MD4202C1 - Procedeu de obţinere a derivaţilor carbometoxi ai spiro[ciclopropan-oxindolilor] - Google Patents
Procedeu de obţinere a derivaţilor carbometoxi ai spiro[ciclopropan-oxindolilor] Download PDFInfo
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- MD4202C1 MD4202C1 MDA20120031A MD20120031A MD4202C1 MD 4202 C1 MD4202 C1 MD 4202C1 MD A20120031 A MDA20120031 A MD A20120031A MD 20120031 A MD20120031 A MD 20120031A MD 4202 C1 MD4202 C1 MD 4202C1
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- cyclopropane
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- 238000000034 method Methods 0.000 title claims abstract description 14
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000005888 cyclopropanation reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 238000009835 boiling Methods 0.000 claims abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000036436 anti-hiv Effects 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 125000003003 spiro group Chemical group 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- GGFAZNCZEXSGIY-UHFFFAOYSA-N 4-diazo-1,3a-dihydroindole-2,3-dione Chemical class [N-]=[N+]=C1C=CC=C2NC(=O)C(=O)C12 GGFAZNCZEXSGIY-UHFFFAOYSA-N 0.000 abstract description 3
- -1 carbomethoxy group Chemical group 0.000 abstract description 3
- 239000002243 precursor Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 4
- HBURLQPOAYRMFA-UHFFFAOYSA-N ethyl 3-(4-bromophenyl)-1,2-oxazole-5-carboxylate Chemical compound O1C(C(=O)OCC)=CC(C=2C=CC(Br)=CC=2)=N1 HBURLQPOAYRMFA-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- Indole Compounds (AREA)
Abstract
Invenţia se referă la sinteza spiro[ciclopropan-oxindolilor] funcţionalizaţi cu grupa carbometoxică, care pot servi ca precursori în sinteza substanţelor cu activitate anti-HIV.Procedeul include reacţia de ciclopropanare a diazoizatinelor cu metilacrilat, care este utilizat atât în calitate de reagent, cât şi de solvent la temperatura lui de fierbere.Procedeul propus permite efectuarea reacţiei într-un timp mai scurt cu randamente înalte, fără utilizarea catalizatorilor şi a atmosferei inerte.
Description
Invenţia se referă la sinteza spiro[ciclopropan-oxindolilor] funcţionalizaţi cu grupa carbometoxică, care pot servi ca precursori în sinteza substanţelor cu activitate anti-HIV.
HIV/SIDA este o ameninţare la nivel global a sănătăţii, cauza principală a decesului fiind bolile infecţioase. Mai mult de 20 mil de oameni s-au stins din viaţă de la primele cazuri de îmbolnăvire în anul 1981. Inhibitorii transcriptazei inverse nenucleozidice stopează replicarea virusului HIV prin blocarea enzimei transcriptazei inverse.
Este cunoscut că unii derivaţi ai spirooxindolilor în forma racemică, chiar la concentraţii foarte scăzute (6-15 nM EC50) manifestă o activitate înaltă anti-HIV in vitro (pentru Nevirapine 50nM EC50) [1-2].
Reacţia de condensare a diazoizatinelor cu olefine este una dintre metodele principale în sinteza spirociclopropan-oxindolilor cu structură asemănătoare.
Diazoizatinele pot fi obţinute în două etape de sinteză simplă şi de scurtă durată din reagenţi ieftini, ce este foarte important pentru industria farmaceutică. Etapa următoare de ciclopropanare este o reacţie catalitică, care include interacţiunea diazocompuşilor cu compuşi nesaturaţi cu formarea spiroizatinciclopropanilor, care pot fi folosiţi pentru sinteza substanţelor ce manifestă activitate anti-HIV [2]. S-a stabilit că numai cis-derivaţii spiro[ciclopropan-oxindolilor] posedă bioactivitatea menţionată.
