chem. 2019, Vol. 89, pp. 1177–1182. https://doi.org/10.1134/S1070363219060124; V. V. Dabayeva, M. R. Baghdasaryan, E. G. Paronikyan, I. M. Barkhudaryants, H. A. Panosyan, H. M. Stepanyan, Sh. Sh. Dashyan, Synthesis of new fused pyrano[4,3-b]pyridines from ethyl 3-aminopyrano[4,3-b]thieno[3,2-e]pyridine-2-carboxylate // Russ. J. Org. Chem. 2023, Vol. 59, pp. 78–84. https://doi.org/10.1134/S1070428023010086]:

The disadvantages of this method are the two-stage synthesis and the need to preliminary obtain substituted ethyl esters of 3-(phenyloxycarbonylamino)thieno[2,3-b]pyridine-2-carboxylic acids, the duration of the synthesis, as well as the need to work with toxic phenylchloroformate.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by boiling substituted 3-aminothieno[2,3-b]pyridine-2 -carboxamides in diethyl carbonate for 4-5 hours [Othman, I. M., Gad-Elkareem, M. A., Snoussi, M., Aouadi, K., Kadri, A. Novel fused pyridine derivatives containing pyrimidine moiety as prospective tyrosyl-tRNA synthetase inhibitors: Design, synthesis, pharmacokinetics and molecular docking studies // Journal of Molecular Structure, 2020, 1219, paper 128651. https://www.sciencedirect.com/science/article/abs/pii/S0022286020309765; Sanad S. M. H., Ahmed A. A. M., Mekky A. E. M. Efficient synthesis and molecular docking of novel antibacterial pyrimidines and their related fused heterocyclic derivatives // Journal of Heterocyclic Chemistry. 2020. Vol. 57. No. 2. pp. 590-605. https://doi.org/10.1002/jhet.3789]:

The disadvantages of this method are the harsh conditions and duration of synthesis due to the relatively low activity of diethyl carbonate in this reaction, as well as the use of a large excess of diethyl carbonate as a solvent and reagent.

A known method for producing substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione by reaction of substituted 2-mercaptonicotinonitrile with ethyl-N-(chloroacetyl)carbamate in the presence of triethylamine in butoxyethoxyethanol at 80–180 °C for 1-1.5 hours [Reichelt, Claudia; Ludwig, Alexander; Schulze, Alexander; Daghish, Mohammed; Leistner, Siegfried. Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones and -4(3H)-ones, substituted thieno[2,3-d :4,5-d']dipyrimidine-2,4(1H,3H)-diones and -4(3H)-ones, substituted pyrido[3',2':4,5]furo[3,2-d] pyrimidine-2,4(1H,3H)-diones and -4(3H). Patent WO2006010568A2, 2006-02-02 https://worldwide.espacenet.com/patent/search/family/035385316/publication/WO2006010568A2?q=pn%3DWO2006010568]:

The disadvantages of this method are the harsh conditions and duration of synthesis, the use of an exotic high-boiling solvent (butoxyethoxyethanol), and the need to first obtain ethyl-N-(chloroacetyl)carbamate.

There is a known method for the preparation of substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of substituted 3-cyanopyridine-2(1H)-thiones with ethyl -N-(chloroacetyl)carbamate in the presence of sodium ethoxide in an ethanol–DMF mixture or absolute ethanol at boiling [Shestopalov, AM, Nikishin, KG, Gromova, AV et al . One-pot synthesis of 4,6-diaryl-3-cyanopyridine-2(1 H )-thiones and their transformation to substituted thieno[2,3- b ;4,5- b ]dipyridines and pyrido[3,2" :4,5]thieno[3,2- d ]pyrimidines // Russ. Chem. Bull. 2003. Vol. 52, pp. 2203–2206 (2003). https://doi.org/10.1023/B:RUCB.0000011879.89900.1f; AA Shestopalov, AV Gromova, LA Rodinovskaya, KG Nikishin, VP Litvinov, AM Shestopalov. One-step synthesis of 3-cyano-6-methyl-4-thienyl-5,6,7,8-tetrahydro[1,6]naphthyridine-2(1H)-thiones and annelated heterocyclic systems on their basis // Russ. Chem. Bull. 2004, Vol. 53, pp. 2353–2354. https://doi.org/10.1007/s11172-005-0133-7]:

