RU2574412C1 - METHOD FOR OBTAINING ALKYL-SUBSTITUTED 4-HALOGEN-3-HYDROXYFURO[3,4-c]PYRIDIN-1(3H)-ONES - Google Patents
METHOD FOR OBTAINING ALKYL-SUBSTITUTED 4-HALOGEN-3-HYDROXYFURO[3,4-c]PYRIDIN-1(3H)-ONES Download PDFInfo
- Publication number
- RU2574412C1 RU2574412C1 RU2015112994/04A RU2015112994A RU2574412C1 RU 2574412 C1 RU2574412 C1 RU 2574412C1 RU 2015112994/04 A RU2015112994/04 A RU 2015112994/04A RU 2015112994 A RU2015112994 A RU 2015112994A RU 2574412 C1 RU2574412 C1 RU 2574412C1
- Authority
- RU
- Russia
- Prior art keywords
- hlg
- pyridin
- hydroxy
- hydroxyfuro
- ones
- Prior art date
Links
- -1 phosphorus (III) Chemical compound 0.000 claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000009835 boiling Methods 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 3
- 230000000875 corresponding Effects 0.000 claims description 2
- DPNAVSHYPWUMCE-UHFFFAOYSA-N NC=1NC(C2(C=1C#N)C(NC(C2)O)=O)=O Chemical compound NC=1NC(C2(C=1C#N)C(NC(C2)O)=O)=O DPNAVSHYPWUMCE-UHFFFAOYSA-N 0.000 claims 1
- 102100011141 ALK Human genes 0.000 abstract description 7
- 108010005474 Anaplastic Lymphoma Kinase Proteins 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- ZFGOPJASRDDARH-ZQCBGZRTSA-N 3-[[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]p Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C(C1)[C@]2(C)CC[C@@H]1OC1CC2=CCC3C4CCC(C(C)CCCC(C)C)C4(C)CCC3C2(C)CC1 ZFGOPJASRDDARH-ZQCBGZRTSA-N 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 102000004257 potassium channel family Human genes 0.000 abstract description 4
- 108020001213 potassium channel family Proteins 0.000 abstract description 4
- 239000012190 activator Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 229940093499 ethyl acetate Drugs 0.000 abstract 1
- 235000019439 ethyl acetate Nutrition 0.000 abstract 1
- 102000004169 proteins and genes Human genes 0.000 abstract 1
- 108090000623 proteins and genes Proteins 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000002194 synthesizing Effects 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 102220240796 rs553605556 Human genes 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- CGFBFKHEQXNPLY-UHFFFAOYSA-N C1OC(C=2C=NC=CC=21)O Chemical compound C1OC(C=2C=NC=CC=21)O CGFBFKHEQXNPLY-UHFFFAOYSA-N 0.000 description 5
- DUCOJBIDVDVXQG-UHFFFAOYSA-N NC=1NC(C2(C=1C#N)C(NC(C2C)(C)O)=O)=O Chemical compound NC=1NC(C2(C=1C#N)C(NC(C2C)(C)O)=O)=O DUCOJBIDVDVXQG-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- VPCDQGACGWYTMC-UHFFFAOYSA-N Nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000003293 cardioprotective Effects 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 239000012268 protein inhibitor Substances 0.000 description 3
- 229940121649 protein inhibitors Drugs 0.000 description 3
- WBNLAHSOVLAWCE-UHFFFAOYSA-N 1,3-dihydrofuro[3,4-c]pyridine Chemical compound N1=CC=C2COCC2=C1 WBNLAHSOVLAWCE-UHFFFAOYSA-N 0.000 description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- FRHBXASFXOPUMH-UHFFFAOYSA-N 8-amino-4-ethyl-3-hydroxy-3-methyl-1,6-dioxo-2,7-diazaspiro[4.4]non-8-ene-9-carbonitrile Chemical compound CCC1C(C)(O)NC(=O)C11C(C#N)=C(N)NC1=O FRHBXASFXOPUMH-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- FCTZJILCEJMJIE-UHFFFAOYSA-N N1=CN=CC2=C1C=C1C(N2)=C2C=NC=CC2=N1 Chemical class N1=CN=CC2=C1C=C1C(N2)=C2C=NC=CC2=N1 FCTZJILCEJMJIE-UHFFFAOYSA-N 0.000 description 2
- 206010025310 Other lymphomas Diseases 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- CTSPAMFJBXKSOY-UHFFFAOYSA-N ellipticine Chemical compound N1=CC=C2C(C)=C(NC=3C4=CC=CC=3)C4=C(C)C2=C1 CTSPAMFJBXKSOY-UHFFFAOYSA-N 0.000 description 2
- QYNDTTJOWNQBII-UHFFFAOYSA-N furo[3,4-c]pyridine Chemical class C1=NC=CC2=COC=C21 QYNDTTJOWNQBII-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QAUIZSWZXQFEJL-UHFFFAOYSA-N 1H-furo[3,4-c]pyridin-3-one Chemical compound C1=NC=C2C(=O)OCC2=C1 QAUIZSWZXQFEJL-UHFFFAOYSA-N 0.000 description 1
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 1
- HNMHAFWWHHBJPC-UHFFFAOYSA-N 2H-pyrrolo[3,4-c]quinoline Chemical class C1=CC=C2C3=CNC=C3C=NC2=C1 HNMHAFWWHHBJPC-UHFFFAOYSA-N 0.000 description 1
- YQMHKUFHTUIBAF-UHFFFAOYSA-N 3-hydroxy-3H-furo[3,4-c]pyridin-1-one Chemical compound C1=NC=C2C(O)OC(=O)C2=C1 YQMHKUFHTUIBAF-UHFFFAOYSA-N 0.000 description 1
- PHEZJEYUWHETKO-UHFFFAOYSA-N 6-Fluoro-2-(2'-Fluoro-1,1'-Biphenyl-4-Yl)-3-Methylquinoline-4-Carboxylic Acid Chemical class N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 1
- KSEHRXUCGLUTMA-UHFFFAOYSA-N 6H-pyrido[4,3-b]carbazole Chemical class C1=NC=C2C=C3C4=CC=CC=C4NC3=CC2=C1 KSEHRXUCGLUTMA-UHFFFAOYSA-N 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N Acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N BBR-2778 Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- DTVFWJLTYULGGX-UHFFFAOYSA-N C1=CC=CC2=C3CSC=CC3=CN=C21 Chemical compound C1=CC=CC2=C3CSC=CC3=CN=C21 DTVFWJLTYULGGX-UHFFFAOYSA-N 0.000 description 1