Sunt cunoscute procedee, unde pentru sinteza deverşilor spirociclooxindoli în calitate de catalizatori la ciclopropanarea diazoizatinelor cu olefine se aplică Rh(OAc)2 [2-4]. În acest caz produşii principali ai reacţiei sunt trans-diastereomerii (până la 72%), care, cum a fost menţionat anterior, nu manifestă activitate anti-HIV. Sunt cunoscute, de asemenea, procedee, unde în calitate de catalizator se aplică Pd(OAc)2 [5]. În aceste condiţii se obţine un amestec de cis- şi trans-izomeri în raport de 1 : 1.
Dezavantajele procedeelor menţionate sunt cauzate de faptul că aceşti catalizatori (Rh(OAc)2 [1-5], Pd(OAc)2 [4,5]) fac parte din grupul reagenţilor toxici şi reziduurile rămase în urma reacţiilor poluează mediul înconjurător. Actualmente, conform cerinţelor noi referitoare la reagenţii utilizaţi în diverse reacţii chimice, accentul se pune pe înlocuirea catalizatorilor toxici, explozibili şi corozivi cu alţii de alternativă, mai puţin nocivi sau ecologici. Toate acestea, plus necesitatea de a obţine materiale care nu conţin nici urme de metale, ne impun sarcina de a crea procedee alternative de sinteză.
Problema tehnică rezolvată de această invenţie constă în simplificarea procedeului de obţinere a spiro[ciclopropan-oxindolilor] funcţionalizaţi cu grupa carbometoxică, excluderea necesităţii de a folosi catalizatorii nedoriţi.
Procedeul, conform invenţiei, include reacţia de ciclopropanare a diazoizatinei cu metilacrilat la temperaturi ridicate (temperatura de fierbere a metilacrilatului 80,5ºC), totodată metilacrilatul este folosit atât în calitate de reagent, cât şi în calitate de solvent.
Au fost efectuate reacţiile de ciclopropanare în condiţiile revendicate, folosind în calitate de compuşi iniţiali deferite diazoizatine III a-i, conform schemei:
Exemplu de realizare a invenţiei
În calitate de materie primă se folosesc diferite izatine I a-j, din care, conform metodicii descrise în referinţa [6], prin refluxare în metanol împreună cu hidrazida acidului p-toluensulfonic, se obţin hidrazonii corespunzători II a-j. În rezultatul hidrolizei acestor compuşi în mediu apos se formează diazoizatinele IIIa-j, ciclopropanarea ulterioară a cărora se efectuează prin metoda descrisă mai jos.
Suspensia diazoizatinei (3,18 mmol) în metilacrilat (5 mL) se refluxează până la dispariţia substratului (control prin TLC). Apoi solventul se evaporă în vacuum, iar reziduul brut se cromatografiază pe silicagel folosind ca eluant CH2Cl2:MeOH (de la 0,5 până la 2%).
În condiţiile procedeului revendicat, după cum se vede din tab. 1, reacţiile decurg destul de repede cu randamente înalte. O mică diastereoselectivitate a trans- sau cis-diastereomerului depinde de factorii sterici, furnizaţi de substituenţi în inelul indolic. Totuşi, formarea cis-izomerului cinetic este mai favorabilă, decât a celui trans- (se confirmă de faptul că în cazul diazoizatinei nesubstituite diastereomerii s-au format în raportul trans/cis =1:2).
Tabelul 1
Caracteristicile reacţiilor realizate în condiţiile revendicate
№ Produs Randament, % Durata reacţiei, ore DS, trans/cis 1 a 71 1,5 1 : 2 2 b 87 5,0 1,5 : 1 3 c 86 1,0 1,43 : 1 4 d 82 2,0 1,45 : 1 5 e 77 1,5 1 : 1,36 6 f 78 1,0 1,09 : 1 7 g 82 1,0 1 : 1,17 8 h 94 2,0 1,34 : 1 9 i 94 2,0 1 : 1,16
Produşii reacţiilor IV, V a-i au fost obţinuţi în formă cristalină, iar constantele fizico-chimice ale compuşilor sintetizaţi sunt prezentate mai jos.
