MD4201C1

MD4201C1 - Process for production of carbonitrile derivatives of spiro[cyclopropane-oxindoles]

Info

Publication number: MD4201C1
Application number: MDA20120030A
Authority: MD
Inventors: Наталия СУКМАН; Флюр МАКАЕВ
Original assignee: Институт Химии Академии Наук Молдовы
Priority date: 2012-03-21
Filing date: 2012-03-21
Publication date: 2013-09-30
Also published as: MD4201B1

Abstract

The invention relates to the synthesis of carbonitrile derivatives of spiro[cyclopropane-oxindoles], which can serve as precursors in the synthesis of substances with anti-HIV activity.The process involves the reaction of cyclopropanation of diazoisatins with acrylonitrile, used both as reagent and solvent at its boiling point.The proposed process allows of carrying out the reaction in a shorter time with high yields, without the use of catalysts and inert atmosphere.

Description

Invenţia se referă la sinteza compuşilor spiro[ciclopropan-oxindolici] carbonitril funcţionalizaţi din diazoizatine, care pot servi ca precursori în sinteza preparatelor medicamentoase noi cu activitate biologică anti-HIV pronunţată. The invention refers to the synthesis of spiro[cyclopropane-oxindolic] carbonitrile compounds functionalized from diazoizatins, which can serve as precursors in the synthesis of new medicinal preparations with pronounced anti-HIV biological activity.

HIV/SIDA este o ameninţare la nivel global a sănătăţii, cauza principală a decesului fiind bolile infecţioase. Mai mult de 20 de millioane 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. Anterior s-a demonstrat că unii derivaţi ai spirooxindolilor în formă racemică, chiar la concentraţii foarte scăzute (6…15 nM EC50) manifestă o activitate înaltă in vitro (pentru Nevirapine 50nM EC50) [1-2]. 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. It was previously demonstrated that some derivatives of spirooxindoles in racemic form, even at very low concentrations (6...15 nM EC50) show a high 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 se caracterizează prin interacţiunea diazocompuşilor cu compuşi nesaturaţi cu formarea spiroizatinciclopropanilor, care pot fi aplicaţi în sinteza substanţelor ce manifestă activitate anti-HIV [2]. Este 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 is characterized by the interaction of diazo compounds with unsaturated compounds with the formation of spiroizatin cyclopropanes, which can be applied in the synthesis of substances that exhibit anti-HIV activity [2]. It is established that only cis-derivatives of spiro[cyclopropane-oxindoles] possess the mentioned bioactivity.

Este cunoscut că pentru sinteza diverşilor spirociclooxindoli în calitate de catalizatori în ciclopropanarea diazoizatinelor cu olefine s-au aplicat Rh(OAc)2 [2-4]. În acest caz produşii principali ai reacţiei au fost trans-diastereomerii (până la 72%), care, cum a fost menţionat, nu posedă activitate anti-HIV. Sunt cunoscute şi exemple unde în calitate de catalizator a fost folosit Pd(OAc)2 [5]. În aşa condiţii se obţine un amestec de cis- şi trans-izomeri în raportul 1 : 1. It is known that Rh(OAc)2 was used for the synthesis of various spirocyclooxindoles as catalysts in the cyclopropanation of diazoisatins with olefins [2-4]. In this case the main products of the reaction were the trans-diastereomers (up to 72%), which, as mentioned, do not possess anti-HIV activity. Examples are also known where Pd(OAc)2 was used as a catalyst [5]. In such conditions, a mixture of cis- and trans-isomers is obtained in the ratio 1:1.

Dezavantajele acestor metode sunt cauzate de faptul că catalizatorii menţionaţi (Rh(OAc)2 [1-5], Pd(OAc)2 [5,6]) fac parte din grupul reagenţilor toxici şi reziduurile rămase în urma reacţiilor poluează mediul înconjurător. Actualmente, conform cerinţelor noi referitor la regenţii 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 metode alternative de sinteză. The disadvantages of these methods are caused by the fact that the mentioned catalysts (Rh(OAc)2 [1-5], Pd(OAc)2 [5,6]) 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 reagents used in various chemical reactions, the focus 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 methods of synthesis.

Problema tehnică rezolvată de această invenţie constă în simplificarea procedeului de obţinere a spiro[ciclopropanoxindolilor] carbonitril funcţionalizaţi, excluderea necesităţii de a folosi catalizatorii nedoriţi. The technical problem solved by this invention consists in simplifying the process of obtaining functionalized spiro[cyclopropaneoxindoles] carbonitrile, excluding the need to use unwanted catalysts.

Procedeul, conform invenţiei, include reacţia de ciclopropanare a diazoizatinei cu acrilonitril la temperaturi ridicate (la temperatura de fierbere a acrilonitrilului t=77ºC ), totodată acrilonitrilul 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 acrylonitrile at high temperatures (at the boiling temperature of acrylonitrile t=77ºC), while acrylonitrile 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 diverse diazoizatine IIIa-j, conform schemei: The cyclopropanation reactions were carried out under the claimed conditions, using various diazoizatins IIIa-j as initial compounds, according to the scheme:

Exemplu de realizare a invenţiei: Example of realization of the invention:

În calitate de materie primă se aplică diferite izatine I a-j, din care, conform metodicii descrise [6], prin refluxul lor în metanol cu hidrazida acidului p-toluensulfonic se obţin hidrazonele corespunzătoare 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 method described [6], by refluxing them in methanol 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 acrilonitril (5 mL) se refluxează până la dispariţia substratului (control prin TLC). Mai departe 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 acrylonitrile (5 mL) is refluxed until the substrate disappears (control by TLC). Further, the solvent is 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, 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 izomerului trans- (confirmată de faptul, că în cazul diazoizatinei nesubstituite diastereomerii s-au format în raportul trans/cis =1:1,17). Under the conditions of the claimed procedure, 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-isomer (confirmed by the fact that, in the case of unsubstituted diazoisatin, the diastereomers were formed in the ratio trans/cis = 1:1.17).