- 102100002130 DHODH Human genes 0.000 description 1
- 240000001340 Gmelina philippensis Species 0.000 description 1
- 108009000301 Hedgehog Signaling Pathway Proteins 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N Isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- CZFNISFYDPIDNM-UHFFFAOYSA-N N,N-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 108010052167 dihydroorotate dehydrogenase Proteins 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000007074 heterocyclization reaction Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000006205 intramolecular heterocyclization reaction Methods 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 244000045947 parasites Species 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 229960002862 pyridoxine Drugs 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000008410 smoothened signaling pathway Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Abstract
Description
Изобретение относится к области органической химии, а именно к области получения функционально замещенных фуро[3,4-с]пиридинов, конкретно алкилзамещенных 4-галоген-3-гидроксифуро[3,4-с]пиридин-1(3H)-оновThe invention relates to the field of organic chemistry, namely to the field of obtaining functionally substituted furo [3,4-c] pyridines, specifically alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones
где R1=R2=CH3, Hlg=Cl; R1=СН3, R2=C2H5, Hlg=Cl; R1=CH3, R2=C3H7, Hlg=Cl; R1=R2=CH3, Hlg=Br; R1=CH3, R2=C2H5, Hlg=Br; R1=СН3, R2=C3H7, Hlg=Br, которые могут найти применение в качестве активатора калиевых каналов, ингибиторов киназы анапластической лимфомы (Anaplastic Lymphoma Kinase), ингибитора белка переноса холестерилового эфира (СЕТР), а также в качестве кардиопротекторных агентов.where R 1 = R 2 = CH 3 , Hlg = Cl; R 1 = CH 3 , R 2 = C 2 H 5 , Hlg = Cl; R 1 = CH 3 , R 2 = C 3 H 7 , Hlg = Cl; R 1 = R 2 = CH 3 , Hlg = Br; R 1 = CH 3 , R 2 = C 2 H 5 , Hlg = Br; R 1 = CH 3 , R 2 = C 3 H 7 , Hlg = Br, which can be used as potassium channel activator, anaplastic lymphoma kinase inhibitors (Anaplastic Lymphoma Kinase), cholesteryl ether transfer protein inhibitor (CETP), as well as as cardioprotective agents.
Известен способ получения 3-гидрокси-1,3-дигидрофуро[3,4-с]пиридина путем окисления 1,3-дигидрофуро[3,4-с]пиридина кислородом воздуха [Parnell С.А., Peter V. Regioselective construction of the tetrasubstituted pyridine nucleus by cobalt-catalyzed alkyne-nitrile cooligomerizations // Tetrahedron. 1985, 24, 5791-5796]. Недостатком этого способа являются низкие (следовые) количества образующегося продукта реакции.A known method for producing 3-hydroxy-1,3-dihydrofuro [3,4-c] pyridine by oxidation of 1,3-dihydrofuro [3,4-c] pyridine with atmospheric oxygen [Parnell S. A., Peter V. Regioselective construction of the tetrasubstituted pyridine nucleus by cobalt-catalyzed alkyne-nitrile cooligomerizations // Tetrahedron. 1985, 24, 5791-5796]. The disadvantage of this method is the low (trace) amount of the resulting reaction product.
Известны способы получения 3-гидрокси-1,3-дигидрофуро[3,4-с]пиридина, заключающиеся в восстановлении карбонильной функции фуро[3,4-с]пиридин-3(1H)-она [Mukherjee P., Roy S.J.S., Sarkar Т.K. A diversity-oriented synthesis of bicycliccis-dihydroarenediols, cis-4-hydroxyscytalones, and bicyclic conduritol analogues // Org. Lett. 2010, 11, 2472-2475; EP 2072519 A61K 31/438; A61K 31/444; A61K 31/497 Diaryl ketimine derivative; Dormoy H. Tetrahedron. 1993, 14, 2915-2938; Desarbre E., Coudret S., Meheust C., Merour J.-Y. Synthesis of 2-substituted-1H-Pyrrolo[2,3-b]pyridines: preparation of 7-azaolivacine analogue and 7-azaindolopyridopyrimidine derivatives // Tetrahedron. 1997, 10, 3637-3648]. Недостатками данных способов являются труднодоступные исходные реагенты, использование безводных растворителей, необходимость обеспечения низких температур проведения синтеза и инертной атмосферы.Known methods for producing 3-hydroxy-1,3-dihydrofuro [3,4-c] pyridine, which consists in restoring the carbonyl function of furo [3,4-c] pyridin-3 (1H) -one [Mukherjee P., Roy SJS, Sarkar T.K. A diversity-oriented synthesis of bicycliccis-dihydroarenediols, cis-4-hydroxyscytalones, and bicyclic conduritol analog // Org. Lett. 2010, 11, 2472-2475; EP 2072519 A61K 31/438; A61K 31/444; A61K 31/497 Diaryl ketimine derivative; Dormoy H. Tetrahedron. 1993, 14, 2915-2938; Desarbre E., Coudret S., Meheust C., Merour J.-Y. Synthesis of 2-substituted-1H-Pyrrolo [2,3-b] pyridines: preparation of 7-azaolivacine analogue and 7-azaindolopyridopyrimidine derivatives // Tetrahedron. 1997, 10, 3637-3648]. The disadvantages of these methods are hard-to-reach starting reagents, the use of anhydrous solvents, the need to ensure low synthesis temperatures and an inert atmosphere.