Trans-metil 2'-oxospiro[ciclopropan -1,3'-indol]-2-carboxilat IVa
Cristale albe, p.t. 193...196ºC. Calculat, %: C, 66.35; H, 5.10; N, 6.45; O, 22.10. C12H11NO3. Găsit, %: C, 66.22; H, 5.22; N, 6.51; O, 22.05.
1H-RMN, (400 MHz, CDCl3, δ, ppm, J/Hz): 8.82 (s; 1H; NH); 7.37...6.84 (m; 4H; ind.); 3.77 (s; 3H; CH3); 2.70 (dd; 1H; J1=7.6; J2=8.4; CHCO); 2.42 (dd; 1H; J1=5.2; J2=7.6; CHH); 1.86 (dd; 1H; J1=5.2; J2=8.4; CHH).
13C-RMN, (100 MHz, CDCl3, δ, ppm): 175.72; 167.51; 140.84; 129.29; 127.78; 122.24; 118.79; 110.06; 52.44; 33.34; 32.66; 21.14.
IR, (ν, cm-1, praf): 3272.2 (NH); 2989.3, 2950.3 (ciclopr.); 1739.9 (C(O)N); 1723.0, 1702.3 (COO).
Cis-metil 2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Va
Cristale albe, p.t. 171…172ºC. Calculat, C, 66.35; H, 5.10; N, 6.45; O, 22.10. C12H11NO3. Găsit, %: C, 66.27; H, 5.25; N, 6.47; O, 22.01.
1H-RMN, (400 MHz, CDCl3, δ, ppm, J/Hz): 8.89 (s; 1H; NH); 7.37…6.98 (m; 4H; ind.); 3.71 (s; 3H; CH3); 2.75 (dd; 1H; J1=7.2; J2=8.4; CHCO); 2.20 (dd; 1H; J1=4.8; J2=7.2; CHH); 2.07 (dd; 1H; J1=4.8; J2=8.4; CHH).
13C-RMN, (100 MHz, CDCl3, δ, ppm): 176.80; 169.07; 141.37; 127.76; 126.22; 122.96; 122.31; 109.90; 52.21; 34.00; 32.77; 20.92.
IR, (ν, cm-1, praf): 3259.0 (NH); 2956.0 (ciclopr.); 1726.0 (C(O)N); 1671.6 (COO).
Trans-metil 5'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVb
Cristale albe, p.t. 208…211ºC. Calculat, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; O, 16.21. C12H10BrNO3. Găsit, %: C, 48.78; H, 3.29; Br, 26.87; N, 4.82; O, 16.23.
1H-RMN, (400 MHz, CDCl3, δ, ppm, J/Hz): 9.51 (s; 1H; NH); 7.52 (d; 1H; J=1.6; C4H); 7.37 (dd; 1H; J1=1.6; J2=8; C6H); 6.88 (d; 1H; J=8.0; C7H); 3.75 (s; 3H; CH3); 2.75 (dd; 1H; J1=7.6; J2=8.4; CHCO); 2.19 (dd; 1H; J1=4.8; J2=7.6; CHH); 2.08 (dd; 1H; J1=4.8; J2=8.4; CHH).
13C-RMN, (100 MHz, CDCl3, δ, ppm): 176.62; 168.77; 140.47; 130.65; 128.36; 126.23; 115.12; 111.32; 52.41; 33.94; 33.04; 21.39.
IR, (ν, cm-1, praf): 3153.8 (NH); 3028.8, 2864.9 (ciclopr.); 1725.8 (C(O)N); 1701.8 (COO).