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 91 5,0 1:1,17 2 b 84 3,0 1,4:1 3 c 82 6,0 1:1,3 4 d 74 4,0 1,3:1 5 e 89 1,5 1,1:1 6 f 92 1,0 1,3:1 7 g 85 1,0 1,9:1 8 h 63 2,0 1:1,68 9 i 89 3,0 1:1,45 10 j 74 2,0 1:1,4 № Product Yield, % Duration of reaction, hours DS, trans/cis 1 a 91 5.0 1:1.17 2 b 84 3.0 1.4:1 3 c 82 6.0 1:1.3 4 d 74 4.0 1.3:1 5 e 89 1.5 1.1:1 6 f 92 1.0 1.3:1 7 g 85 1.0 1.9:1 8 h 63 2.0 1:1 .68 9 i 89 3.0 1:1.45 10 j 74 2.0 1:1.4

Produşii reacţiilor IV a-j, V a-j au fost obţinuţi în formă cristalină, iar constantele fizico-chimice ale compuşilor sintetizaţi sunt prezentate mai jos. The products of reactions IV a-j, V a-j were obtained in crystalline form, and the physico-chemical constants of the synthesized compounds are presented below.

Trans-2'-oxospiro[ciclopropan -1,3'-indol]-2-nitril IVa Trans-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVa

Cristale albe, p.t. 236…239°C. Calculat, %: C, 71.73; H, 4.38; N, 15.21; O, 8.69. C11H8N2O. Găsit, %: C, 71.61; H, 4.49; N, 15.30; O, 8.61. White crystals, m.p. 236…239°C. Calculated, %: C, 71.73; H, 4.38; N, 15.21; Oh, 8.69. C11H8N2O. Found, %: C, 71.61; H, 4.49; N, 3.30 p.m.; Oh, 8.61.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.74 (s; 1H; NH); 7.17…6.87 (m; 4H; ind.); 2.69 (dd; 1H; J1=7.2; J2=9.6; CHCN); 2.03 (dd; 1H; J1=4,0; J2=9.6; CHH); 1.92 (dd; 1H; J1=4,0; J2=7.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.74 (s; 1H; NH); 7.17...6.87 (m; 4H; ind.); 2.69 (dd; 1H; J1=7.2; J2=9.6; CHCN); 2.03 (dd; 1H; J1=4.0; J2=9.6; CHH); 1.92 (dd; 1H; J1=4.0; J2=7.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173,02; 142.84; 128.18; 127.06; 121.46; 120.14; 116.29; 110.24; 32.05; 20.96; 14.36. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.02; 142.84; 128.18; 127.06; 121.46; 120.14; 116.29; 110.24; 32.05; 20.96; 14.36.

IR, cm-1: 3204.8 (NH); 3089.3, 3042.7 (ciclopr.); 2242.9 (CN); 1724.4 (CO); 1685.1 (OCN). IR, cm-1: 3204.8 (NH); 3089.3, 3042.7 (cyclopr.); 2242.9 (CN); 1724.4 (CO); 1685.1 (OCN).

Cis-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Va Cis-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Va

Cristale albe, p.t. 151…152°C. Calculat, %: C, 71.73; H, 4.38; N, 15.21; O, 8.69. C11H8N2O. Găsit, %: C, 71.81; H, 4.30; N, 15.29; O, 8.61. White crystals, m.p. 151…152°C. Calculated, %: C, 71.73; H, 4.38; N, 15.21; Oh, 8.69. C11H8N2O. Found, %: C, 71.81; H, 4.30; N, 15.29; Oh, 8.61.

1H-RMN, ppm(400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.78 (s; 1H; NH); 7.25…6.96 (m; 4H; ind.); 2.42 (dd; 1H; J1=7.2; J2=9.2; CHCN); 1.97 (dd; 1H; J1=4.4; J2=9.2; CHH); 1.95 (dd; 1H; J1=4.4; J2=7.2; CHH). 1H-NMR, ppm(400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.78 (s; 1H; NH); 7.25...6.96 (m; 4H; ind.); 2.42 (dd; 1H; J1=7.2; J2=9.2; CHCN); 1.97 (dd; 1H; J1=4.4; J2=9.2; CHH); 1.95 (dd; 1H; J1=4.4; J2=7.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.10; 143.20; 128.43; 124.94; 121.59; 121.11; 116.92; 110.47; 31.90; 20.82; 14.41. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 174.10; 143.20; 128.43; 124.94; 121.59; 121.11; 116.92; 110.47; 31.90; 20.82; 14.41.

IR (ν, cm-1, praf): 3204.6 (NH); 3088.8, 3042.7 (ciclopr.); 3.7 (CN); 1725.4 (CO); 1682.8 (OCN). IR (ν, cm-1, powder): 3204.6 (NH); 3088.8, 3042.7 (cyclopr.); 3.7 (CN); 1725.4 (CO); 1682.8 (OCN).

Trans-5'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVb Trans-5'-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVb

Cristale albe, p.t. 238…241°C. Calculat, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; O, 6.08. C11H7BrN2O. Găsit, %: C, 50.27; H, 2.63; Br, 30.48; N, 10.59; O, 6.03. White crystals, m.p. 238…241°C. Calculated, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; Oh, 6.08. C11H7BrN2O. Found, %: C, 50.27; H, 2.63; Br, 30.48; N, 10.59; Oh, 6.03.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.87 (s; 1H; NH); 7.27 (dd; 1H; J1=1.6; J2=8; C6H); 7.24 (d; 1H; J=1.6; C4H); 6.85 (d; 1H; J=8.0; C7H); 2.82 (dd; 1H; J1=7.6; J2=9.2; CHCN); 2.11 (dd; 1H; J1=4.4; J2=9.2; CHH); 1.91 (dd; 1H; J1=4.4; J2=7.6; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.87 (s; 1H; NH); 7.27 (dd; 1H; J1=1.6; J2=8; C6H); 7.24 (d; 1H; J=1.6; C4H); 6.85 (d; 1H; J=8.0; C7H); 2.82 (dd; 1H; J1=7.6; J2=9.2; CHCN); 2.11 (dd; 1H; J1=4.4; J2=9.2; CHH); 1.91 (dd; 1H; J1=4.4; J2=7.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm):172.69; 142.01; 130.81; 129.54; 123.71; 116.10; 113.76; 111.79; 32.05; 21.33; 14.69. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 172.69; 142.01; 130.81; 129.54; 123.71; 116.10; 113.76; 111.79; 32.05; 21.33; 14.69.

