Method for preparing derivative of indolinospiropyrane

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

 

The scope of the invention

The present invention relates to compounds of spiropyran. In particular, the present invention relates to compounds endosonography and ways of their industrial production. These compounds are useful as photochromic compounds.

Prior art

Different classes of photochromic compounds have been synthesized and is recommended for use in applications where sunlight is called reversible color change or darkening. For example, Spiro(indoline)naphthopyrans and Spiro(indoline)chinaberry described in the patent GB 2174711. Spiropyran described in Brown, Glenn H. ed., Photochromism (New York, 1971) and dürr, Heinz and Henri Bouas-Laurent, eds., Photochromism (Elsevier, 1990).

Derivatives of spiropyran can present the most well-known organic compounds, having the effect of photochromism, but the patterns described by spiropyranes largely limited. Thus, there is a need in the compounds of spiropyran, allowing further simple modification, and methods of synthesis of various compounds of spiropyran.

Description of the invention and the preferred options of the incarnation

The present invention relates to compounds endosonography and, in particular, photochromic compounds endosonography, as well as methods of synthesis are shown the connections. Connection endosonography according to the invention is substituted on the indole ring succinimido, and this substitution allows disclosure cycle succinimide and modulation of volume and photochromic properties of compounds.

In one embodiment of the present invention is a compound comprising a compound of the following formula, or essentially consisting of compounds of the following formula, or consisting of the following compounds of the following formula:

where R1means C1-C18-alkyl, allyl, phenyl, mono - or disubstituted phenyl, phenyl(C1-C4)alkyl or (C1-C4)alkoxycarbonyl(C1-C4)alkyl, each of R2and R3independently mean C1-C4-alkyl, phenyl, mono - or disubstituted phenyl, benzyl or, together, form a cyclic structure, which represents the core of cyclohexyl, norbornyl or adamantyl, R4means hydrogen, hydroxy, trichloromethyl, trifluoromethyl, formyl, C1-C4-alkyl, halogen, C1-C4-alkoxy, nitro, cyano, C1-C4-monohalogenated, C1-C4-alkoxycarbonyl or aromatic structure having two common adjacent carbon atom with the benzene ring part benzopyrano cycle, which leads to the formation of condensers the frame aromatic cycle, including, but without limitation, naphthyl, phenanthrene, chinoline, x is 1, 2 or 3, provided that when x=1, R4can be localized on any of the available carbon atoms of the benzene ring benzopyranones group, preferably in position 6, 7 or 8, and when x=2, each of R4may be the same or different and are located in positions 6 and 8 or 5 and 7, preferably in positions 6 and 8. R1preferably means C1-C4-alkyl, phenyl, benzyl, allyl or ethoxycarbonylethyl, each of R2and R3independently denotes methyl, ethyl or phenyl and R4preferably means C1-C4-alkyl, C1-C2-alkoxy, chlorine, bromine, iodine, trifluoromethyl or nitro.

In a preferred embodiment of the invention is the connection, including the connection following formula, or essentially consisting of such compounds, or consisting of such a connection:

where R4means hydrogen, hydroxy, trifluoromethyl, formyl, methyl, ethyl, methoxy, ethoxy, nitro, fluorine, chlorine, bromine or iodine, x is 1 or 2.

Since the compounds of formulas I and II contain operations group, properties of the compounds according to the invention, such as solubility, sensitivity and the like, can be managed through disclosure cycle succinimide Jobim from a variety of known methods. Suitable methods are described, for example, 48 (12) Heterocycles, 2677-2691 (1998).

Compounds of formulas I and II can be obtained by any suitable known manner and preferably get them organic synthesis in the solid phase. The use of solid-phase synthesis has the advantage consisting in the fact that it provides convenience in performing the interaction, ease of cleaning product and the usability of polar molecules in the implementation of the methods of synthesis. In addition, this is an opportunity of application of industrially produced raw materials and the use of excess reagent to bring the interaction to completion and to exceed speed main reaction on adverse reactions. The key point of the synthesis is the use of indoline on the polymer carrier of the formula

where R1, R2and R3have the same values for the formula I.