The disadvantage of this method is the harsh conditions and duration of synthesis, as well as the need to first obtain ethyl-N-(chloroacetyl)carbamate.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of 3-amino-N'-cyanothieno[2,3-b ]pyridine-2-carboximimides with sodium nitrite in the presence of sulfuric acid at 0 °C [Artemov, V.A., Rodinovskaya, L.A., Shestopalov, A.M., Litvinov, V.P. Regioselective synthesis of substituted thieno[2,3-b]pyrimidines and pyrido[3′,2′:4,5]thienopyrimidines and their [3,2-d]selenopheno analogs from 3-cyanopyridine-2(1H)-thiones, 3-cyano-pyridine-2(1H)-selenones, and N-cyanochloracetamidine // Chem Heterocycl Compd. 1994, Vol. 30, 110–120. https://doi.org/10.1007/BF01164746]:

The disadvantage of this method is the need for preliminary synthesis of 3-amino-N'-cyanothieno[2,3-b]pyridine-2-carboximidamides, and the inaccessibility of the starting N-cyanochloroacetamidine required for this synthesis.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of 3-aminothieno[2,3-b]pyridine-ethyl ester 2-carboxylic acid with organic isocyanates in a mixture of tert-butanol and DMF in the presence of 1 eq. potassium tert-butoxide by boiling for 4 hours [Roshani, M., Davoodnia, A., Hedayat, M. S., & Bakavoli, M. A convenient synthesis of new pyridothienopyrimidin-4 (3H) ones and pyridothienopyrimidin-2,4-( 1H,3H)-diones // Phosphorus, Sulfur, and Silicon, 2004, 179(6), 1153-1157. https://doi.org/10.1080/10426500490459759]:

The disadvantage of this method is the duration and harsh conditions of synthesis, as well as the inaccessibility and toxicity of the isocyanates used.

There is a known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by cyclization of 3-(ethoxycarbonylamino)thieno[2,3-b] ethyl esters ]pyridine-2-carboxylic acids under the influence of excess amine during boiling [G. Wagner; N. Bohm. Synthese von 3-alkyl-2-amino-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-onen aus 3-Ethoxycarbonylamino-thieno[2,3-b]pyridin- 2-carbonsäurethylestem and -2-carbonsaureamiden // Die Pharmazie, 1993, 48(2), S. 95-99]:

The disadvantages of this method are its two-stage nature, the need to first obtain an intermediate urethane and the associated need to work with toxic chloroethyl formate, the duration and harsh conditions of the synthesis, and the use of excess chloroethyl formate and amine.

A known method for the preparation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by cyclization of 3-(ethoxycarbonylamino)thieno[2,3-b]pyridine -2-carboxamides in pyridine at boiling [G. Wagner; N. Bohm. Synthese von 3-alkyl-2-amino-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-onen aus 3-Ethoxycarbonylamino-thieno[2,3-b]pyridin- 2-carbonsäurethylestem and -2-carbonsaureamiden // Die Pharmazie, 1993, 48(2), S. 95-99]:

The disadvantage of this method is the need to first obtain an intermediate urethane and the associated need to work with toxic chloroethyl formate, as well as the duration and harsh conditions of the synthesis.

The closest analogue (prototype) to the proposed technical solution is a method for producing substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones by the reaction of substituted 3- aminothieno[2,3-b]pyridine-2-carboxamides with diphosgene (trichloromethylchloroformate) in dioxane at boiling for 3 hours [Reichelt, Claudia; Ludwig, Alexander; Schulze, Alexander; Daghish, Mohammed; Leistner, Siegfried; Kroedel, Andreas; Heinicke, Jochen. Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2': 4,5]furo[3,2-d]pyrimidines used as inhibitors of the pde -4 and/or the release of TNF$g(a), WO2006010567A1·2006-02-02, https://worldwide.espacenet.com/patent/search/family/035169819/publication/WO2006010567A1?q=pn%3DWO2006010567 ; Reichelt, Claudia; Ludwig, Alexander; Schulze, Alexander; Daghish, Mohammed; Leistner, Siegfried. Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones and -4(3H)-ones, substituted thieno[2,3-d :4,5-d']dipyrimidine-2,4(1H,3H)-diones and -4(3H)-ones, substituted pyrido[3',2':4,5]furo[3,2-d] pyrimidine-2,4(1H,3H)-diones and -4(3H). Patent WO2006010568A2, 2006-02-02 https://worldwide.espacenet.com/patent/search/family/035385316/publication/WO2006010568A2?q=pn%3DWO2006010568; Redinbo, Matthew R.; Jin, Jian; James, Lindsey; Pellock, Sam; Ariyarathna, Ranathunga Arachchillage Yamuna; Frye, Stephen. Inhibitors of microbial beta-glucuronidase enzymes and uses thereof. Patent WO2018017874A1, 2018-01-25, https://worldwide.espacenet.com/patent/search/family/060996088/publication/WO2018017874A1?q=pn%3DWO2018017874; Redinbo, Matthew; Bhatt, Aadra. Inhibitors of microbial beta-glucuronidase enzymes and uses thereof. Patent WO2018142365A1, 2018-08-09, https://worldwide.espacenet.com/patent/search/family/063040309/publication/WO2018142365A1?q=pn%3DWO2018142365]:

The advantages of this method are usually high yields of target products (52-96%), atom-saving synthesis, availability of starting reagents, and one-stage process.