IR, (ν, cm-1, praf): 3266.7 (NH); 3020.2, 2987.9, 2900.2 (ciclopr.); 2253.2 (CN); 1717.1 (CON). IR, (ν, cm-1, powder): 3266.7 (NH); 3020.2, 2987.9, 2900.2 (cyclopr.); 2253.2 (CN); 1717.1 (CON).

Cis-5'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vb Cis-5'-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vb

Cristale albe, p.t. 197…199°C. Calculat, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; O, 6.08. C11H7BrN2O. Găsit, %: C, 50.34; H, 2.56; Br, 30.46; N, 10.60; O, 6.04. White crystals, m.p. 197…199°C. Calculated, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; Oh, 6.08. C11H7BrN2O. Found, %: C, 50.34; H, 2.56; Br, 30.46; N, 10.60; Oh, 6.04.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.01 (s; 1H; NH); 7.31 (dd; 1H; J1=1.6; J2=8; C6H); 7.22 (d; 1H; J=1.6; C4H); 6.87 (d; 1H; J=8.0; C7H); 2.63 (dd; 1H; J1=7.6; J2=9.2; CHCN); 2.05 (dd; 1H; J1=4.4; J2=9.2; CHH); 1.94 (dd; 1H; J1=4.4; J2=7.6; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.01 (s; 1H; NH); 7.31 (dd; 1H; J1=1.6; J2=8; C6H); 7.22 (d; 1H; J=1.6; C4H); 6.87 (d; 1H; J=8.0; C7H); 2.63 (dd; 1H; J1=7.6; J2=9.2; CHCN); 2.05 (dd; 1H; J1=4.4; J2=9.2; CHH); 1.94 (dd; 1H; J1=4.4; J2=7.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.69; 142.39; 131.17; 127.37; 124.31; 116.56; 113.88; 112.01; 31.81; 20.98; 14.93. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.69; 142.39; 131.17; 127.37; 124.31; 116.56; 113.88; 112.01; 31.81; 20.98; 14.93.

IR, (ν, cm-1, praf): 3264.5 (NH); 3023.6, 2988.4, 2901.4 (ciclopr.); 2251.3 (CN); 1717.9 (CON). IR, (ν, cm-1, powder): 3264.5 (NH); 3023.6, 2988.4, 2901.4 (cyclopr.); 2251.3 (CN); 1717.9 (CON).

Trans-7'-bromo-5-cloro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVc Trans-7'-bromo-5-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVc

Cristale albe, p.t. 257…259°C. Calculat, %: C, 44.40; H, 2.03; Br, 26.86; Cl, 11.92; N, 9.42; O, 5.38. C11H6ClBrN2O. Găsit, %: C, 44.52; H, 2.13; Br, 26.76; Cl, 11.83; N, 9.39; O, 5.38. White crystals, m.p. 257…259°C. Calculated, %: C, 44.40; H, 2.03; Br, 26.86; Cl, 11.92; N, 9.42; Oh, 5.38. C11H6ClBrN2O. Found, %: C, 44.52; H, 2.13; Br, 26.76; Cl, 11.83; N, 9.39; Oh, 5.38.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.24 (s; 1H; NH); 7.39 (s; 1H; C4H); 7.22 (s; 1H; C6H); 3.01 (dd; 1H; J1=6.8; J2=8.0; CHCN); 2.22 (dd; 1H; J1=4.8; J2=8.0; CHH); 1.94 (dd; 1H; J1=4.8; J2=6.8; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.24 (s; 1H; NH); 7.39 (s; 1H; C4H); 7.22 (s; 1H; C6H); 3.01 (dd; 1H; J1=6.8; J2=8.0; CHCN); 2.22 (dd; 1H; J1=4.8; J2=8.0; CHH); 1.94 (dd; 1H; J1=4.8; J2=6.8; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 172.79; 141.19; 130.55; 130.38; 126.94; 120.53; 116.20; 102.78; 33.07; 30.93; 21.96; 15.31. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 172.79; 141.19; 130.55; 130.38; 126.94; 120.53; 116.20; 102.78; 33.07; 30.93; 21.96; 15.31.

IR, (ν, cm-1, praf): 3146.2 (NH); 3077.6 (ciclopr.); 2246.3 (CN); 1714.7 (CON). IR, (ν, cm-1, powder): 3146.2 (NH); 3077.6 (cyclopr.); 2246.3 (CN); 1714.7 (CON).

Cis-7'-bromo-5-cloro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vc Cis-7'-bromo-5-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vc

Cristale albe, p.t. 233…234°C. Calculat, %: C, 44.40; H, 2.03; Br, 26.86; Cl, 11.92; N, 9.42; O, 5.38. C11H6ClBrN2O. Găsit, %: C, 44.48; H, 1.95; Br, 26.94; Cl, 11.81; N, 9.45; O, 5.38. White crystals, m.p. 233...234°C. Calculated, %: C, 44.40; H, 2.03; Br, 26.86; Cl, 11.92; N, 9.42; Oh, 5.38. C11H6ClBrN2O. Found, %: C, 44.48; H, 1.95; Br, 26.94; Cl, 11.81; N, 9.45; Oh, 5.38.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.28 (s; 1H; NH); 7.47 (s; 1H; C4H); 7.17 (s; 1H; C6H); 2.65 (dd; 1H; J1=7.6; J2=9.6; CHCN); 2.35 (dd; 1H; J1=5.2; J2=7.6; CHH); 1.98 (dd; 1H; J1=5.2; J2=9.6; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.28 (s; 1H; NH); 7.47 (s; 1H; C4H); 7.17 (s; 1H; C6H); 2.65 (dd; 1H; J1=7.6; J2=9.6; CHCN); 2.35 (dd; 1H; J1=5.2; J2=7.6; CHH); 1.98 (dd; 1H; J1=5.2; J2=9.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.91; 141.60; 130.71; 128.59; 126.91; 121.00; 116.86; 103.01; 32.90; 21.26; 16.01. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.91; 141.60; 130.71; 128.59; 126.91; 121.00; 116.86; 103.01; 32.90; 21.26; 16.01.

