MD4202C1 - Process for production of carbomethoxy derivatives of spiro[cyclopropane-oxindoles] - Google Patents
Process for production of carbomethoxy derivatives of spiro[cyclopropane-oxindoles] 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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- 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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Abstract
Изобретение относится к синтезу спиро[циклопропан-оксиндолов], функционализированных карбометокси группой, которые могут служить прекурсорами в синтезе веществ с анти-ВИЧ активностью.Способ включает реакцию циклопропанирования диазоизатинов метилакрилатом, который используют как в качестве реагента, так и растворителя при температуре его кипения.Предложенный способ позволяет более быстрое проведение реакции с высокими выходами, без использования катализаторов и инертной атмосферы.The invention relates to the synthesis of spiro [cyclopropane-oxindoles] functionalized with a carbomethoxy group, which can serve as precursors in the synthesis of substances with anti-HIV activity. The method includes a cyclopropanation reaction of diazoisatines with methyl acrylate, which is used both as a reagent and a solvent at its boiling point. The proposed method allows a more rapid reaction with high yields, without the use of catalysts and an inert atmosphere.
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. The invention refers to the synthesis of spiro[cyclopropane-oxindoles] functionalized with the carbomethoxy group, which can serve as precursors in the synthesis of substances with anti-HIV activity.
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. HIV/AIDS is a global health threat, the main cause of death being infectious diseases. More than 20 million people have died since the first cases of the disease in 1981. Non-nucleoside reverse transcriptase inhibitors stop the replication of the HIV virus by blocking the reverse transcriptase enzyme.
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]. It is known that some derivatives of spirooxindoles in racemic form, even at very low concentrations (6-15 nM EC50) show a high anti-HIV activity in vitro (for Nevirapine 50nM EC50) [1-2].
Reacţia de condensare a diazoizatinelor cu olefine este una dintre metodele principale în sinteza spirociclopropan-oxindolilor cu structură asemănătoare. The condensation reaction of diazoisatins with olefins is one of the main methods in the synthesis of spirocyclopropane-oxindoles with a similar structure.
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. Diazoizatins can be obtained in two simple and short synthesis steps from cheap reagents, which is very important for the pharmaceutical industry. The next stage of cyclopropanation is a catalytic reaction, which includes the interaction of diazo compounds with unsaturated compounds with the formation of spiroizatincyclopropanes, which can be used for the synthesis of substances that exhibit anti-HIV activity [2]. It has been established that only cis-derivatives of spiro[cyclopropane-oxindoles] possess the mentioned bioactivity.
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. Processes are known, where Rh(OAc)2 is applied for the synthesis of spirocyclooxindole spills as catalysts for the cyclopropanation of diazoisatins with olefins [2-4]. In this case, the main products of the reaction are the trans-diastereomers (up to 72%), which, as previously mentioned, do not show anti-HIV activity. Processes are also known, where Pd(OAc)2 is applied as a catalyst [5]. Under these conditions, a mixture of cis- and trans-isomers is obtained in a ratio of 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. The disadvantages of the mentioned processes are caused by the fact that these catalysts (Rh(OAc)2 [1-5], Pd(OAc)2 [4,5]) are part of the group of toxic reagents and the residues left after the reactions pollute the environment. Currently, according to the new requirements regarding the reagents used in various chemical reactions, the emphasis is on replacing toxic, explosive and corrosive catalysts with alternative, less harmful or ecological ones. All this, plus the need to obtain materials that do not contain any traces of metals, impose on us the task of creating alternative synthesis procedures.
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. The technical problem solved by this invention consists in simplifying the process of obtaining spiro[cyclopropane-oxindoles] functionalized with the carbomethoxy group, excluding the need to use unwanted catalysts.
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. The process, according to the invention, includes the cyclopropanation reaction of diazoizatin with methylacrylate at high temperatures (boiling temperature of methylacrylate 80.5ºC), at the same time methylacrylate is used both as a reagent and as a solvent.
Au fost efectuate reacţiile de ciclopropanare în condiţiile revendicate, folosind în calitate de compuşi iniţiali deferite diazoizatine III a-i, conform schemei: The cyclopropanation reactions were carried out under the claimed conditions, using as initial compounds different diazoizatins III a-i, according to the scheme:
Exemplu de realizare a invenţiei Example of realization of the invention
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. Different isatines I a-j are used as raw material, from which, according to the methodology described in reference [6], by refluxing in methanol together with p-toluenesulfonic acid hydrazide, the corresponding hydrazones II a-j are obtained. As a result of the hydrolysis of these compounds in aqueous medium, diazoisatins IIIa-j are formed, the subsequent cyclopropanation of which is carried out by the method described below.
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%). The suspension of diazoisatin (3.18 mmol) in methyl acrylate (5 mL) is refluxed until the disappearance of the substrate (control by TLC). The solvent is then evaporated in vacuo and the crude residue is chromatographed on silica gel using CH2Cl2:MeOH (from 0.5 to 2%) as eluent.