A solid carrier can be selected from a number hydroxytrol. Suitable hydroxypoly include, but without limiting them, hydroxymethylprednisolone resin, the resin Wang'a (also known as 4-hydroxymethylbenzene or "GMF-resin"), HMPA-PEGA (GMPW-PAGE) resin (or 4-gidroksimetilfurfuralya acid and bisacrylamide-1-inpolitical), HMPB-BHA (GMFB-BHA) resin (or 4-hydroxy-3-methoxyphenoxy the Naya acid-benzhydrylamine), HMPB-MBHA (GMFB-MBHA) resin (4-hydroxymethyl-3-methoxyphenylalanine acid-methylbenzhydrylamine) and their combinations. theoretical loading of the resin may be either a low (for example, less than about 0.1 mmol/g)or high (for example, greater than about 0.4 mmol/g), but to make a product more preferred high load, more preferably about 0.4-1.5 mmol/g, you Can use the resin or of the order of 100-200 mesh, or about 200-400 mesh. The preferred resins are resins hydroxymatairesinol or resin Wang'a approximately 100-200 mesh, at high load.

Used solid media depends on the selected reagents, the solvent used and the desired product. Resin usually has a functional group such type and quantity, which allow effective accession of reagents, as well as the effective release of the product. In addition, the resin must be capable of swelling in the used solvent. Used amount of resin depends on the amount of reagents used and the required scale of the reaction. You can usually use about 1 mg to 100 g of resin.

The compounds of formula III can be obtained by either of the two reaction schemes using connection aminoindane the following formula:

where R1, R2and R3take the same values for the formula I.

The reaction scheme for obtaining compounds of formula III using aminopentanedioic shown below:

According to the method And aminoindazole compound IV is treated with succinic anhydride under conditions suitable for the formation of succinic acid. More specifically, the interaction is carried out at a temperature of about 0-60°C, preferably at a temperature close to the room temperature, in an inert atmosphere, including, but without limitation, argon or nitrogen, for about 3-24 hours. The amount of reagents used is determined by the amount of the desired product and is usually from about 1 mg to 100 g, preferably from about 100 mg to 10, click to the mixture hydroximino along with diisopropylcarbodiimide ("DIC " DICK") and dimethylaminopyridine ("DMAP-DMAP") to obtain a suspension of the granules of the polymer. The above suspension of the granules of the polymer shaken under conditions suitable for the reaction combinations. Appropriate interaction conditions are a temperature of about 0-60°C, preferably close to the room temperature, approximately 14-24 hours in an inert atmosphere. The reaction of the combination can be controlled by devices using conventional methods, on the make, but not in the manner restrictions, FT-IR (infrared spectroscopy with Fourier transform) or single (single bead) FT-IR. Usually interactions, leading to the formation of carrier indolin resin, terminated after 24 hours at room temperature.

According to the method B hydroximino shaken with an excess of succinic anhydride under conditions suitable for the reaction combinations. Appropriate interaction conditions are a temperature of about 60-120°C, preferably about 70-100°C, for about 10 to 60 hours, preferably about 24 to 48 hours. The reaction can be monitored using any conventional methods, and usually the interaction is terminated after 48 hours of heating to the boiling temperature under reflux. After completion of the interaction of an excess of succinic anhydride wash and resin, now connected with succinic acid, process aminoindole formula IV along with 1-hydroxybenzotriazole ("HOBT-HOBT") and DICK. Suitable processing conditions are a temperature of about 0-60°C, preferably room temperature, and inert atmosphere.

Both ways of loading usually exceeds 95%. Can be used any conventional method of load test, including, but not limited to them, are described in 63(3) J. Org. Chem., 708-718 (1998). Hexamethyldisilane the Academy of Sciences ("HMDSO-HMDSO") can be used as an internal standard for the purposes of 1H-NMR analysis.

Connection aminoindane formula IV can be obtained by reduction of the derivatives nitroindoline formula

where R1, R2and R3take the same values for the formula I.

Suitable derivatives nitroindoline formula V can be obtained by nitration derivatives of indoline, as described in 101 (8) Bull. Soc. Chim. Bdg., 719-739 (1992). Derivatives indoline you can netravati nitric acid cooled below 10°C sulfuric acid, preferably below 7°C, approximately over a period of 10 hours.

During the synthesis in solid phase compounds endosonography according to the invention, the resin carrier indolin in the amount of usually about 100 mg to 100 g, preferably about 100 mg to 10 g, corresponding to the formula III, can be split and processed in any of a variety of derivative salicylaldehyde under conditions suitable for the formation of the desired connection endosonography. Suitable conditions for the synthesis are a temperature of about 50-120°C in an inert atmosphere for about 14 hours 11 days, preferably from about 14 hours to 3 days. Suitable derivatives of salicylaldehyde have the formula

where R4and x take the same values for the formula I.