IR, (ν, cm-1, praf): 3252.9 (NH); 3046.4 (ciclopr.); 2255.0 (CN); 1721.8 (CON). IR, (ν, cm-1, powder): 3252.9 (NH); 3046.4 (cyclopr.); 2255.0 (CN); 1721.8 (CON).

Trans-5'-iodo-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVd Trans-5'-iodo-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVd

Cristale albe, p.t. 244…246°C. Calculat, %: C, 42.61; H, 2.28; I, 40.92; N, 9.03; O, 5.16. C11H7IN2O. Găsit, %: C, 42.72; H, 2.17; I, 40.82; N, 9.08; O, 5.21. White crystals, m.p. 244…246°C. Calculated, %: C, 42.61; H, 2.28; I, 40.92; N, 9.03; Oh, 5.16. C11H7IN2O. Found, %: C, 42.72; H, 2.17; I, 40.82; N, 9.08; Oh, 5.21.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.88 (s; 1H; NH); 7.48 (d; 1H; J1=8.0; C6H); 7.40 (s; 1H; C4); 6.75 (d; 1H; J=8.0; C7); 2.88 (dd; 1H; J1=7.6; J2=8.4; CHCN); 2.12 (dd; 1H; J1=4.8; J2=8.4; CHH); 1.90 (dd; 1H; J1=4.48; J2=7.6; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.88 (s; 1H; NH); 7.48 (d; 1H; J1=8.0; C6H); 7.40 (s; 1H; C4); 6.75 (d; 1H; J=8.0; C7); 2.88 (dd; 1H; J1=7.6; J2=8.4; CHCN); 2.12 (dd; 1H; J1=4.8; J2=8.4; CHH); 1.90 (dd; 1H; J1=4.48; J2=7.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 172.51; 142.63; 136.76; 129.92; 129.24; 116.23; 112.37; 83.83; 31.82; 21.33; 14.63. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 172.51; 142.63; 136.76; 129.92; 129.24; 116.23; 112.37; 83.83; 31.82; 21.33; 14.63.

IR, (ν, cm-1, praf): 3156.8 (NH); 2988.3 (ciclopr.); 2243.8 (CN); 1707.0 (CON). IR, (ν, cm-1, powder): 3156.8 (NH); 2988.3 (cyclopr.); 2243.8 (CN); 1707.0 (CON).

Cis-5'-iodo-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vd Cis-5'-iodo-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vd

Cristale albe, p.t. 227…228°C. Calculat, %: C, 42.61; H, 2.28; I, 40.92; N, 9.03; O, 5.16. C11H7IN2O. Găsit, %: C, 42.55; H, 2.34; I, 40.86; N, 9.09; O, 5.16. White crystals, m.p. 227…228°C. Calculated, %: C, 42.61; H, 2.28; I, 40.92; N, 9.03; Oh, 5.16. C11H7IN2O. Found, %: C, 42.55; H, 2.34; I, 40.86; N, 9.09; Oh, 5.16.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.93 (s; 1H; NH); 7.56 (dd; 1H; J1=1.2; J2=8.0; C6); 7.39 (s; 1H; C4); 6.81 (d; 1H; J=8.0; C7H); 2.53 (dd; 1H; J1=6.8; J2=9.2; CHCN); 2.19 (dd; 1H; J1=4.8; J2=6.8; CHH); 1.93 (dd; 1H; J1=4.48; J2=9.6; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.93 (s; 1H; NH); 7.56 (dd; 1H; J1=1.2; J2=8.0; C6); 7.39 (s; 1H; C4); 6.81 (d; 1H; J=8.0; C7H); 2.53 (dd; 1H; J1=6.8; J2=9.2; CHCN); 2.19 (dd; 1H; J1=4.8; J2=6.8; CHH); 1.93 (dd; 1H; J1=4.48; J2=9.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.62; 142.98; 137.14; 129.90; 127.88; 117.00; 112.64; 83.98; 31.63; 20.85; 15.10. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.62; 142.98; 137.14; 129.90; 127.88; 117.00; 112.64; 83.98; 31.63; 20.85; 15.10.

IR, (ν, cm-1, praf): 3194.9 (NH); 3033.6 (ciclopr.); 2241.3 (CN); 1720.1 (CON). IR, (ν, cm-1, powder): 3194.9 (NH); 3033.6 (cyclopr.); 2241.3 (CN); 1720.1 (CON).