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). Under the conditions of the claimed process, as can be seen from tab. 1, the reactions proceed quite quickly with high yields. A small diastereoselectivity of the trans- or cis-diastereomer depends on the steric factors provided by the substituents in the indole ring. However, the formation of the kinetic cis-isomer is more favorable than the trans- (this is confirmed by the fact that in the case of unsubstituted diazoisatin the diastereomers were formed in the ratio trans/cis = 1:2).
Tabelul 1 Table 1
Caracteristicile reacţiilor realizate în condiţiile revendicate The characteristics of the reactions carried out under the claimed conditions
№ 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 № Product Yield, % Duration of reaction, hours 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 and 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. The products of reactions IV, V a i were obtained in crystalline form, and the physico-chemical constants of the synthesized compounds are presented below.
Trans-metil 2'-oxospiro[ciclopropan -1,3'-indol]-2-carboxilat IVa Trans-methyl 2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 193...196ºC. Calculated, %: C, 66.35; H, 5.10; N, 6.45; Oh, 22.10. C12H11NO3. Found, %: C, 66.22; H, 5.22; N, 6.51; Oh, 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). 1H-NMR, (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. 13 C-NMR, (100 MHz, CDCl 3 , 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). IR, (ν, cm-1, powder): 3272.2 (NH); 2989.3, 2950.3 (cyclopr.); 1739.9 (C(O)N); 1723.0, 1702.3 (COO).
Cis-metil 2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Va Cis-methyl 2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 171…172ºC. Calculated, C, 66.35; H, 5.10; N, 6.45; Oh, 22.10. C12H11NO3. Found, %: C, 66.27; H, 5.25; N, 6.47; Oh, 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). 1H-NMR, (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. 13 C-NMR, (100 MHz, CDCl 3 , 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). IR, (ν, cm-1, powder): 3259.0 (NH); 2956.0 (cyclopr.); 1726.0 (C(O)N); 1671.6 (COO).
Trans-metil 5'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVb Trans-methyl 5'-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 208…211ºC. Calculated, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; Oh, 16.21. C12H10BrNO3. Found, %: C, 48.78; H, 3.29; Br, 26.87; N, 4.82; Oh, 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). 1H-NMR, (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. 13 C-NMR, (100 MHz, CDCl 3 , 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). IR, (ν, cm-1, powder): 3153.8 (NH); 3028.8, 2864.9 (cyclopr.); 1725.8 (C(O)N); 1701.8 (COO).
Cis-metil 5'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vb Cis-methyl 5'-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 165…167ºC. Calculated, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; Oh, 16.21. C12H10BrNO3. Found, %: C, 48.76; H, 3.31; Br, 26.89; N, 4.79; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3156.9 (NH); 3024.3, 2960.4, 2858.4 (cyclopr.); 1734.6 (C(O)N); 1703.1 (COO).
Trans-metil 5-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVc Trans-methyl 5-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 172...173ºC. Calculated, %: C, 67.52; H, 5.67; N, 6.06; Oh, 20.76. C13H13NO3. Found, %: C, 67.46; H, 5.75; N, 6.00; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3163.4 (NH); 3033.2, 2959.1, 2918.4 (cyclopr.); 1734.9 (C(O)N); 1715.6 (COO).
Cis-metil 5-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vc Cis-methyl 5-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 167…169ºC. Calculated, %: C, 67.52; H, 5.67; N, 6.06; Oh, 20.76. C13H13NO3. Found, %: C, 67.59; H, 5.60; N, 6.11; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3227.2 (NH); 2944.8 (cyclopr.); 1739.9 (C(O)N); 1715.6 (COO).
Trans-metil 7-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVd Trans-methyl 7-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 182…183ºC. Calculated, %: C, 67.52; H, 5.67; N, 6.06; Oh, 20.76. C13H13NO3. Found, %: C, 67.55; H, 5.64; N, 6.13; Oh, 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). 1H-NMR, (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; OCH 3 ); 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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3143.2 (NH); 2999.9, 2953.8 (cyclopr.); 1731.2 (C(O)N); 1701.3 (COO).
Cis-metil 7-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vd Cis-methyl 7-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 161…163ºC. Calculated, %: C, 67.52; H, 5.67; N, 6.06; Oh, 20.76. C13H13NO3. Found, %: C, 67.50; H, 5.65; N, 6.08; Oh, 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). 1H-NMR, (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; OCH 3 ); 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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3155.2 (NH); 2989.2, 2954.9 (cyclopr.); 1725.1 (C(O)N); 1700.7 (COO).