Synthesis in the solid phase will crack the AET as follows:

The synthesis is carried out in any suitable solvent, preferably dioxane, dimethylformamide ("DMF-DMF"), N-organic ("NMP-NRM"), tetrahydrofuran ("THF-THF") or their combination. The release of the compounds of formula I with a solid carrier can be accomplished by any convenient method, such as method of base catalysis using any appropriate reason, including, but without limitation, piperidine, DBU-DBC, sodium methylate, tert-butyl potassium. Usually use about 3-4 equivalents derived salicylaldehyde to interact with about 1.1 to 10 equivalents, preferably about 2 to 5, more preferably from about 3-4 equivalents carrier indole resin.

Compounds according to the invention is useful for a wide range of possible applications, such as ophthalmic lenses, windshields, Windows, and similar products, which can be used the phenomenon of photochromism. More specifically, an effective amount of the compounds according to the invention is introduced into the eye lenses, windshields, Windows and the like products, or cover these products are effective amount of the compounds according to the invention. Products that include the connection or to which it is applied as a layer to darken under the action of ultraviolet light and return the original color or colorless in the absence of UV light at ambient temperatures. Effective number of connections is the number of order 10-5-10-2mol/l, preferably of the order of 10-5-10-3mol/L. Methods of inclusion in such products photochromic compounds or coating photochromic compounds, such as compounds according to the invention, are well known in the prior art.

The invention is illustrated in the following non-limiting examples.

Example 1

5-Nitro-1,3 .3m-trimethylindolenine

2,3,4-Trimethylindolenine (17.3 g, 0.1 mol) is added to 45 ml of chilled sulfuric acid dropwise at a temperature below 5°C and stirring. Then 7.0 g of nitric acid (1 mol) in 18 ml of sulfuric acid is added dropwise with stirring over 1 h, maintaining the temperature below 7°C. Stirring is continued for 3 h at 7°C. Then leave the mixture to stand in the refrigerator overnight, after which the orange-brown solution was poured on crushed ice and carefully neutralized aqueous sodium hydroxide to pH 4-5. The resulting orange-red precipitate is filtered by suction and washed thoroughly with water before absorption of diethyl ether. Remove the solvent from piratage solution, dried with anhydrous sodium sulfate, and the residue is recrystallized from methylene chloride, obtaining 13 g of a yellowish brown solid. Output 5-nitro-1,3 .3m-trimethylindolenine the Aven to 59.6%.

Example 2

5-Amino-1,3 .3m-trimethylindolenine

5-Nitro-1,3 .3m-trimethylindolenine (8,16 g, 40 mmol) are added to a solution of chloride of divalent tin (53 g, 280 mmol) in 200 ml of hydrochloric acid with stirring. The mixture is gently heated to the boiling temperature under reflux for 16 h the Cooled reaction mixture was poured on crushed ice, alkalinized with concentrated sodium hydroxide solution and extracted with ethyl acetate (4×200 ml). United an ethyl acetate solution is dried with anhydrous sodium sulfate and discolor a small amount of activated charcoal. The solvent is removed and the residue is recrystallized from ethyl acetate, getting 5,96 g yellow solid, yield 5-amino-1,3 .3m-trimethylindolenine is 80%.

Example 3a

Ester amide 1,3 .3m-trimethylindolenine-5-yl-

succinic acid and resin Wang'a

5-Amino-1,3 .3m-trimethylindolenine (1,94 g of 10.3 mmol) in 5 ml of anhydrous tetrahydrofuran is added dropwise under nitrogen atmosphere to a 5 ml THF solution with 1.0 g (10 mmol) of succinic anhydride for 1 h the Mixture was stirred at room temperature for 7 hours Add resin Wang'a (theoretical loading 1.28 mmol/g, 5 g, 6.4 mmol), diisopropylcarbodiimide (1.26 g, 10 mmol) and DMAP (61,1 mg, 0.5 mmol). The suspension is shaken at room temperature for 24 h and then filtered through sintered glass eglo erat, washed with THF (4×15 ml), DMF (4×15 ml), dichloromethane (4×10 ml) and dried in vacuum. Get of 7.82 g of polymer granules.

50.9 mg of polymer granules leave to swell in 1 ml THF and allocate 0.01 M THF solution of potassium tert-butylate (3×0.2 ml, 3×15 min). The combined THF solution was shaken with finely ground sodium dihydrophosphate and anhydrous sodium sulfate, filtered, and washed with THF. The solvent is removed in vacuum. To the residue is added chloroform and then removed in vacuum to remove traces of THF. The residue is dried in vacuum and add 1 ml of 0.01 M hexamethyldisiloxane in CDCl3. From the value of the integral for the proton N-Me or succinyl against the corresponding integral for the internal standard to calculate the loading of ester amide 1,3 .3m-trimethylindolenine-5-yantarnoi acid on the resin Wang'a, which is 95.6%.