Trans-5'-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVe Trans-5'-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVe

Cristale albe, p.t. 238…240°C. Calculat, %: C, 72.71; H, 5.08; N, 14.13; O, 8.07. C12H10N2O. Găsit, %: C, 72.62; H, 5.16; N, 14.18; O, 8.01. White crystals, m.p. 238...240°C. Calculated, %: C, 72.71; H, 5.08; N, 14.13; Oh, 8.07. C12H10N2O. Found, %: C, 72.62; H, 5.16; N, 14.18; Oh, 8.01.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.65 (s; 1H; NH); 6.95 (d; 1H; J=8.0; C6H); 6.81 (s; 1H; C4H); 6.78 (d; 1H; J=8.0; C5H); 2.67 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.26 (s; 3H; CH3); 2.00 (dd; 1H; J1=4.8; J2=9.2; CHH); 1.88 (dd; 1H; J1=4.8; J2=7.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.65 (s; 1H; NH); 6.95 (d; 1H; J=8.0; C6H); 6.81 (s; 1H; C4H); 6.78 (d; 1H; J=8.0; C5H); 2.67 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.26 (s; 3H; CH3); 2.00 (dd; 1H; J1=4.8; J2=9.2; CHH); 1.88 (dd; 1H; J1=4.8; J2=7.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.11; 140.34; 130.58; 128.59; 127.08; 120.88; 116.56; 109.97; 32.08; 21.19; 20.91; 14.23. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.11; 140.34; 130.58; 128.59; 127.08; 120.88; 116.56; 109.97; 32.08; 21.19; 20.91; 14.23.

IR, (ν, cm-1, praf): 3197.4 (NH); 3034.0, 2923.5 (ciclopr.); 2240.6 (CN); 1720.1 (CON). IR, (ν, cm-1, powder): 3197.4 (NH); 3034.0, 2923.5 (cyclopr.); 2240.6 (CN); 1720.1 (CON).

Cis-5'-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Ve Cis-5'-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Ve

Cristale albe, p.t. 200…202°C. Calculat, %: C, 72.71; H, 5.08; N, 14.13; O, 8.07. C12H10N2O. Găsit, %: C, 72.83; H, 5.08; N, 14.13; O, 8.07. White crystals, m.p. 200…202°C. Calculated, %: C, 72.71; H, 5.08; N, 14.13; Oh, 8.07. C12H10N2O. Found, %: C, 72.83; H, 5.08; N, 14.13; Oh, 8.07.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.68 (s; 1H; NH); 7.03 (d; 1H; J=8.0; C6H); 6.88 (s; 1H; C4H); 6.84 (d; 1H; J=8.0; C7H); 2.43 (t; 1H; CHCN); 2.34 (s; 3H; CH3); 1.93 (d; 2H; J=8.8; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.68 (s; 1H; NH); 7.03 (d; 1H; J=8.0; C6H); 6.88 (s; 1H; C4H); 6.84 (d; 1H; J=8.0; C7H); 2.43 (t; 1H; CHCN); 2.34 (s; 3H; CH3); 1.93 (d; 2H; J=8.8; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.16; 140.72; 130.62; 128.86; 125.03; 121.84; 117.45; 110.19; 31.90; 21.35; 20.73; 14.38. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 174.16; 140.72; 130.62; 128.86; 125.03; 121.84; 117.45; 110.19; 31.90; 21.35; 20.73; 14.38.

IR, (ν, cm-1, praf): 3194.2 (NH); 2988.4, 2921.8 (ciclopr.); 2243.8 (CN); 1717.8 (CON). IR, (ν, cm-1, powder): 3194.2 (NH); 2988.4, 2921.8 (cyclopr.); 2243.8 (CN); 1717.8 (CON).

Trans-7'-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVf Trans-7'-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVf

Cristale albe, p.t. 222°C. Calculat, %: C, 72.71; H, 5.08; N, 14.13; O, 8.07. C12H10N2O. Găsit, %: C, 72.68; H, 5.11; N, 14.09; O, 8.11. White crystals, m.p. 222°C. Calculated, %: C, 72.71; H, 5.08; N, 14.13; Oh, 8.07. C12H10N2O. Found, %: C, 72.68; H, 5.11; N, 14.09; Oh, 8.11.

1H-RMN (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.83 (s; 1H; NH); 6.97 (d; 1H; J=8.0; C4H); 6.83…6.79 (m; 2H; C6H şi C5H); 2.71 (dd; 1H; J1=6.4; J2=8.8; CHCN); 2.03 (dd; 1H; J1=4.4; J2=8.8; CHH); 1.89 (dd; 1H; J1=4.4; J2=6.4; CHH). 1H-NMR (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.83 (s; 1H; NH); 6.97 (d; 1H; J=8.0; C4H); 6.83…6.79 (m; 2H; C6H and C5H); 2.71 (dd; 1H; J1=6.4; J2=8.8; CHCN); 2.03 (dd; 1H; J1=4.4; J2=8.8; CHH); 1.89 (dd; 1H; J1=4.4; J2=6.4; CHH).

13C-RMN (100 Hz, DMSO-d6, δ, ppm): 174.78; 141.68; 130.04; 124.73; 121.72; 119.84; 118.66; 117.45; 32.21; 20.76; 16.86; 14.67. 13 C-NMR (100 Hz, DMSO-d6, δ, ppm): 174.78; 141.68; 130.04; 124.73; 121.72; 119.84; 118.66; 117.45; 32.21; 20.76; 16.86; 14.67.

IR, (ν, cm-1, praf): 3150.1 (NH); 3043.3, 2850.4 (ciclopr.); 2243.3 (CN); 1702.7 (CON). IR, (ν, cm-1, powder): 3150.1 (NH); 3043.3, 2850.4 (cyclopr.); 2243.3 (CN); 1702.7 (CON).

Cis-7'-metil-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vf Cis-7'-methyl-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vf

Cristale albe, p.t. 210…213°C. Calculat, %: C, 72.71; H, 5.08; N, 14.13; O, 8.07. C12H10N2O. Găsit, %: C, 72.59; H, 5.14; N, 14.23; O, 8.11. White crystals, m.p. 210…213°C. Calculated, %: C, 72.71; H, 5.08; N, 14.13; Oh, 8.07. C12H10N2O. Found, %: C, 72.59; H, 5.14; N, 14.23; Oh, 8.11.