Авторами [WO 2009/146555 A61K 31/44; A61K 31/4427; А61Р 31/12; А61Р 31/18; C07D 213/81; C07D 405/12; C07D 493/04 HIV integrase inhibitors from pyridoxine; Dormoy H. Synthese industrielle en serie ellipticine II: Elaboration d'une nouvelle voie d′acces aux 6H-pyrido[4,3-b]carbazoles et analogues: B. Obtention des structures tétracycliques // Tetrahedron. 1993, 14, 2915-2938; Boa A.N., Canavan S.P., Hirst P.R., Ramsey C., Stead A.M.W., McConkey G.A. Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase // Bioorg. Med. Chem. 2005, 6, 1945-1967; Desarbre E., Coudret S., Meheust C., Merour J.-Y. Synthesis of 2-substimted-1H-Pyrrolo[2,3-b]pyridines: preparation of 7-azaolivacine analogue and 7-azaindolopyridopyrimidine derivatives // Tetrahedron. 1997, 10, 3637-3648; Pokhodylo N.T., Matiychuk V.S., Obushak P.M. A convenient method for the synthesis of thiopyrano[4,3-c]quinoline, a new heterocyclic system // Chem. Heterocycl. Compd. 2009, 1, 121-122; EP 503537 A61K 31/435; A61K 31/473; A61K 31/535 6,9-Bis(substituted-amino)benzo-[g]isoquinoline-5,10-diones] описан способ получения 1,3-дигидрофуро[3,4-с] пиридина построением фуранового цикла путем внутримолекулярной гетероциклизации функциональных групп пиридинового кольца. Недостатками данных способов являются их многостадийность, использование инертной атмосферы и низкая температура проведения синтеза.The authors [WO 2009/146555 A61K 31/44; A61K 31/4427; A61P 31/12; A61P 31/18; C07D 213/81; C07D 405/12; C07D 493/04 HIV integrase inhibitors from pyridoxine; Dormoy H. Synthese industrielle en serie ellipticine II: Elaboration d'une nouvelle voie d′acces aux 6H-pyrido [4,3-b] carbazoles et comparative: B. Obtention des structures tétracycliques // Tetrahedron. 1993, 14, 2915-2938; Boa A.N., Canavan S.P., Hirst P.R., Ramsey C., Stead A.M.W., McConkey G.A. Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase // Bioorg. Med. Chem. 2005, 6, 1945-1967; Desarbre E., Coudret S., Meheust C., Merour J.-Y. Synthesis of 2-substimted-1H-Pyrrolo [2,3-b] pyridines: preparation of 7-azaolivacine analogue and 7-azaindolopyridopyrimidine derivatives // Tetrahedron. 1997, 10, 3637-3648; Pokhodylo N.T., Matiychuk V.S., Obushak P.M. A convenient method for the synthesis of thiopyrano [4,3-c] quinoline, a new heterocyclic system // Chem. Heterocycl. Compd 2009, 1, 121-122; EP 503537 A61K 31/435; A61K 31/473; A61K 31/535 6,9-Bis (substituted-amino) benzo- [g] isoquinoline-5,10-diones] describes a method for producing 1,3-dihydrofuro [3,4-c] pyridine by building the furan ring by intramolecular functional heterocyclization pyridine ring groups. The disadvantages of these methods are their multi-stage, the use of an inert atmosphere and low temperature synthesis.
В ряде источников описаны способы получения производных фуро[3,4-с]пиридина, которые используются в качестве интермедиатов для получения целевых продуктов, путем внутримолекулярной гетероциклизации функциональных групп пиридинового кольца [US 5519029 C07D 471/06; A61K 31/435; C07D 419/14 2-Aminoalkyl-5-aminoalkylamino substituted-isoquinoindazole-6(2H)-ones; US 5596097 C07D 471/06; C07D 487/06; A61K 31/47 Hetero-annulated indazoles; WO 2015/1348 A61K 31/502; A61K 31/5025; A61P 35/00 Pyridazine derivatives as hedgehog pathway inhibitors; US 5506232 A61K 31/47; A61K 31/473; A61P 35/00 6,9-Bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione and its dimaleate salt; WO 2014/191737 A61K 31/501; A61K 31/502; A61K 31/5025 Heterocyclic compounds as hedgehog signaling pathway inhibitors; US 4268513 A61K 31/47; A61K 31/535; A61P 25/04 Pyrrolo[3,4-c]quinoline compounds and pharmaceutical compositions, methods for their use and preparation]. Недостатками данных способов являются их многостадийность, использование инертной атмосферы и низкая температура проведения синтеза.A number of sources describe methods for the preparation of furo [3,4-c] pyridine derivatives, which are used as intermediates to obtain the desired products by intramolecular heterocyclization of the functional groups of the pyridine ring [US 5519029 C07D 471/06; A61K 31/435; C07D 419/14 2-Aminoalkyl-5-aminoalkylamino substituted-isoquinoindazole-6 (2H) -ones; US 5596097 C07D 471/06; C07D 487/06; A61K 31/47 Hetero-annulated indazoles; WO 2015/1348 A61K 31/502; A61K 31/5025; A61P 35/00 Pyridazine derivatives as hedgehog pathway inhibitors; US 5506232 A61K 31/47; A61K 31/473; A61P 35/00 6,9-Bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione and its dimaleate salt; WO 2014/191737 A61K 31/501; A61K 31/502; A61K 31/5025 Heterocyclic compounds as hedgehog signaling pathway inhibitors; US 4,268,513 A61K 31/47; A61K 31/535; A61P 25/04 Pyrrolo [3,4-c] quinoline compounds and pharmaceutical compositions, methods for their use and preparation]. The disadvantages of these methods are their multi-stage, the use of an inert atmosphere and low temperature synthesis.