Cis-metil 5'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vb
Cristale albe, p.t. 165…167ºC. Calculat, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; O, 16.21. C12H10BrNO3. Găsit, %: C, 48.76; H, 3.31; Br, 26.89; N, 4.79; O, 16.24.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.62 (s; 1H; NH); 7.24 (dd; 1H; J1=1.6; J2=8; C6H); 7.08 (d; 1H; J=1.6; C4H); 6.82 (d; 1H; J=8.0; C7H); 3.77 (s; 3H; CH3); 2.76 (dd; 1H; J1=8.0; J2=8.4; CHCO); 2.08 (dd; 1H; J1=4.8; J2=8.0; CHH); 1.82 (dd; 1H; J1=4.8; J2=8.4; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.19; 166.75; 141.64; 131.95; 130.05; 122.50; 113.64; 111.44; 51.88; 32.85; 32.33; 21.01.
IR, (ν, cm-1, praf): 3156.9 (NH); 3024.3, 2960.4, 2858.4 (ciclopr.); 1734.6 (C(O)N); 1703.1 (COO).
Trans-metil 5-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVc
Cristale albe, p.t. 172...173ºC. Calculat, %: C, 67.52; H, 5.67; N, 6.06; O, 20.76. C13H13NO3. Găsit, %: C, 67.46; H, 5.75; N, 6.00; O, 20.82.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.51 (s; 1H; NH); 6.97 (s; 1H; C4H); 6.92 (d; 1H; J=8.0; C6H); 6.77 (d; 1H; J=7.6; C7H); 3.66 (s; 3H; CH3); 2.44 (dd; 1H; J1=7.2; J2=8.0; CHCO); 1.95 (dd; 1H; J1=4.0; J2=7.2; CHH); 1.83 (dd; 1H; J1=4.0; J2=8.0; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 175.45; 168.72; 140.82; 130.07; 128.00; 126.19; 123.19; 109.74; 51.96; 33.77; 31.88; 21.37; 20.22.
IR, (ν, cm-1, praf): 3163.4 (NH); 3033.2, 2959.1, 2918.4 (ciclopr.); 1734.9 (C(O)N); 1715.6 (COO).
Cis-metil 5-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vc
Cristale albe, p.t. 167…169ºC. Calculat, %: C, 67.52; H, 5.67; N, 6.06; O, 20.76. C13H13NO3. Găsit, %: C, 67.59; H, 5.60; N, 6.11; O, 20.71.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.37 (s; 1H; NH); 6.90 (d; 1H; J=7.6; C6H); 6.76 (d; 1H; J=7.6; C7H); 6.66 (s; 1H; C4H); 3.66 (s; 3H; CH3); 2.62 (dd; 1H; J1=7.6; J2=8.4; CHCO); 2.06 (dd; 1H; J1=4.0; J2=7.6; CHH); 1.72 (dd; 1H; J1=4.0; J2=8.4; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.62; 167.09; 140.05; 130.24; 129.53; 127.77; 119.78; 109.63; 51.84; 32.46; 32.36; 21.21; 20.49.
IR, (ν, cm-1, praf): 3227.2 (NH); 2944.8 (ciclopr.); 1739.9 (C(O)N); 1715.6 (COO).
Trans-metil 7-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVd
Cristale albe, p.t. 182…183ºC. Calculat, %: C, 67.52; H, 5.67; N, 6.06; O, 20.76. C13H13NO3. Găsit, %: C, 67.55; H, 5.64; N, 6.13; O, 20.69.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.66 (s; 1H; NH); 6.96 (d; 1H; J=7.6; C4H); 6.90 (d; 1H; J=7.6; C6H); 6.75 (t; 1H; J=7.6; C5H); 3.64 (s; 3H; OCH3); 2.46 (dd; 1H; J1=7.6; J2=8.4; CHCO); 2.24 (s; 3H; CH3); 1.97 (dd; 1H; J1=4.0; J2=7.6; CHH); 1.84 (dd; 1H; J1=4.0; J2=8.4; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 176.00; 168.52; 141.78; 129.04; 125.75; 121.21; 119.74; 119.22; 51.79; 33.94; 31.98; 20.17; 16.79.