1H-RMN, (400 MHz, DMSO-d(100MHz, DMSO-d6, δ, ppm):, δ, ppm, J/Hz): 10.89 (s; 1H; NH); 7.06 (d; 1H; J=8.0; C4H); 6.95…6.90 (m; 2H; C6H şi C5H); 2.51 (dd; 1H; J1=7.2; J2=9.6; CHCN); 2.03 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.94 (dd; 1H; J1=4.8; J2=9.6; CHH). 1H-NMR, (400 MHz, DMSO-d(100MHz, DMSO-d6, δ, ppm):, δ, ppm, J/Hz): 10.89 (s; 1H; NH); 7.06 (d; 1H; J=8.0; C4H); 6.95…6.90 (m; 2H; C6H and C5H); 2.51 (dd; 1H; J1=7.2; J2=9.6; CHCN); 2.03 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.94 (dd; 1H; J1=4.8; J2=9.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.60; 141.37; 129.70; 126.75; 121.62; 119.65 117.57; 116.53; 32.34; 21.07; 16.74; 14.40. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.60; 141.37; 129.70; 126.75; 121.62; 119.65 117.57; 116.53; 32.34; 21.07; 16.74; 14.40.

IR, (ν, cm-1, praf): 3152.3 (NH); 3046.5, 2848.8 (ciclopr.); 2245.2 (CN); 1702.1 (CON). IR, (ν, cm-1, powder): 3152.3 (NH); 3046.5, 2848.8 (cyclopr.); 2245.2 (CN); 1702.1 (CON).

Trans-5'-cloro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVg Trans-5'-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVg

Cristale albe, p.t. 235…236°C. Calculat, %: C, 60.43; H, 3.23; Cl, 16.22; N, 12.81; O, 7.32. C11H7ClN2O. Găsit, %: C, 60.54; H, 3.34; Cl, 16.15; N, 12.74; O, 7.24. White crystals, m.p. 235...236°C. Calculated, %: C, 60.43; H, 3.23; Cl, 16.22; N, 12.81; Oh, 7.32. C11H7ClN2O. Found, %: C, 60.54; H, 3.34; Cl, 16.15; N, 12.74; Oh, 7.24.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.88 (s; 1H; NH); 7.17 (d; 1H; J=1.6; C4H); 6.90 (d; 1H; J=8.0; C6H); 6.86 (d; 1H; J=8.0; C7H); 2.91(dd; 1H; J1=7.2; J2=9.2; CHCN); 2.15 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.91 (dd; 1H; J1=4.8; J2=9.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.88 (s; 1H; NH); 7.17 (d; 1H; J=1.6; C4H); 6.90 (d; 1H; J=8.0; C6H); 6.86 (d; 1H; J=8.0; C7H); 2.91(dd; 1H; J1=7.2; J2=9.2; CHCN); 2.15 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.91 (dd; 1H; J1=4.8; J2=9.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.44; 142.15; 128.78; 126.46; 124.53; 121.74; 117.91; 112.49; 31.90; 20.68; 15.23. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.44; 142.15; 128.78; 126.46; 124.53; 121.74; 117.91; 112.49; 31.90; 20.68; 15.23.

IR, (ν, cm-1, praf): 3124.9 (NH); 2999.5 (ciclopr.); 2246.7 (CN); 1715.9 (CON). IR, (ν, cm-1, powder): 3124.9 (NH); 2999.5 (cyclopr.); 2246.7 (CN); 1715.9 (CON).

Cis-5'-cloro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vg Cis-5'-chloro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vg

Cristale albe, p.t. 203…205°C. Calculat, %: C, 60.43; H, 3.23; Cl, 16.22; N, 12.81; O, 7.32. C11H7ClN2O. Găsit, %: C, 60.50; H, 3.28; Cl, 16.17; N, 12.76; O, 7.27. White crystals, m.p. 203…205°C. Calculated, %: C, 60.43; H, 3.23; Cl, 16.22; N, 12.81; Oh, 7.32. C11H7ClN2O. Found, %: C, 60.50; H, 3.28; Cl, 16.17; N, 12.76; Oh, 7.27.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.93 (s; 1H; NH); 7.26 (d; 1H; J=8.0; C6H); 7.14 (d; 1H; J=1.6; C4H); 6.96 (d; 1H; J=8.0; C7H); 2.56 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.23 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.95 (dd; 1H; J1=4.8; J2=9.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.93 (s; 1H; NH); 7.26 (d; 1H; J=8.0; C6H); 7.14 (d; 1H; J=1.6; C4H); 6.96 (d; 1H; J=8.0; C7H); 2.56 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.23 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.95 (dd; 1H; J1=4.8; J2=9.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.87; 141.95; 128.34; 127.09; 126.59; 121.64; 116.84; 111.54; 31.96; 20.95; 15.00. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.87; 141.95; 128.34; 127.09; 126.59; 121.64; 116.84; 111.54; 31.96; 20.95; 15.00.

IR, (ν, cm-1, praf): 3174.1 (NH); 3077.2, 2988.5 (ciclopr.); 2246.3 (CN); 1715.1 (CON). IR, (ν, cm-1, powder): 3174.1 (NH); 3077.2, 2988.5 (cyclopr.); 2246.3 (CN); 1715.1 (CON).

Trans-7'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVh Trans-7'-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVh

Cristale albe, p.t. 232…234°C. Calculat, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; O, 6.08. C11H7BrN2O. Găsit, %: C, 50.14; H, 2.76; Br, 30.30; N, 10.75; O, 6.05. White crystals, m.p. 232…234°C. Calculated, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; Oh, 6.08. C11H7BrN2O. Found, %: C, 50.14; H, 2.76; Br, 30.30; N, 10.75; Oh, 6.05.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.08 (s; 1H; NH); 7.39 (dd; 1H; J1=0.8; J2=8.0; C4H); 7.07 (d; 1H; J=7.2; C6H); 6.96 (t; 1H; C5H); 2.54 (dd; 1H; J1=7.2; J2=9.6; CHCN); 2.08 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.99 (dd; 1H; J1=4.8; J2=9.6; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.08 (s; 1H; NH); 7.39 (dd; 1H; J1=0.8; J2=8.0; C4H); 7.07 (d; 1H; J=7.2; C6H); 6.96 (t; 1H; C5H); 2.54 (dd; 1H; J1=7.2; J2=9.6; CHCN); 2.08 (dd; 1H; J1=4.8; J2=7.2; CHH); 1.99 (dd; 1H; J1=4.8; J2=9.6; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.01; 142.52; 131.53; 126.92; 123.09; 120.21; 116.84; 103.06; 32.75; 21.23; 15.27. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 174.01; 142.52; 131.53; 126.92; 123.09; 120.21; 116.84; 103.06; 32.75; 21.23; 15.27.