Известен способ получения 3-гидрокси-1,3-дигидрофуро[3,4-с]пиридина путем конденсации никотинальдегида с замещенными бензальдегидами [WO 2006/91800 A61K 31/44; А61Р 9/00; C07D 213/30 Novel pyridine derivatives as potassium ion channel openers]. Недостатком данного способа является низкая температура проведения синтеза.A known method of producing 3-hydroxy-1,3-dihydrofuro [3,4-c] pyridine by condensation of nicotinaldehyde with substituted benzaldehydes [WO 2006/91800 A61K 31/44; A61P 9/00; C07D 213/30 Novel pyridine derivatives as potassium ion channel openers]. The disadvantage of this method is the low temperature of the synthesis.
Известен способ получения 3-гидрокси-1,3-дигидрофуро[3,4-с]пиридина взаимодействием индолин-2,3-диона с пентан-2,4-дионами [Godard A., Queguiner G. Polyazaphenanthrenes. Synthese de pyridazino[4,5-c]quinoleines // Chem. Heterocycl. Chem. 1984, 1, 27-32]. Недостатком данного способа является длительность процесса (6 часов).A known method of producing 3-hydroxy-1,3-dihydrofuro [3,4-c] pyridine by the interaction of indoline-2,3-dione with pentane-2,4-dione [Godard A., Queguiner G. Polyazaphenanthrenes. Synthese de pyridazino [4,5-c] quinoleines // Chem. Heterocycl. Chem. 1984, 1, 27-32]. The disadvantage of this method is the duration of the process (6 hours).
Известен способ получения 3-гидрокси-1,3-дигидрофуро[3,4-с]пиридина в результате многостадийной реакции между 2-метоксипиридном, N1,N1,N2-триметил-N2-винилэтан-1,2-диамином и кетонами [Hong Н., Comins D.L. A Three-Step Synthesis of Cerpegin // J. Org. Chem. 1996, 1, 391-392]. Недостатком данного способа является многостадийность, а следовательно, длительность и трудоемкость процесса.A known method for producing 3-hydroxy-1,3-dihydrofuro [3,4-c] pyridine as a result of a multistep reaction between 2-methoxypyridine, N 1 , N 1 , N 2 -trimethyl-N 2 -vinyl ethane-1,2-diamine and ketones [Hong N., Comins DL A Three-Step Synthesis of Cerpegin // J. Org. Chem. 1996, 1, 391-392]. The disadvantage of this method is the multi-stage, and therefore, the duration and complexity of the process.
Наиболее близким к заявляемому является способ получения 3-гидроксифуро[3,4-с]пиридин-1(3H)-она, заключающийся в обработке 2,2,6,6-тетраметилпиперидина н-бутиллитием в среде сухого тетрагидрофурана и н-гексана с последующим добавлением раствора 2,6-дибромникотиновой и 2,6-дибромизоникотиновой кислот в тетрагидрофуране и N,N-диметилформамида при температуре минус 78°С в течение 15 часов [WO 2012/97682 A61K 31/435; A61K 31/495; A61K 31/551 Bicyclic inhibitors of alk; WO 2012/97479 A61K 31/4375; A61K 31/4985; A61P 35/00 Bicyclic inhibitors of anaplastic lymphoma kinase]. Недостатком данного способа являются длительность процесса и низкая температура проведения синтеза.Closest to the claimed is a method for producing 3-hydroxyfuro [3,4-c] pyridin-1 (3H) -one, which consists in processing 2,2,6,6-tetramethylpiperidine with n-butyllithium in a medium of dry tetrahydrofuran and n-hexane with the subsequent addition of a solution of 2,6-dibromonicotinic and 2,6-dibromisoniconic acids in tetrahydrofuran and N, N-dimethylformamide at a temperature of minus 78 ° C for 15 hours [WO 2012/97682 A61K 31/435; A61K 31/495; A61K 31/551 Bicyclic inhibitors of alk; WO 2012/97479 A61K 31/4375; A61K 31/4985; A61P 35/00 Bicyclic inhibitors of anaplastic lymphoma kinase]. The disadvantage of this method is the duration of the process and the low temperature of the synthesis.
Основным недостатком всех описанных выше способов является то, что они не позволяют получить 4-галоген-3-гидроксифуро[3,4-с]пиридин-1(3H)-оны.The main disadvantage of all the above methods is that they do not allow to obtain 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones.
Задачей данного изобретения является разработка способа получения ранее неизвестных алкилзамещенных 4-галоген-3-гидроксифуро [3,4-с]пиридин-1(3H)-онов, которые могут найти применение в качестве активатора калиевых каналов, ингибиторов киназы анапластической лимфомы (Anaplastic Lymphoma Kinase), ингибитора белка переноса холестерилового эфира (СЕТР), а также в качестве кардиопротекторных агентов.The objective of this invention is to develop a method for producing previously unknown alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones, which can be used as an activator of potassium channels, kinase inhibitors of anaplastic lymphoma (Anaplastic Lymphoma Kinase), a cholesteryl ether transfer protein inhibitor (CETP), and also as cardioprotective agents.
Техническим результатом является разработка способа получения ранее неописанных в литературе алкилзамещенных 4-галоген-3-гидроксифуро[3,4-с]пиридин-1(3H)-онов.The technical result is the development of a method of obtaining previously not described in the literature of alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones.
Технический результат достигается тем, что способ получения алкилзамещенных 4-галоген-3-гидроксифуро[3,4-с]пиридин-1(3H)-онов общей формулой (1)The technical result is achieved by the fact that the method of producing alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones by the general formula (1)
где R1=R2=CH3, Hlg=Cl; R1=CH3, R2=C2H5, Hlg=Cl; R1=CH3, R2=C3H7, Hlg=Cl; R1=R2=CH3, Hlg=Br; R1=CH3, R2=C2H5, Hlg=Br; R1=CH3, R2=C3H7, Hlg=Br, согласно изобретению характеризуется тем, что соответствующий 3-амино-8-гидрокси-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрил растворяют в 2-5-кратном избытке концентрированной галогеноводородной кислоты и добавляют 5-7-кратный избыток галогенида фосфора (III), кипятят 40-50 минут, охлаждают, разбавляют водой и экстрагируют этилацетатом, экстракт упаривают, образовавшийся осадок перекристаллизовывают из пропан-2-ола.where R 1 = R 2 = CH 3 , Hlg = Cl; R 1 = CH 3 , R 2 = C 2 H 5 , Hlg = Cl; R 1 = CH 3 , R 2 = C 3 H 7 , Hlg = Cl; R 1 = R 2 = CH 3 , Hlg = Br; R 1 = CH 3 , R 2 = C 2 H 5 , Hlg = Br; R 1 = CH 3 , R 2 = C 3 H 7 , Hlg = Br, according to the invention is characterized in that the corresponding 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro [4.4] non-3 en-4-carbonitrile is dissolved in a 2-5-fold excess of concentrated hydrohalic acid and a 5-7-fold excess of phosphorus (III) halide is added, boiled for 40-50 minutes, cooled, diluted with water and extracted with ethyl acetate, the extract is evaporated, the precipitate formed recrystallized from propan-2-ol.