IR, (ν, cm-1, praf): 3143.2 (NH); 2999.9, 2953.8 (ciclopr.); 1731.2 (C(O)N); 1701.3 (COO).
Cis-metil 7-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vd
Cristale albe, p.t. 161…163ºC. Calculat, %: C, 67.52; H, 5.67; N, 6.06; O, 20.76. C13H13NO3. Găsit, %: C, 67.50; H, 5.65; N, 6.08; O, 20.78.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.57 (s; 1H; NH); 6.92 (d; 1H; J=7.6; C4H); 6.79 (t; 1H; J=7.6; C5H); 6.67 (d; 1H; J=7.6; C6H); 3.64 (s; 3H; OCH3); 2.64 (dd; 1H; J1=7.6; J2=8.0; CHCO); 2.24 (s; 3H; CH3); 2.06 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.73 (dd; 1H; J1=4.4; J2=8.0; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 175.14; 167.13; 141.01; 129.13; 128.91; 121.39; 119.25; 116.45; 51.85; 32.62; 20.63; 16.70.
IR, (ν, cm-1, praf): 3155.2 (NH); 2989.2, 2954.9 (ciclopr.); 1725.1 (C(O)N); 1700.7 (COO).
Trans-metil 5,7-dibrom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVe
Cristale albe, p.t. 233…234ºC. Calculat, %: C, 38.43; H, 2.42; Br, 42.61; N, 3.73; O, 12.80. C12H9Br2NO3. Găsit, %: C, 38.54; H, 2.31; Br, 42.68; N, 3.70; O, 12.76.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.20 (s; 1H; NH); 7.54 (d; 1H; J=2.0; C4H); 7.32 (d; 1H; J=2.0; C6H); 3.67 (s; 3H; CH3); 2.54 (dd; 1H; J1=7.6; J2=8.8; CHCO); 2.10 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.96 (dd; 1H; J1=4.4; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm, J/Hz): 11.20 (s; 1H; NH); 7.54 (d; 1H; J=2.0; C4H); 7.32 (d; 1H; J=2.0; C6H); 3.67 (s; 3H; CH3); 2.54 (dd; 1H; J1=7.6; J2=8.8; CHCO); 2.10 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.96 (dd; 1H; J1=4.4; J2=8.8; CHH).
IR, (ν, cm-1, praf): 3111.1 (NH); 2998.2, 2952.0 (ciclopr.); 1728.6 (C(O)N); 1703.8 (COO).
Cis-metil 5,7-dibrom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Ve
Cristale albe, p.t. 213…215ºC. Calculat, %: C, 38.43; H, 2.42; Br, 42.61; N, 3.73; O, 12.80. C12H10Br2NO3. Găsit, %: C, 38.30; H, 2.55; Br, 42.53; N, 3.84; O, 12.76.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.00 (s; 1H; NH); 7.44 (s; 1H; C4H); 7.24 (s; 1H; C6H); 3.81 (s; 3H; CH3); 2.93 (dd; 1H; J1=7.6; J2=8.8; CHCO); 2.05 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.93 (dd; 1H; J1=4.4; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.17; 166.78; 141.18; 133.26; 132.22; 122.20; 113.91; 102.94; 52.13; 33.50; 33.23; 21.78.
IR, (ν, cm-1, praf): 3195.3 (NH); 2988.7, 2901.5 (ciclopr.); 1713.2 (C(O)N), (COO).
Trans-metil 5-clor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVf
Cristale albe, p.t. 201…203ºC. Calculat, %: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57; O, 19.07. C12H10ClNO3. Găsit, %: C, 57.39; H, 4.08; Cl, 14.00; N, 5.52; O, 19.02.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.82 (s; 1H; NH); 7.19 (s; 1H; C4H); 7.17 (d; 1H; J=2.0; C6H); 6.89 (d; 1H; J=8.0; C7H); 3.68 (s; 3H; CH3); 2.51 (dd; 1H; J1=7.6; J2=8.8; CHCO); 2.04 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.89 (dd; 1H; J1=4.4; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 175.12; 168.79; 142.07; 128.18; 127.69; 126.03; 122.93; 111.24; 52.38; 33.84; 32.37; 20.90.