Example 3b

Resin Wang'a (theoretical loading 1.28 mmol/g, 3.0 g, of 3.84 mmol), 2.0 g (20 mmol) of succinic acid and 47 mg (0.38 mmol) of DMAP heated to the boiling point under reflux in THF for 48 h, cooled, filtered through sintered glass sinter and washed with THF (3×10 ml), DMF (3×10 ml), dichloromethane (2×10 ml), methanol (3×10 ml) and dichloromethane (2×10 ml). After drying in vacuo get 3,524 g white resin.

of 1.37 g (1.5 mmol) of a suspension of the resin pellets, 5-amino-1,3 .3m-three who ethylindole (3,76 g, 2.0 mmol), HOBT (12% water, 322 mg, 2.1 mmol) and DICK (265 mg, 2.1 mmol) in 15 ml THF shaken over night at room temperature in a nitrogen atmosphere, filtered through sintered glass sinter and washed with THF (3×5 ml), water (2×5 ml), DMF (2×3 ml), THF (3×3 ml) and dichloromethane (3×3 ml). After drying in vacuo get 1,725 g purple granules of ester amide 1,3 .3m-trimethylindolenine-5-yantarnoi acid on the resin Wang'a. Loading determined quantitatively using the method described in example 3a.

Example 4

5-Succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Split the polymer granules according to example 3a (0,243 g, corresponding to 0.2 mmol theoretical loading) leave to swell in 3 ml of DMF under nitrogen atmosphere for 1 h, and then shaken with 100 mg (0.8 mmol) of salicylaldehyde at 60°C for 14 h, then cooled, filtered through sintered glass sinter and washed with DMF (5×3 ml) and left in 3 ml of DMF overnight. Again filtered and washed with DMF (3×3 ml), dichloromethane (3×3 ml), THF (3×2 ml) and anhydrous THF (3×2 ml).

The polymer granules are suspended in 2 ml of THF, is added to 0.25 ml of (0.1 M) THF solution of potassium tert-butylate, leave on for 15-20 minutes, filtered and washed with 1 ml anhydrous THF. Procedure release is repeated using 0.1-0.15 ml (0.1 M) solution of tert-bout the LVL of potassium in THF. The combined THF solution was shaken with a small amount of finely ground sodium dihydrophosphate, filtered, the solvent removed and the residue is dried in vacuum. Get an 80.5 mg of a viscous oil, yield 5-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96,4% purity is 106,6%.

Example 5

6-Bromo-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use 5-bromosalicylaldehyde (121 mg, 0.6 mmol). Output 6-bromo-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 94,3% purity is 118%.

Example 6

6-Chloro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use 5-chlorosalicylaldehyde (95 mg, 0.6 mmol). Output 6-chloro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline is 97.6% purity is 111,8%.

Example 7

6-F-5'-Succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use 5-F-salicylaldehyde (84 mg, 0.6 mmol). Output 6-F-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] is 97.6% purity is 119,4%.

Example 8

6-Nitro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use 5-nitrosalicylic legid (100 mg, 0.6 mmol). Output 6-nitro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 97,9% purity is to 119.8%.

Example 9

6,8-Dichloro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use a 3.5-dichlorosalicylaldehyde (115 mg, 0.6 mmol). The output of 6,8-dichloro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] and 97.8% purity is to 107.7%.

Example 10

6,8-Dibromo-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use a 3.5-dibromosalicylic (167 mg, 0.6 mmol). The output of 6,8-dibromo-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] is 97.6% purity is 106,6%.

Example 11

6,8-Diid-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use a 3.5-diiodosalicylic (225 mg, 0.6 mmol). The output of 6.8-diid-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 97,7% purity of 99.5%.

Example 12

6-Bromo-8-methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except using 5-bromo-2-hydroxy-3-methoxybenzaldehyde (139 mg, 0.6 mmol). Output 6-bromo-8-methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 98.6% of the number is the notes is 96,1%.

Example 13

8-Formyl-6-methyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4 except using 2-hydroxy-5-methyl-1,3-benzylcarbamoyl (99 mg, 0.6 mmol) and the suspension of the polymer in granules shaken for 24 h at 60°C. Output 8-formyl-6-methyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96.1 per cent purity is to 98.6%.

Example 14

8-Hydroxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 13, except that the use of 2,3-dihydroxybenzaldehyde (100 mg, 0.6 mmol). Exit 8-hydroxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] is 112,6%.