Сопоставительный анализ заявляемого решения с известными показывает, что способы получения алкилзамещенных 4-галоген-3-гидроксифуро[3,4-с]пиридин-1(3Н)-онов в литературе не описаны. Важно отметить, что в качестве реагента и растворителя в предлагаемом способе используются дешевые и доступные водный раствор галогеноводорода и галогенид фосфора (III).A comparative analysis of the proposed solution with the known shows that methods for producing alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones are not described in the literature. It is important to note that the proposed method uses a cheap and affordable aqueous solution of hydrogen halide and phosphorus (III) halide as a reagent and solvent.
Сущность изобретения представлена в примерах:The invention is presented in the examples:
Пример 1. Способ получения 3-гидрокси-6,7-диметил-4-хлорфуро[3,4-с]пиридин-1(3H)-онаExample 1. The method of obtaining 3-hydroxy-6,7-dimethyl-4-chlorofuro [3,4-c] pyridin-1 (3H) -one
0.47 г (0.002 моль) 3-амино-8-гидрокси-8,9-диметил-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрила при интенсивном перемешивании растворяют в 3 мл концентрированной соляной кислоты, добавляют 1 мл PCl3. Кипят 40-50 минут, охлаждают, разбавляют водой и экстрагируют этилацетатом. Экстракт упаривают, образовавшийся осадок перекристаллизовывают из пропан-2-ола. Выход 0.16 г (38%), т.пл. 180-181°С. ИК-спектр ν, см-1: 3522 (ОН), 1771 (С=O). Спектр ЯМР 1Н (ДМСО-d6), δ, м.д.: 2.53 с (3Н, СН3), 2.55 с (3Н, СН3), 6.65 с (1Н, ОН), 8.34 уш. с (1Н, СН). Найдено, %: С, 50.51; Н, 3.74; N, 6.66. C9H8ClNO3. Вычислено, %: С, 50.60; Н, 3.77; N, 6.56. Масс-спектр, m/z (Ioтн., %): 213 [М, 35Cl]+ (44%), 215 [М, 37Cl]+ (13%).0.47 g (0.002 mol) of 3-amino-8-hydroxy-8,9-dimethyl-1,6-dioxo-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile is dissolved in 3 ml with vigorous stirring concentrated hydrochloric acid, add 1 ml of PCl 3 . Boil for 40-50 minutes, cool, dilute with water and extract with ethyl acetate. The extract was evaporated, the precipitate formed was recrystallized from propan-2-ol. Yield 0.16 g (38%), mp. 180-181 ° C. IR spectrum ν, cm -1 : 3522 (OH), 1771 (C = O). 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 2.53 s (3H, CH 3 ), 2.55 s (3H, CH 3 ), 6.65 s (1H, OH), 8.34 br. s (1H, CH). Found,%: C, 50.51; H, 3.74; N, 6.66. C 9 H 8 ClNO 3 . Calculated,%: C, 50.60; H, 3.77; N, 6.56. Mass spectrum, m / z ( Irel ,%): 213 [M, 35 Cl] + (44%), 215 [M, 37 Cl] + (13%).
Пример 2. Способ получения 3-гидрокси-6-метил-4-хлор-7-этилфуро[3,4-с]пиридин-1(3Н)-онаExample 2. A method of obtaining 3-hydroxy-6-methyl-4-chloro-7-ethylfuro [3,4-c] pyridin-1 (3H) -one
Способ осуществляется аналогично способу 1, при этом вместо 3-амино-8-гидрокси-8,9-диметил-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрила используется 3-амино-8-гидрокси-8-метил-1,6-диоксо-9-этил-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрил. Выход 0.19 г (42%), т.пл. 203-205°С (разл.). ИК-спектр ν, см-1: 3527 (ОН), 1769 (С=0). Спектр ЯМР 1Н (ДМСО-d6), δ, м.д.: 1.13 т (3Н, J 7.5, СН2СН3), 2.59 с (3Н, СН3), 3.03 к (2Н, J7.3, СН2СН3),6.64 уш. с (1Н, ОН), 8.33 уш. с (1H, СН). Найдено, %: С С, 52.87; Н, 4.40; N, 6.09. C10H10ClNO3. Вычислено, %: С, 52.76; Н, 4.43; N, 6.15. Масс-спектр, m/z (Ioтн., %): 227 [М, 35Cl]+ (39%), 229 [М, 37Cl]+ (13%).The method is carried out similarly to method 1, while instead of 3-amino-8-hydroxy-8,9-dimethyl-1,6-dioxo-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile, 3-amino -8-hydroxy-8-methyl-1,6-dioxo-9-ethyl-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile. Yield 0.19 g (42%), mp. 203-205 ° C (decomp.). IR spectrum ν, cm -1 : 3527 (OH), 1769 (C = 0). 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 1.13 t (3Н, J 7.5, СН 2 СН 3 ), 2.59 s (3Н, СН 3 ), 3.03 k (2Н, J7.3, CH 2 CH 3 ), 6.64 br. s (1H, OH), 8.33 br. s (1H, CH). Found,%: С С, 52.87; H, 4.40; N, 6.09. C 10 H 10 ClNO 3 . Calculated,%: C, 52.76; H, 4.43; N, 6.15. Mass spectrum, m / z ( Irel ,%): 227 [M, 35 Cl] + (39%), 229 [M, 37 Cl] + (13%).