IR, (ν, cm-1, praf): 3153.2 (NH); 3063.7, 2991.9, 2873.6 (ciclopr.); 1730.8 (C(O)N); 1699.8 (COO).
Cis-metil 5-clor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vf
Cristale albe, p.t. 176…178ºC. Calculat, %: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57; O, 19.07. C12H10ClNO3. Găsit, %: C, 57.24; H, 4.06; Cl, 14.01; N, 5.55; O, 19.13.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.64 (s; 1H; NH); 7.14 (d; 1H; J=8.4; C6H); 7.10 (s; 1H; C4H); 6.86 (d; 1H; J=8.4; C7H); 3.62 (s; 3H; CH3); 2.89 (dd; 1H; J1=7.6; J2=8.8; CHCO); 2.01 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.89 (dd; 1H; J1=4.4; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.53; 167.19; 141.13; 131.66; 127.32; 126.20; 120.36; 110.95; 52.10; 32.93; 32.1; 21.09.
IR, (ν, cm-1, praf): 3151.5 (NH); 3061.8, 2990.6, 2870.2 (ciclopr.); 1732.7 (C(O)N); 1699.3 (COO).
Trans-metil 7-brom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVg
Cristale albe, p.t. 183…185ºC. Calculat, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; O, 16.21. C12H10BrNO3. Găsit, %: C, 48.76; H, 3.31; Br, 26.89; N, 4.79; O, 16.24.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.78 (s; 1H; NH); 7.28 (d; 1H; J=8.0; C5H); 6.92 (d; 1H; J=7.6; C4H); 6.84 (t; 1H; C6H); 3.80 (s; 3H; CH3); 2.79 (dd; 1H; J1=8.0; J2=8.8; CHCO); 2.08 (dd; 1H; J1=4.4; J2=8.0; CHH); 1.84 (dd; 1H; J1=4.4; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.41; 166.86; 141.72; 131.37; 130.49; 122.86; 118.47; 102.56; 52.01; 33.19; 33.18; 21.29.
IR, (ν, cm-1, praf): 3159.9 (NH); 3005.6, 2953.0 (ciclopr.); 1731.8 (C(O)N); 1704.6 (COO).
Cis-metil 7-brom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vg
Cristale albe, p.t. 214…215ºC. Calculat, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; O, 16.21. C12H10BrNO3. Găsit, %: C, 48.74; H, 3.34; Br, 26.86; N, 4.83; O, 16.22.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.86 (s; 1H; NH); 7.28 (d; 1H; J=8.0; C5H); 7.16 (d; 1H; J=7.6; C4H); 6.80 (t; 1H; C6H); 3.66 (s; 3H; CH3); 2.52 (dd; 1H; J1=7.6; J2=8.8; CHCO); 2.02 (dd; 1H; J1=4.4; J2=7.6; CHH); 1.91 (dd; 1H; J1=4.4; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 175.13; 168.39; 142.56; 130.72; 128.01; 122.57; 121.39; 102.84; 52.03; 34.54; 32.58; 20.81.
IR, (ν, cm-1, praf): 3140.8 (NH); 3028.0, 2953.6 (ciclopr.); 1725.5 (C(O)N); 1700.9 (COO).