The disadvantages of the prototype are the need to work with very toxic diphosgene (phosgene dimer) - a synthetic equivalent of the chemical warfare agent phosgene COCl ₂ .

The objective of the invention is to expand the arsenal of methods for producing pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones using low-toxic reagents under mild conditions.

The technical result of the proposed method is the improvement of the method for obtaining pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones 1 by eliminating the use of highly toxic reagents without loss efficiency.

To achieve a technical result, it is proposed to carry out processing of available [Litvinov VP, Dotsenko VV, Krivokolysko SG // Russ. Chem. Bull. 2005. Vol. 54. N 4. P. 864. doi: 10.1007/s11172-005-0333-1; Litvinov VP, Dotsenko VV, Krivokolysko SG // Adv. Heterocycl. Chem. 2007. Vol. 93. P. 117. DOI: 10.1016/S0065-2725(06)93003-7; Litvinov V.P., Dotsenko V.V., Krivokolysko S.G. Chemistry of thienopyridines and related systems. M.: Nauka, 2006; Dotsenko V.V., Buryi D.S., Lukina D.Yu., Krivokolysko S.G. // Russ. Chem. Bull. 2020. Vol. 69. N 10. P. 1829. doi: 10.1007/s11172-020-2969-2.] 3-aminothieno[2,3-b]pyridine-2-carboxamides 2 available synthetic equivalent of phosgene - 1,1'-carbonyldiimidazole 3 (CDI) in boiling dioxane for 3 hours:

where R = R ² = CH ₃ , R ¹ = H, R = R ¹ = R ² = CH ₃ , or R+R ¹ = (CH ₂ ) ₃ , R ² = 2-furyl.

To construct a pyrimidine ring in the pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones system, most of the above examples use the [5+1] – An N,N-dinucleophilic pentaatomic reagent reacts with an active one-carbon dielectrophile. The cyclization strategy can be represented by the following diagram:

Phosgene COCl ₂ , which could be introduced into the reaction as an active C1 dielectrophile, is not used in practice for this purpose for obvious reasons - the extremely high toxicity and gaseous state of aggregation make it difficult to work with this reagent.

Synthetic equivalents of phosgene are known - diphosgene (trichloromethylchloroformate Cl ₃ COC(O)Cl), triphosgene (bis(trichloromethyl)carbonate Cl ₃ CO–C(O)–OCCl ₃ ), diethyl carbonate, various chloroformates, the mentioned 1,1'-carbonyldiimidazole 3 (CDI), as well as di(N-succinimidyl) carbonate 4 (DSC):

In the prototype, 3-aminothieno[2,3-b]pyridine-2-carboxamides are reacted with diphosgene (trichloromethylchloroformate). Diphosgene is a liquid in its state of aggregation. Although diphosgene is for this reason more convenient to use than phosgene, it is less active compared to the latter, but it is equally highly toxic, causes asphyxiating and irritating effects, and is a chemical warfare agent.

Triphosgene is a crystalline substance, but it has proven carcinogenicity, its toxicity is quite comparable to phosgene and requires the use of the same precautions when working.

Diethyl carbonate is non-toxic and cheap, but, as shown in the examples above, diethyl carbonate is inferior in electrophilic activity to other reagents; the reaction with diethyl carbonate requires a large excess of the latter; the synthesis takes longer and proceeds under relatively harsh conditions.

Di-(N-succinimidyl) carbonate 4 (DSC) is low-toxic and is used for the determination of amines by HPLC, as well as an activating reagent for primary and sterically hindered secondary alcohols, as a coupling agent for the synthesis of thiophospholipids, etc. However, a significant disadvantage of DSC is its high cost.

1,1'-Carbonyldiimidazole 3 (CDI) is a low-toxic, stable crystalline substance, relatively cheap and widely used in organic synthesis for the activation of carboxylic acids, etc. In general, CDI is a successful alternative to the highly toxic phosgene [Armstrong A., Li W. N, N′-Carbonyldiimidazole // e-EROS Encyclopedia of Reagents for Organic Synthesis. 2007. doi: 10.1002/9780470842898.rc024.pub2.]