Пример 3. Способ получения 3-гидрокси-6-метил-7-пропил-4-хлорфуро[3,4-с]пиридин-1(377)-онаExample 3. The method of obtaining 3-hydroxy-6-methyl-7-propyl-4-chlorofuro [3,4-c] pyridin-1 (377) -one
Способ осуществляется аналогично способу 1, при этом вместо 3-амино-8-гидрокси-8,9-диметил-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрила используется 3-амино-8-гидрокси-8-метил-1,6-диоксо-9-пропил-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрил. Выход 0.20 г (41%), т.пл. 173-174°С (разд.). ИК-спектр ν, см-1: 3524 (ОН), 1770 (С=O). Спектр ЯМР 1Н (ДМСО-d6), δ, м.д.: 0.95 т (3Н, J 7.3, СН2СН2СН3), 1.53 секстет (2Н, J 7.5, CH2CH2CH3), 2.59 с (3Н, СН3), 2.99 т (2Н, J 7.7, СН2СН2СН3), 6.65 с (1Н, ОН), 8.32 уш. с (1Н, СН). Найдено, %: С, 54.79; Н, 4.96; N, 5.87. C11H12ClNO3. Вычислено, %: С, 54.67; Н, 5.00; N, 5.80. Масс-спектр, m/z (Ioтн., %): 241 [М, 35Cl]+ (100%), 243 [М, 37Cl]+.The method is carried out similarly to method 1, while instead of 3-amino-8-hydroxy-8,9-dimethyl-1,6-dioxo-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile, 3-amino -8-hydroxy-8-methyl-1,6-dioxo-9-propyl-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile. Yield 0.20 g (41%), mp. 173-174 ° C (section). IR spectrum ν, cm -1 : 3524 (OH), 1770 (C = O). 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 0.95 t (3H, J 7.3, CH 2 CH 2 CH 3 ), 1.53 sextet (2H, J 7.5, CH 2 CH 2 CH 3 ), 2.59 s (3H, CH 3 ), 2.99 t (2H, J 7.7, CH 2 CH 2 CH 3 ), 6.65 s (1H, OH), 8.32 br. s (1H, CH). Found,%: C, 54.79; H, 4.96; N, 5.87. C 11 H 12 ClNO 3 . Calculated,%: C, 54.67; H, 5.00; N, 5.80. Mass spectrum, m / z ( Irel ,%): 241 [M, 35 Cl] + (100%), 243 [M, 37 Cl] + .
Пример 4. Способ получения 4-бром-3-гидрокси-6,7-диметилфуро[3,4-с]пиридин-1(3H)-онаExample 4. A method for producing 4-bromo-3-hydroxy-6,7-dimethylfuro [3,4-c] pyridin-1 (3H) -one
Способ осуществляется аналогично способу 1, при этом вместо соляной кислоты используется бромоводородная кислота, вместо PCl3 используется PBr3. Выход 0.18 г (35%), т.пл. 186-187°С (разл.). ИК-спектр ν, см-1: 3527 (ОН), 1770 (С=O). Спектр ЯМР 1Н (ДМСО-d6), δ, м.д.: 2.51 с (3Н, СН3), 2.55 с (3Н, СН3), 6.57 с (1H, ОН), 8.32 с (1H, СН). Найдено, %: С, 41.77; Н, 3.16; N, 5.48. C9H8BrNO3. Вычислено, %: С, 41.89; Н, 3.12; N, 5.43. Масс-спектр, m/z (Ioтн., %): 257 [М, 79Br]+ (14%), 259 [М, 81Br]+(13%).The process is carried out analogously to method 1, wherein hydrochloric acid is used instead of hydrobromic acid is used instead of PCl 3 PBr 3. Yield 0.18 g (35%), mp. 186-187 ° C (decomp.). IR spectrum ν, cm -1 : 3527 (OH), 1770 (C = O). 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 2.51 s (3H, CH 3 ), 2.55 s (3H, CH 3 ), 6.57 s (1H, OH), 8.32 s (1H, CH ) Found,%: C, 41.77; H, 3.16; N, 5.48. C 9 H 8 BrNO 3 . Calculated,%: C, 41.89; H, 3.12; N, 5.43. Mass spectrum, m / z ( Irel ,%): 257 [M, 79 Br] + (14%), 259 [M, 81 Br] + (13%).
Пример 5. Способ получения 4-бром-3-гидрокси-6-метил-7-этилфуро[3,4-с]пиридин-1(3H)-онаExample 5. A method of obtaining 4-bromo-3-hydroxy-6-methyl-7-ethylfuro [3,4-c] pyridin-1 (3H) -one
Способ осуществляется аналогично способу 1, при этом вместо 3-амино-8-гидрокси-8,9-диметил-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрила используется 3-амино-8-гидрокси-8-метил-1,6-диоксо-9-этил-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрил, вместо соляной кислоты используется бромоводородная кислота, вместо РС13 используется PBr3. Выход 0.23 г (43%), т.пл. 211-212°С (разл.). ИК-спектр ν, см-1: 3525 (ОН), 1770 (С=O). Спектр ЯМР 1H (ДМСО-d6), δ, м.д.: 1.12 т (3Н, J 7.5, СН2СН3), 2.60 с (3Н, СН3), 3.00 к (2Н, J 7А, СН2СН3),6.61 уш. с (1Н, ОН), 8.31 уш. с (1Н, СН). Найдено, %: С, 44.03; Н, 3.67; N, 5.19. C10H10BrNO3. Вычислено, %: С, 44.14; Н, 3.70; N, 5.15. Масс-спектр, m/z (Ioтн., %): 271 [М, 79Br]+ (74%), 273 [М, 81Br]+ (72%).The method is carried out similarly to method 1, while instead of 3-amino-8-hydroxy-8,9-dimethyl-1,6-dioxo-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile, 3-amino -8-hydroxy-8-methyl-1,6-dioxo-9-ethyl-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile, hydrobromic acid is used instead of hydrochloric acid, PBr 3 is used instead of PC1 3 . Yield 0.23 g (43%), mp. 211-212 ° C (decomp.). IR spectrum ν, cm -1 : 3525 (OH), 1770 (C = O). 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 1.12 t (3Н, J 7.5, СН 2 СН 3 ), 2.60 s (3Н, СН 3 ), 3.00 k (2Н, J 7А, СН 2 CH 3 ), 6.61 br. s (1H, OH), 8.31 br. s (1H, CH). Found,%: C, 44.03; H, 3.67; N, 5.19. C 10 H 10 BrNO 3 . Calculated,%: C, 44.14; H, 3.70; N, 5.15. Mass spectrum, m / z ( Irel ,%): 271 [M, 79 Br] + (74%), 273 [M, 81 Br] + (72%).