Trans-metil 7-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVh
Cristale albe, p.t. 228…230ºC. Calculat, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; O, 20.41. C12H10FNO3. Găsit, %: C, 61.33; H, 4.24; F, 8.04; N, 6.01; O, 20.39.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.26 (s; 1H; NH); 7.23 (d; 1H; J=8.2; C5H); 6.94 (d; 1H; J=8.2; C6H); 3.63 (s; 3H; CH3); 3.39 (dd; 1H; J1=7.9; J2=9.0; CHCO); 2.42 (dd; 1H; J1=4.6; J2=9.0; CHH); 1.95 (dd; 1H; J1=4.6; J2=7.9; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.91; 167.22; 142.02; 129.13; 125.63; 125.47; 123.54; 113.96; 52.28; 33.71; 29.34; 17.91.
IR, (ν, cm-1, praf): 3170.4 (NH); 3007.7, 2960.8 (ciclopr.); 1723.5 (C(O)N); 1702.8 (COO).
Cis-metil 7-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vh
Cristale albe, p.t. 214…215ºC. Calculat, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; O, 20.41. C12H10FNO3. Găsit, %: C, 61.36; H, 4.21; F, 8.16; N, 5.91; O, 20.415.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.29 (s; 1H; NH); 7.21 (d; 1H; J=7.8; C5H); 6.91 (d; 1H; J=7.8; C6H); 3.62 (s; 3H; CH3); 2.65 (dd; 1H; J1=4.0; J2=8.0; CHCO); 2.59 (dd; 1H; J1=8.0; J2=9.5; CHH); 1.74 (dd; 1H; J1=4.0; J2=9.5; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 175.24; 167.76; 142.64; 129.03; 126.87; 124.66; 123.58; 114.03; 52.56; 32.71; 29.27; 16.57.
IR, (ν, cm-1, praf): 3182.0 (NH); 2959.4 (ciclopr.); 1730.9 (C(O)N); 1707.2 (COO).
Trans-metil 5-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVi
Cristale albe, p.t. 199…198ºC. Calculat, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; O, 20.41. C12H10FNO3. Găsit, %: C, 61.19; H, 4.38; F, 7.99; N, 5.96; O, 20.49.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.69 (s; 1H; NH); 6.99…6.86 (m; 3H; ind.); 3.68 (d, 3H; J=1.8; CH3); 2.51 (dd; 1H; J1=7.2; J2=8.5; CHCO); 2.01 (dd; 1H; J1=4.3; J2=7.2; CHH); 1.90 (dd; 1H; J1=4.3; J2=8.5; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 175.35; 168.79; 158.13 (J=236); 139.36; 127.89 (J=9); 114.07 (J=23); 110.65 (J=8); 110.48 (J=10); 52.27; 34.11; 32.23; 20.84.
IR, (ν, cm-1, praf): 3198.1 (NH); 3085.0, 2962.3 (ciclopr.); 1729.5 (C(O)N); 1701.4 (COO).
Cis-metil 5-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vi
Cristale albe, p.t. 189…190ºC. Calculat, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; O, 20.41. C12H10FNO3. Găsit, %: C, 61.33; H, 4.34; F, 8.02; N, 5.89; O, 20.43.
1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.51 (s; 1H; NH); 6.91…6.82 (m; 3H; ind.); 3.63 (c, 3H; CH3); 2.84 (dd; 1H; J1=5.6; J2=8.8; CHCO); 2.02 (dd; 1H; J1=4.3; J2=5.6; CHH); 1.85 (dd; 1H; J1=4.3; J2=8.8; CHH).
13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.72; 167.19; 158.55 (J=236); 138.42; 131.45 (J=10); 113.67 (J=24); 110.36 (J=8); 107.96 (J=16); 52.03; 32.93; 32.87; 21.02.
IR, (ν, cm-1, praf): 3169.1(NH); 2955.1, 2900.9 (ciclopr.); 1727.2 (C(O)N); 1698.1 (COO).
Rezultatul invenţiei constă în faptul că condiţiile revendicate au permis sinteza mult mai ieftină, mai prietenoasă ecologic, într-un timp mai scurt, cu randament înalt a unui şir de spiro[ciclopropan-oxindoli] funcţionalizaţi cu grupa ester, care manifestă activitate anti-HIV.