IR, (ν, cm-1, praf): 3151.5 (NH); 3084.4, 3019.1 (ciclopr.); 2249.8 (CN); 1710.8 (CON). IR, (ν, cm-1, powder): 3151.5 (NH); 3084.4, 3019.1 (cyclopr.); 2249.8 (CN); 1710.8 (CON).

Cis-7'-bromo-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vh Cis-7'-bromo-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vh

Cristale albe, p.t. 213…215°C. Calculat, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; O, 6.08. C11H7BrN2O. Găsit, %: C, 50.33; H, 2.78; Br, 30.27; N, 10.59; O, 6.02. White crystals, m.p. 213...215°C. Calculated, %: C, 50.22; H, 2.68; Br, 30.37; N, 10.65; Oh, 6.08. C11H7BrN2O. Found, %: C, 50.33; H, 2.78; Br, 30.27; N, 10.59; Oh, 6.02.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.06 (s; 1H; NH); 7.32 (d; 1H; J=8.0; C4H); 7.01 (d; 1H; J=7.2; C6H); 6.86 (t; 1H; C5H); 2.86 (dd; 1H; J1=7.2; J2=8.8; CHCN); 2.12 (dd; 1H; J1=4.8; J2=8.8; CHH); 1.94 (dd; 1H; J1=4.8; J2=7.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.06 (s; 1H; NH); 7.32 (d; 1H; J=8.0; C4H); 7.01 (d; 1H; J=7.2; C6H); 6.86 (t; 1H; C5H); 2.86 (dd; 1H; J1=7.2; J2=8.8; CHCN); 2.12 (dd; 1H; J1=4.8; J2=8.8; CHH); 1.94 (dd; 1H; J1=4.8; J2=7.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 172.92; 142.13; 131.25; 129.00; 123.06; 119.56; 116.25; 102.81; 32.91; 21.58; 14.95. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 172.92; 142.13; 131.25; 129.00; 123.06; 119.56; 116.25; 102.81; 32.91; 21.58; 14.95.

IR, (ν, cm-1, praf): 3149.5 (NH); 3081.7, 3020.8 (ciclopr.); 2243.5 (CN); 1709.6 (CON). IR, (ν, cm-1, powder): 3149.5 (NH); 3081.7, 3020.8 (cyclopr.); 2243.5 (CN); 1709.6 (CON).

Trans-7'-fluoro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVi Trans-7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVi

Cristale albe, p.t. 239…242°C. Calculat, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; O, 7.91. C11H7FN2O. Găsit, %: C, 65.44; H, 3.58; F, 9.34; N, 13.80; O, 7.85. White crystals, m.p. 239…242°C. Calculated, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; Oh, 7.91. C11H7FN2O. Found, %: C, 65.44; H, 3.58; F, 9.34; N, 13.80; Oh, 7.85.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.30 (s; 1H; NH); 7.10…7.00 (m; 2H; C6H şi C5H); 6.92 (dd; 1H; J1=1.0; J2=7.4; C4H); 2.52 (dd; 1H; J1=7.0; J2=9.5; CHCN); 2.06 (dd; 1H; J1=5.0; J2=7.0; CHH); 2.00 (dd; 1H; J1=5.0; J2=9.5; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 11.30 (s; 1H; NH); 7.10…7.00 (m; 2H; C6H and C5H); 6.92 (dd; 1H; J1=1.0; J2=7.4; C4H); 2.52 (dd; 1H; J1=7.0; J2=9.5; CHCN); 2.06 (dd; 1H; J1=5.0; J2=7.0; CHH); 2.00 (dd; 1H; J1=5.0; J2=9.5; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 173.89; 147.20 (J=242); 130.29 (J=13); 128.12 (J=5); 122.47; 117.03 (J=38); 115.69 (J=18); 32.22 (J=2); 21.26; 15.13. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.89; 147.20 (J=242); 130.29 (J=13); 128.12 (J=5); 122.47; 117.03 (J=38); 115.69 (J=18); 32.22 (J=2); 21.26; 15.13.

IR, (ν, cm-1, praf): 3159.4 (NH); 3038.9, 2988.7, 2901.7 (ciclopr.); 2245.1 (CN); 1714.3 (CON). IR, (ν, cm-1, dust): 3159.4 (NH); 3038.9, 2988.7, 2901.7 (cyclopr.); 2245.1 (CN); 1714.3 (CON).

Cis-7'-fluoro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vi Cis-7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vi

Cristale albe, p.t. 190…193°C. Calculat, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; O, 7.91. C11H7FN2O. Găsit, %: C, 65.44; H, 3.44; F, 9.34; N, 13.94; O, 7.83. White crystals, m.p. 190…193°C. Calculated, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; Oh, 7.91. C11H7FN2O. Found, %: C, 65.44; H, 3.44; F, 9.34; N, 13.94; Oh, 7.83.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz ): 11.21 (c; 1H; NH); 7.01…6.93 (m; 3H; C6H, C4H şi C5H); 2.79 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.12 (dd; 1H; J1=4.6; J2=7.2; CHH); 1.96 (dd; 1H; J1=4.6; J2=9.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz ): 11.21 (c; 1H; NH); 7.01…6.93 (m; 3H; C6H, C4H and C5H); 2.79 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.12 (dd; 1H; J1=4.6; J2=7.2; CHH); 1.96 (dd; 1H; J1=4.6; J2=9.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 172.87; 147.04 (J=242); 130.28 (J=4); 129.90 (J=2); 122.50; 116.46 (J=28); 115.44 (J=17); 32.37 (J=4); 21.58; 14.92. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 172.87; 147.04 (J=242); 130.28 (J=4); 129.90 (J=2); 122.50; 116.46 (J=28); 115.44 (J=17); 32.37 (J=4); 21.58; 14.92.