Trans-metil 5,7-dibrom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVe Trans-methyl 5,7-dibromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 233…234ºC. Calculated, %: C, 38.43; H, 2.42; Br, 42.61; N, 3.73; Oh, 12.80. C12H9Br2NO3. Found, %: C, 38.54; H, 2.31; Br, 42.68; N, 3.70; Oh, 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). 1H-NMR, (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). 13 C-NMR, (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). IR, (ν, cm-1, powder): 3111.1 (NH); 2998.2, 2952.0 (cyclopr.); 1728.6 (C(O)N); 1703.8 (COO).
Cis-metil 5,7-dibrom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Ve Cis-methyl 5,7-dibromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 213...215ºC. Calculated, %: C, 38.43; H, 2.42; Br, 42.61; N, 3.73; Oh, 12.80. C12H10Br2NO3. Found, %: C, 38.30; H, 2.55; Br, 42.53; N, 3.84; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3195.3 (NH); 2988.7, 2901.5 (cyclopr.); 1713.2 (C(O)N), (COO).
Trans-metil 5-clor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVf Trans-methyl 5-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 201…203ºC. Calculated, %: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57; Oh, 19.07. C12H10ClNO3. Found, %: C, 57.39; H, 4.08; Cl, 14.00; N, 5.52; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3153.2 (NH); 3063.7, 2991.9, 2873.6 (cyclopr.); 1730.8 (C(O)N); 1699.8 (COO).
Cis-metil 5-clor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vf Cis-methyl 5-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 176…178ºC. Calculated, %: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57; Oh, 19.07. C12H10ClNO3. Found, %: C, 57.24; H, 4.06; Cl, 14.01; N, 5.55; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3151.5 (NH); 3061.8, 2990.6, 2870.2 (cyclopr.); 1732.7 (C(O)N); 1699.3 (COO).
Trans-metil 7-brom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVg Trans-methyl 7-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 183…185ºC. Calculated, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; Oh, 16.21. C12H10BrNO3. Found, %: C, 48.76; H, 3.31; Br, 26.89; N, 4.79; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3159.9 (NH); 3005.6, 2953.0 (cyclopr.); 1731.8 (C(O)N); 1704.6 (COO).
Cis-metil 7-brom-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vg Cis-methyl 7-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 214...215ºC. Calculated, %: C, 48.67; H, 3.40; Br, 26.98; N, 4.73; Oh, 16.21. C12H10BrNO3. Found, %: C, 48.74; H, 3.34; Br, 26.86; N, 4.83; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3140.8 (NH); 3028.0, 2953.6 (cyclopr.); 1725.5 (C(O)N); 1700.9 (COO).
Trans-metil 7-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVh Trans-methyl 7-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 228...230ºC. Calculated, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; Oh, 20.41. C12H10FNO3. Found, %: C, 61.33; H, 4.24; F, 8.04; N, 6.01; Oh, 8:39 p.m.
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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3170.4 (NH); 3007.7, 2960.8 (cyclopr.); 1723.5 (C(O)N); 1702.8 (COO).
Cis-metil 7-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vh Cis-methyl 7-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 214...215ºC. Calculated, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; Oh, 20.41. C12H10FNO3. Found, %: C, 61.36; H, 4.21; F, 8.16; N, 5.91; Oh, 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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3182.0 (NH); 2959.4 (cyclopr.); 1730.9 (C(O)N); 1707.2 (COO).
Trans-metil 5-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat IVi Trans-methyl 5-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 199…198ºC. Calculated, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; Oh, 20.41. C12H10FNO3. Found, %: C, 61.19; H, 4.38; F, 7.99; N, 5.96; Oh, 8:49 p.m.
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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3198.1 (NH); 3085.0, 2962.3 (cyclopr.); 1729.5 (C(O)N); 1701.4 (COO).
Cis-metil 5-fluor-2'-oxospiro[ciclopropan-1,3'-indol]-2-carboxilat Vi Cis-methyl 5-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-carboxylate 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. White crystals, m.p. 189...190ºC. Calculated, %: C, 61.28; H, 4.29; F, 8.08; N, 5.95; Oh, 20.41. C12H10FNO3. Found, %: C, 61.33; H, 4.34; F, 8.02; N, 5.89; Oh, 8:43 p.m.
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). 1H-NMR, (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. 13 C-NMR, (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). IR, (ν, cm-1, powder): 3169.1(NH); 2955.1, 2900.9 (cyclopr.); 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. The result of the invention consists in the fact that the claimed conditions allowed the much cheaper, more ecologically friendly synthesis, in a shorter time, with high yield of a series of spiro[cyclopropane-oxindoles] functionalized with the ester group, which exhibit anti-HIV activity .
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 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 2. Kumari G, Nutan I, Modi M, Gupta SK, Singh RK Eur. J. Med. Chem., 2011, 46, 1181-1188
3. Marti C., Carreira E.M. J. Am. Chem. Soc., 2005, 127, 11505-11515 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 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 5. Cava M.P., Litle R.L., Napier D.R. J. Amer. Chem. Soc., 1958, 80, 2257-2262
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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
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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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