Пример 6. Способ получения 4-бром-3-гидрокси-6-метил-7-пропилфуро[3,4-с]пиридин-1(3H)-онаExample 6. A method of obtaining 4-bromo-3-hydroxy-6-methyl-7-propylfuro [3,4-c] pyridin-1 (3H) -one
Способ осуществляется аналогично способу 1, при этом вместо 3-амино-8-гидрокси-8,9-диметил-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрила используется 3-амино-8-гидрокси-8-метил-1,6-диоксо-9-пропил-2,7-диазаспиро[4.4]нон-3- ен-4-карбонитрил, вместо соляной кислоты используется бромоводородная кислота, вместо PCl3 используется PBr3. Выход 0.25 г (44%), т.пл. 179-181°С (разл.). ИК-спектр ν, см-1: 3526 (ОН), 1767 (С=O). Спектр ЯМР 1Н (ДМСО-d6), δ, м.д.: 0.95 т (3Н, J 7.3, СН2СН2СН3), 1-53 секстет (2Н, J 7.5, СН2СН2СН3), 2.59 с (3Н, СН3), 2.98 т (2Н, J 7.7, СН2СН2СН3), 6.57 с (1Н, ОН), 8.31 уш. с (1Н, СН). Найдено, %: С, 46.27; Н, 4.25; N, 4.94. C11H12BrNO3. Вычислено, %: С, 46.18; Н, 4.23; N, 4.90. Масс-спектр, m/z (Ioтн., %): 285 [М, 79Br]+(28%), 287 [М, 81Br]+ (26%).The method is carried out similarly to method 1, while instead of 3-amino-8-hydroxy-8,9-dimethyl-1,6-dioxo-2,7-diazaspiro [4.4] non-3-en-4-carbonitrile, 3-amino -8-hydroxy-8-methyl-1,6-dioxo-9-propyl-2,7-diazaspiro [4.4] non-3- ene-4-carbonitrile instead of hydrochloric acid, hydrobromic acid is used instead of using PCl 3 PBr 3 . Yield 0.25 g (44%), mp. 179-181 ° C (decomp.). IR spectrum ν, cm -1 : 3526 (OH), 1767 (C = O). 1 H NMR spectrum (DMSO-d 6 ), δ, ppm: 0.95 t (3H, J 7.3, CH 2 CH 2 CH 3 ), 1-53 sextet (2H, J 7.5, CH 2 CH 2 CH 3 ), 2.59 s (3H, CH 3 ), 2.98 t (2H, J 7.7, CH 2 CH 2 CH 3 ), 6.57 s (1H, OH), 8.31 br. s (1H, CH). Found,%: C, 46.27; H, 4.25; N, 4.94. C 11 H 12 BrNO 3 . Calculated,%: C, 46.18; H, 4.23; N, 4.90. Mass spectrum, m / z ( Irel ,%): 285 [M, 79 Br] + (28%), 287 [M, 81 Br] + (26%).
Таким образом, предлагаемый способ позволяет получить неописанные в литературе алкилзамещенные 4-галоген-3-гидроксифуро[3,4-с]пиридин-1(3H)-оны, которые могут найти применение в качестве активатора калиевых каналов, ингибиторов киназы анапластической лимфомы (Anaplastic Lymphoma Kinase), ингибитора белка переноса холестерилового эфира (СЕТР), а также в качестве кардиопротекторных агентов.Thus, the proposed method allows to obtain not described in the literature alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones, which can be used as an activator of potassium channels, kinase inhibitors of anaplastic lymphoma (Anaplastic Lymphoma Kinase), a cholesteryl ether transfer protein inhibitor (CETP), as well as cardioprotective agents.