IR, (ν, cm-1, praf): 3156.5 (NH); 3052.0, 2827.9 (ciclopr.); 2250.6 (CN); 1713.7 (CON). IR, (ν, cm-1, powder): 3156.5 (NH); 3052.0, 2827.9 (cyclopr.); 2250.6 (CN); 1713.7 (CON).

Trans-5'-fluoro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril IVj Trans-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile IVj

Cristale albe, p.t. 237…239°C. Calculat, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; O, 7.91. C11H7FN2O. Găsit, %: C, 65.29; H, 3.43; F, 9.34; N, 13.97; O, 8.00. White crystals, m.p. 237...239°C. Calculated, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; Oh, 7.91. C11H7FN2O. Found, %: C, 65.29; H, 3.43; F, 9.34; N, 13.97; Oh, 8.00.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.77 (s; 1H; NH); 7.00…6.93 (m; 2H; C6H şi C4H); 6.89 (dd; 1H; J1=3.8; J2=6.6; C5H); 2.90 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.14 (dd; 1H; J1=4.6; J2=7.2; CHH); 1.90 (dd; 1H; J1=4.6; J2=9.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.77 (s; 1H; NH); 7.00…6.93 (m; 2H; C6H and C4H); 6.89 (dd; 1H; J1=3.8; J2=6.6; C5H); 2.90 (dd; 1H; J1=7.2; J2=9.2; CHCN); 2.14 (dd; 1H; J1=4.6; J2=7.2; CHH); 1.90 (dd; 1H; J1=4.6; J2=9.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm):173.17; 158.44 (J=236); 138.80; 128.99 (J=9); 116.57; 114.59 (J=23); 110.83 (J=8); 108.98 (J=26); 32.55 (J=2); 21.36; 14.59. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 173.17; 158.44 (J=236); 138.80; 128.99 (J=9); 116.57; 114.59 (J=23); 110.83 (J=8); 108.98 (J=26); 32.55 (J=2); 21.36; 14.59.

IR, (ν, cm-1, praf): 3226.9 (NH); 3050.4, 2956.3 (ciclopr.); 2245.8 (CN); 1720.9 (CON). IR, (ν, cm-1, powder): 3226.9 (NH); 3050.4, 2956.3 (cyclopr.); 2245.8 (CN); 1720.9 (CON).

Cis-5'-fluoro-2'-oxospiro[ciclopropan-1,3'-indol]-2-nitril Vj Cis-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indole]-2-nitrile Vj

Cristale albe, p.t. 209…213°C. Calculat, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; O, 7.91. C11H7FN2O. Găsit, %: C, 65.25; H, 3.39; F, 9.32; N, 13.90; O, 7.95. White crystals, m.p. 209…213°C. Calculated, %: C, 65.35; H, 3.49; F, 9.40; N, 13.86; Oh, 7.91. C11H7FN2O. Found, %: C, 65.25; H, 3.39; F, 9.32; N, 13.90; Oh, 7.95.

1H-RMN, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.81 (s; 1H; NH); 7.01 (td; 1H; J1=3.8; J2=7.0; C6H); 6.95…6.92 (m; 2H; C4H +C7H); 2.53 (dd; 1H; J1=6.8; J2=9.2; CHCN); 2.16 (dd; 1H; J1=4.8; J2=6.8; CHH); 1.96 (dd; 1H; J1=4.8; J2=9.2; CHH). 1H-NMR, (400 MHz, DMSO-d6, δ, ppm, J/Hz): 10.81 (s; 1H; NH); 7.01 (td; 1H; J1=3.8; J2=7.0; C6H); 6.95...6.92 (m; 2H; C4H +C7H); 2.53 (dd; 1H; J1=6.8; J2=9.2; CHCN); 2.16 (dd; 1H; J1=4.8; J2=6.8; CHH); 1.96 (dd; 1H; J1=4.8; J2=9.2; CHH).

13C-RMN, (100 MHz, DMSO-d6, δ, ppm): 174.11; 158.28 (J=236); 139.24; 126.90 (J=10); 116.98; 114.80 (J=22); 111.04 (J=8); 109.48 (J=26); 32.31 (J=2); 20.36; 14.99. 13 C-NMR, (100 MHz, DMSO-d6, δ, ppm): 174.11; 158.28 (J=236); 139.24; 126.90 (J=10); 116.98; 114.80 (J=22); 111.04 (J=8); 109.48 (J=26); 32.31 (J=2); 20.36; 14.99.

IR, (ν, cm-1, praf): 3298.8 (NH); 3042.7, 2886.1 (ciclopr.); 2248.2 (CN); 1713.1 (CON). IR, (ν, cm-1, powder): 3298.8 (NH); 3042.7, 2886.1 (cyclopr.); 2248.2 (CN); 1713.1 (CON).

Rezultatul invenţiei constă în faptul că condiţiile revendicate permit a realiza sinteza mult mai ieftină, ecologic pură, cu o durată mult mai mică şi cu randament înalt a unui şir de spiro[ciclopropan-oxindoli] - precursori în sinteza substanţelor cu activitate anti-HIV. The result of the invention consists in the fact that the claimed conditions allow to realize the much cheaper, ecologically pure synthesis, with a much shorter duration and with a high yield of a series of spiro[cyclopropane-oxindoles] - precursors in the synthesis of substances with 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

Claims

Process for obtaining carbonitrile derivatives of spiro[cyclopropane-oxindoles], which includes the cyclopropanation reaction of diazoizatins with acrylonitrile, at the same time acrylonitrile is used as a solvent, and the reaction takes place at the boiling temperature of acrylonitrile.