In the present invention, 1,1'-carbonyldiimidazole is reacted with 3-aminothieno[2,3-b]pyridine-2-carboxamides when heated in an inert solvent (dioxane), which leads to the formation of pyrido[3',2':4 ,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones in one step.

The common features of the proposed method and the prototype are:

- use of dioxane as a solvent;

-carrying out the reaction at the boiling point of dioxane (101 °C);

- formation of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones derivatives as final products;

- one-stage process.

Distinctive features are:

- carrying out the reaction using 1,1'-carbonyldiimidazole instead of diphosgene;

Example 1 . Preparation of 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione ( 1a ).

To a solution of 490 mg (2.2 mmol) 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide 2a [Wagner; Vieweg; Leistner; Böhm; Krasselt; Hanfeld; Prantz; Grupe // Pharmazie, 1990, vol. 45, N 2, p. 102-109] in 10 ml of 1,4-dioxane, previously dried over sodium, 1,1'-carbonyldiimidazole (392 mg, 2.42 mmol) is added with stirring. The mixture is boiled protected from air moisture (calcium chloride tube), and after 20 minutes the formation of a white precipitate is observed. The mixture is boiled with stirring for 3 hours (control according to the results of thin layer chromatography (TLC) on Sorbfil-A plates, eluent - ethyl acetate: hexane = 3: 1), cooled, the precipitate is filtered off, washed with cold ethanol, petroleum ether, and dried at 60 °C. 7,9-Dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione ( 1a ) is obtained in the form of a white powder, yield 79%.

^1H NMR spectrum (400 MHz, DMSO- _d6 ), δ, ppm: 2.55 s (3H, Me), 2.79 s (3H, Me), 7.22 s (1H, H-5), 10.61 (СONH ), 11.65 (CONH).

Mass spectrum, m / z (ESI): 248.6 [M +H] ⁺ .

Found, %: C 53.40; H 3.79; N 16.90. _C11H9N3O2S ( _{M 247.27} ) _. Calculated, %: C, 53.43; H, 3.67; N, 16.99.

Example 2. Preparation of 7,8,9-trimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione ( 1b ).

To a solution of 400 mg (1.7 mmol) 3-amino-4,5,6-trimethylthieno[2,3-b]pyridine-2-carboxamide 2b [Wagner; Vieweg; Leistner; Böhm; Krasselt; Hanfeld; Prantz; Grupe // Pharmazie, 1990, vol. 45, N 2, p. 102-109] in 10 ml of 1,4-dioxane, previously dried over sodium, 1,1'-carbonyldiimidazole (310 mg, 1.9 mmol) is added with stirring. The mixture is boiled with protection from air moisture (calcium chloride tube) with stirring for 3 hours (control according to the results of thin layer chromatography (TLC) on Sorbfil-A plates, eluent - ethyl acetate: hexane = 3: 1), cooled, the precipitate is filtered off, washed with cold ethanol, petroleum ether, dried at 60 °C. 7,8,9-trimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione ( 1b ) is obtained in the form of a white powder, yield 81% .

^1H NMR spectrum (400 MHz, DMSO- _d6 ), δ, ppm: 2.28 s (3H, Me), 2.54 s (3H, Me), 2.79 s (3H, Me), 10.55 (СONH), 11.68 (CONH).

Mass spectrum, m / z (ESI): 262.5 [M +H] ⁺ .

Found, %: C 55.10; H 4.34; N 16.03. C ₁₂ H ₁₁ N ₃ O ₂ S (M 261.30). Calculated, %: C, 55.16; H, 4.24; N, 16.08.

Example 3. Preparation of 10-(2-furyl)-8,9-dihydro-1H-cyclopenta[5',6']-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine -2,4(3H,7H)-dione ( 1c ).

To a suspension of 300 mg (1.0 mmol) 3-amino-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxamide 2c [Dotsenko, VV , Krivokolysko, SG Synthesis of pyrido[3',2':4,5]thieno[3,2-d]-[1,3,2]diazaphosphorine derivatives // Chem. Heterocycl. Comp. 2013, Vol. 48, pp. 1863–1867. https://doi.org/10.1007/s10593-013-1220-6] in 10 ml of 1,4-dioxane, previously dried over sodium, add 1,1'-carbonyldiimidazole (180 mg, 1.1 mmol) with stirring. The mixture is boiled with protection from air moisture (calcium chloride tube) with stirring for 3 hours (control according to the results of thin layer chromatography (TLC) on Sorbfil-A plates, eluent - ethyl acetate: hexane = 4: 1), cooled, the precipitate is filtered off, washed with cold ethanol, petroleum ether, dried at 60 °C. 10-(2-furyl)-8,9-dihydro-1H-cyclopenta[5',6']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4 is obtained (3H,7H)-dione ( 1c ) in the form of a yellow powder, yield 84%.