1. Jiang T., Kuhen K. L., Wolff K., Yin H., Bieza K., Caldwell J., Bursulaya B., Wu T. Y. H., He Y. Bioorganic & Medicinal Chemistry Letters, 2006, 16, 2105-2108
2. Kumari G., Nutan I., Modi M., Gupta S. K., Singh R. K. Eur. J. Med. Chem., 2011, 46, 1181-1188
3. Marti C., Carreira E.M. J. Am. Chem. Soc., 2005, 127, 11505-11515
4. Chen S., Ma J., Wang J. Tetrahedron Lett., 2008, 49, 6781-6783
5. Cava M.P., Litle R.L., Napier D.R. J. Amer. Chem. Soc., 1958, 80, 2257-2262
Claims (1)
- Procedeu de obţinere a derivaţilor carbometoxi ai spiro[ciclopropan-oxindolilor], care include reacţia de ciclopropanare a diazoizatinelor cu metilacrilat, totodată metilacrilatul este utilizat în calitate de solvent, iar reacţia se desfăşoară la temperatura de fierbere a lui.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57102863A (en) * | 1980-12-16 | 1982-06-26 | Takeda Chem Ind Ltd | Spiroindolinone and its preparation |
| US6046341A (en) * | 1995-10-24 | 2000-04-04 | Sanofi-Synthelabo | 3-spiro-indolin-2-one derivatives |
| WO2004037247A1 (en) * | 2002-10-21 | 2004-05-06 | Irm Llc | Oxindoles with anti-hiv activity |
| US20050015776A1 (en) * | 2003-06-02 | 2005-01-20 | Bimal Mehta | Processing convoy workflow scenarios |
| WO2007008664A1 (en) * | 2005-07-13 | 2007-01-18 | Allergan, Inc. | 3-spir0cycl0pr0pyl2-0xind0le kinase inhibitors |
-
2012
- 2012-03-21 MD MDA20120031A patent/MD4202C1/ro not_active IP Right Cessation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57102863A (en) * | 1980-12-16 | 1982-06-26 | Takeda Chem Ind Ltd | Spiroindolinone and its preparation |
| US6046341A (en) * | 1995-10-24 | 2000-04-04 | Sanofi-Synthelabo | 3-spiro-indolin-2-one derivatives |
| WO2004037247A1 (en) * | 2002-10-21 | 2004-05-06 | Irm Llc | Oxindoles with anti-hiv activity |
| US20050015776A1 (en) * | 2003-06-02 | 2005-01-20 | Bimal Mehta | Processing convoy workflow scenarios |
| WO2007008664A1 (en) * | 2005-07-13 | 2007-01-18 | Allergan, Inc. | 3-spir0cycl0pr0pyl2-0xind0le kinase inhibitors |
Non-Patent Citations (6)
| Title |
|---|
| Cava M.P., Litle R.L., Napier D.R. J. Amer. Chem. Soc., 1958, 80, 2257-2262 * |
| Chen S., Ma J., Wang J. Tetrahedron Lett., 2008, 49, 6781-6783 * |
| Jiang T., Kuhen K. L., Wolff K., Yin H., Bieza K., Caldwell J., Bursulaya B., Tuntland T., Zhang K., Karanewsky D., He Y. Bioorganic & Medicinal Chemistry Letters, 2006, 16, 2109-2112 * |
| Jiang T., Kuhen K. L., Wolff K., Yin H., Bieza K., Caldwell J., Bursulaya B., Wu T. Y. H., He Y. Bioorganic & Medicinal Chemistry Letters, 2006, 16, 2105-2108 * |
| Kumari G., Nutan I., Modi M., Gupta S. K., Singh R. K. Eur. J. Med. Chem., 2011, 46, 1181-1188 * |
| Marti C., Carreira E.M. J. Am. Chem. Soc., 2005, 127, 11505-11515 * |
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