Claims (1)
где R1=R2=CH3, Hlg=Cl; R1=CH3, R2=C2H5, Hlg=Cl; R1=CH3, R2=C3H7, Hlg=Cl; R1=R2=CH3, Hlg=Br; R1=СН3, R2=C2H5, Hlg=Br; R1=CH3, R2=C3H7, Hlg=Br, характеризующийся тем, что соответствующий 3-амино-8-гидрокси-1,6-диоксо-2,7-диазаспиро[4.4]нон-3-ен-4-карбонитрил растворяют в 2-5-кратном избытке концентрированной галогеноводородной кислоты и добавляют 5-7-кратный избыток галогенида фосфора (III), кипятят 40-50 минут, охлаждают, разбавляют водой и экстрагируют этилацетатом, экстракт упаривают, образовавшийся осадок перекристаллизовывают из пропан-2-ола. The method of obtaining alkyl substituted 4-halogen-3-hydroxyfuro [3,4-c] pyridin-1 (3H) -ones of the general formula (1)
where R 1 = R 2 = CH 3 , Hlg = Cl; R 1 = CH 3 , R 2 = C 2 H 5 , Hlg = Cl; R 1 = CH 3 , R 2 = C 3 H 7 , Hlg = Cl; R 1 = R 2 = CH 3 , Hlg = Br; R 1 = CH 3 , R 2 = C 2 H 5 , Hlg = Br; R 1 = CH 3 , R 2 = C 3 H 7 , Hlg = Br, characterized in that the corresponding 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro [4.4] non-3-ene -4-carbonitrile is dissolved in a 2-5-fold excess of concentrated hydrohalic acid and a 5-7-fold excess of phosphorus (III) halide is added, boiled for 40-50 minutes, cooled, diluted with water and extracted with ethyl acetate, the extract is evaporated, the precipitate formed is recrystallized from propan-2-ol.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| RU2574412C1 true RU2574412C1 (en) | 2016-02-10 |
Family
ID=
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2680017C1 (en) * | 2018-11-06 | 2019-02-18 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Чувашский государственный университет имени И.Н. Ульянова" | Method of obtaining furo[3,4-c]pyridin-1(3h)-one derivatives |
| RU2738707C1 (en) * | 2020-06-02 | 2020-12-15 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Чувашский государственный университет имени И.Н. Ульянова" | Method of producing furo[3,4-c]pyridine-1(3h)-one derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2302422C2 (en) * | 2003-01-09 | 2007-07-10 | Танабе Сейяку Ко., Лтд | Condensed furan compounds |
| WO2012097479A1 (en) * | 2011-01-21 | 2012-07-26 | Abbott Laboratories | Bicyclic inhibitors of anaphastic lymphoma kinase |
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2302422C2 (en) * | 2003-01-09 | 2007-07-10 | Танабе Сейяку Ко., Лтд | Condensed furan compounds |
| WO2012097479A1 (en) * | 2011-01-21 | 2012-07-26 | Abbott Laboratories | Bicyclic inhibitors of anaphastic lymphoma kinase |
| WO2012097682A1 (en) * | 2011-01-21 | 2012-07-26 | Abbott Laboratories | Bicyclic inhibitors of alk |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2680017C1 (en) * | 2018-11-06 | 2019-02-18 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Чувашский государственный университет имени И.Н. Ульянова" | Method of obtaining furo[3,4-c]pyridin-1(3h)-one derivatives |
| RU2738707C1 (en) * | 2020-06-02 | 2020-12-15 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Чувашский государственный университет имени И.Н. Ульянова" | Method of producing furo[3,4-c]pyridine-1(3h)-one derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Voskressensky et al. | Domino reactions based on Knoevenagel condensation in the synthesis of heterocyclic compounds. Recent advances | |
| Bharate et al. | Metal-free domino one-pot protocols for quinoline synthesis | |
| Ren et al. | Molecular iodine-catalyzed multicomponent reactions: an efficient catalyst for organic synthesis | |
| Mekheimer et al. | Advancements in the synthesis of fused tetracyclic quinoline derivatives | |
| Bowman et al. | Synthesis of heteroarenes using cascade radical cyclisation via iminyl radicals | |
| Ghorbani-Vaghei et al. | N-Bromosuccinimide as an efficient catalyst for the synthesis of indolo [2, 3-b] quinolines | |
| NO313636B1 (en) | Substituted 6.5-heterocyclic derivatives, their use and pharmaceutical preparations | |
| Xia et al. | Efficient one-step synthesis of pyrrolo [3, 4-c] quinoline-1, 3-dione derivatives by organocatalytic cascade reactions of isatins and β-ketoamides | |
| Pin et al. | Intramolecular N-aza-amidoalkylation in association with Witkop–Winterfeldt oxidation as the key step to synthesize Luotonin-A analogues | |
| Dhiman et al. | Copper-catalyzed synthesis of quinoline derivatives via tandem Knoevenagel condensation, amination and cyclization | |
| Kumar et al. | A green, catalyst-free, solvent-free, high yielding one step synthesis of functionalized benzo [f] furo [3, 2-c] chromen-4-(5 H)-ones and furo [3, 2-c] quinolin-4-(5 H)-ones | |
| NO166080B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5,6,8-TRIFLUORKINOLINES. | |
| Dabiri et al. | An efficient synthesis of tetrahydropyrazolopyridine derivatives by a one-pot tandem multi-component reaction in a green media | |
| Mishra et al. | Metal-free regioselective tandem synthesis of diversely substituted benzimidazo-fused polyheterocycles in aqueous medium | |
| Xu et al. | Convenient one-step synthesis of pyrrolo [3, 4-c] quinolin-1-ones via TMSCl-catalyzed cascade reactions of isatins and β-enamino ketones | |
| Patra et al. | The synthesis, biological evaluation and fluorescence study of chromeno [4, 3-b] pyridin/quinolin-one derivatives, the backbone of natural product polyneomarline C scaffolds: a brief review | |
| Jiang et al. | Convenient synthesis of functionalized pyrrolo [3, 4-b] pyridines and pyrrolo [3, 4-b] quinolines via three-component reactions | |
| Lu et al. | One pot synthesis of pyrrolo [3, 4-c] quinolinone/pyrrolo [3, 4-c] quinoline derivatives from 2-aminoarylacrylates/2-aminochalcones and tosylmethyl isocyanide (TosMIC) | |
| Bariwal et al. | Microwave irradiation and multicomponent reactions | |
| RU2574412C1 (en) | METHOD FOR OBTAINING ALKYL-SUBSTITUTED 4-HALOGEN-3-HYDROXYFURO[3,4-c]PYRIDIN-1(3H)-ONES | |
| Brahmachari et al. | Trisodium Citrate Dihydrate-Catalyzed One-Pot Three-component Synthesis of Biologically Relevant Diversely Substituted 2-Amino-3-Cyano-4-(3-Indolyl)-4H-Chromenes under Eco-Friendly Conditions | |
| Ibrahim | Ring transformation of chromone-3-carboxamide | |
| Zhang et al. | Synthesis of polysubstituted 3H-pyrimidin-4-ones from cyanoacetamides under Vilsmeier conditions | |
| Chen et al. | Catalyst-free concise synthesis of imidazo [1, 2-a] pyrrolo [3, 4-e] pyridine derivatives | |
| Vincze et al. | Synthesis and cyclizations of 1-azapolyene derivatives |