^1H NMR spectrum (400 MHz, DMSO- _d6 ), δ, ppm: 2.08-2.16 m (2H, _CH2 ), 2.92-2.96 m (2H, _CH2 ), 3.07-3.12 m (2H, CH ₂ ), 6.80 dd (1H, H-4 furyl, ³ J = 1.8 Hz, ³ J = 3.4 Hz), 6.95 d (1H, H-3 furyl, ³ J = 3.4 Hz), 7.99-8.02 m (1H , H-5 furyl), 10.76 (CONH), 11.70 (CONH).

Mass spectrum, m/z (ESI): 325.5 [M+H] ⁺ .

Found, %: C 59.00; H 3.49; N 12.84. C ₁₆ H ₁₁ N ₃ O ₃ S (M 325.34). Calculated, %: C, 59.07; H, 3.41; N, 12.92.

As can be seen from the given examples of specific implementation, the extremely toxic diphosgene can be successfully replaced by the low-toxic 1,1'-carbonyldiimidazole in reactions with 3-aminothieno[2,3-b]pyridine-2-carboxamides without loss in the yields of the target pyrido[3' ,2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones.

Based on the foregoing, it follows that the proposed technical solution is new, has an inventive step, has distinctive features and can be scaled up for use in fine organic synthesis.

The obtained compounds of the pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione series are of interest as intermediates in the synthesis of microbial beta-glucuronidase inhibitors with antimicrobial effect [Redinbo, Matthew R.; Jin, Jian; James, Lindsey; Pellock, Sam; Ariyarathna, Ranathunga Arachchillage Yamuna; Frye, Stephen. Inhibitors of microbial beta-glucuronidase enzymes and uses thereof. Patent WO2018017874A1, 2018-01-25, https://worldwide.espacenet.com/patent/search/family/060996088/publication/WO2018017874A1?q=pn%3DWO2018017874; Redinbo, Matthew; Bhatt, Aadra. Inhibitors of microbial beta-glucuronidase enzymes and uses thereof. Patent WO2018142365A1, 2018-08-09, https://worldwide.espacenet.com/patent/search/family/063040309/publication/WO2018142365A1?q=pn%3DWO2018142365].

Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones of similar structure are used as intermediates in the synthesis of phosphoinositide 3-kinase inhibitors suitable for the treatment of cancer and autoimmune diseases [Shuttleworth, Stephen Joseph; Cecil, Alexander Richard Liam; Hill, Thomas James; Silva, Franck Alexandre. Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors. Patent WO2011021038A1, 2011-02-24, https://worldwide.espacenet.com/patent/search/family/042756474/publication/WO2011021038A1?q=pn%3DWO2011021038].

Close structural analogues of the obtained compounds exhibit antitumor effects [Reichelt Claudia; Ludwig Alexander; Schulze Alexander; Daghish Mohammed; Leistner Siegfried. Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones and -(3H)-ones, substituted thieno[2,3-d: 4,5-d']dipyrimidine-2,4(1H,3H)-diones and -4(3H)-ones, substituted pyrido[3',2':4,5]furo[3,2-d]pyrimidine -2,4(1H,3H)-diones and -4(3H). Patent WO2006010568 (A2), 2006-02-02, https://ru.espacenet.com/publicationDetails/biblio?FT=D&date=20060202&DB=&locale=ru_RU&CC=WO&NR=2006010568A2&KC=A2&ND=4; Mohi El-Deen, E. M., Anwar, M. M., El-Gwaad, A. A. A., Karam, E. A., El-Ashrey, M. K., & Kassab, R. R. Novel Pyridothienopyrimidine Derivatives: Design, Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents // Molecules, 2022, 27(3), 803. https://doi.org/10.3390/molecules27030803; Naguib, B. H., El-Nassan, H. B., Abdelghany, T. M. Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors // J. Enzyme Inhib. Med. Chem., 2017, 32(1), 457–467. https://doi.org/10.1080/14756366.2016.1261130].

Claims (3)

Method for preparing pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-diones of general formula 1 , where R=R ² =CH ₃ , R ¹ =H, R=R ¹ =R ² =CH ₃ or R+R ¹ =(CH ₂ ) ₃ , R ² =2-furyl, based on the use of 3-aminothieno[ 2,3-b]pyridine-2-carboxamides as starting compounds and characterized in that 3-aminothieno[2,3-b]pyridine-2-carboxamides are reacted with 1,1'-carbonyldiimidazole in boiling dioxane for 3 hours