Example 15

6-Methyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use 5-methylsalicylate (82 mg, 0.6 mmol) and the suspension of the polymer in granules shaken at 60°C 24 h and then 14 h at 80°C. Yield 6-methyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96.3% purity is 95.9%.

Example 16

8-Methyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 15, except using 3-methylsalicylate (82 mg, 0.6 mmol). Output 6-methyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-ind is Lina] 96.3% purity is 103,7%.

Example 17

6-Methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin

Repeat the procedure of example 4 except using 2-hydroxy-5-methoxybenzaldehyde (91 mg, 0.6 mmol) and the suspension of the polymer in granules shaken at 60°C 18 h and then 14 h at 80°C. Yield 6-methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96.1 per cent purity is 97,2%.

Example 18

8 Ethoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 17 except using 2-hydroxy-3-ethoxybenzaldehyde (99 mg, 0.6 mmol). Exit 8-ethoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96,4% purity is 98.8%.

Example 19

8-Methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that the use of O-vanillin (91 mg, 0.6 mmol). Exit 8-methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96.6% purity is 110%.

Example 20

6 Triptoreline-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4 except using 2-hydroxy-5-triphtalocyaninine (95 mg, 0.46 mmol) and a suspension of the polymer in granules shaken 18 h at room temperature and then 3 h at 60°C. Yield 6-triptoreline-5'-su is inimigo-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] is 88%.

Example 21

6-Hydroxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except that use 2.5-dihydroxybenzaldehyde (100 mg, 0.6 mmol) and the suspension of the polymer in granules shaken at 60°C 24 h and then 15 h at 80°C. Yield 6-hydroxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] is 103,2%.

Example 22

6-tert-Butyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 21 except using 5-tert-butylsilane (107 mg, 0.6 mmol). Output 6-tert-butyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96.6% purity is 89.4 per cent.

Example 23

8-tert-Butyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 21 except using 3-tert-butylsilane (107 mg, 0.6 mmol) and the suspension of the polymer in granules shaken at 60°C 18 h and then 14 h at 80°C. Output 8-tert-butyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96% purity or 97.7%.

Example 24

6,8-Di-tert-butyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4, except using 3,5-di-tert-butylsilane (180 mg, 0.6 mmol) and the suspension of the polymer in granules TSA is ahavat at 60° C 18 h and then 14 h at 80°C. Yield 6,8-di-tert-butyl-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 95% purity is to 101.2%.

Example 25

7-Methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4 except using 2-hydroxy-4-methoxybenzaldehyde (91 mg, 0.6 mmol) and the suspension of the polymer in granules shaken at 60°C 58 h and then 14 h at 80°C. Yield 7-methoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] is to 82.1%.

Example 26

5,7-Dimethoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

Repeat the procedure of example 4 except using 2-hydroxy-4,6-dimethoxybenzaldehyde (240 mg, 2.0 mmol) and a suspension of the polymer in granules shaken at 60°C 24 h and then 11 days at 80°C. Yield 5,7-dimethoxy-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 96,8% purity of 82.9%.

Example 27

8-Methoxy-6-nitro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin]

162 mg split of the polymer granules according to example 3b, corresponding to 0.14 mmol theoretical loading, leave to swell in 3 ml of DMF under nitrogen atmosphere for 1 hour, shaking with 8-methoxy-5-nitrosalicylaldehyde (83 mg, 0.42 mmol) at 60°C 14 h, the Suspension is cooled, filtered through sintered glass AG amerat, washed with DMF (5×1 ml), leave in 3 ml of DMF at night, again filtered and washed with DMF (3×1 ml), THF (3×1 ml), dichloromethane (3×2 ml) and THF (3×2 ml). It suspended in 1 ml of THF polymer granules add 1 ml of 0.1 M solution of DBC in THF, leave for 10 h, filtered and washed with THF (2×1 ml). The selection procedure was repeated twice. The combined THF solution passed through a short column with silica gel, elwira THF, removal of DBC. The solvent is removed and the residue is dried in vacuum, obtaining output 8-methoxy-6-nitro-5'-succinimido-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indoline] 104,6%.

1. A method of obtaining compound - derived endosonography formula

where R1means C1-C18-alkyl, each of R2and R3independently mean C1-C4-alkyl, R4means hydrogen, hydroxy, trichloromethyl, trifluoromethyl, formyl, C1-C4-alkyl, halogen, C1-C4-alkoxy, nitro, and x is 1 or 2,

includes stage

(i) receiving indoline on the polymer carrier of the formula

where R1means1-C18-alkyl, each of R2and R3independently mean C1-C4-alkyl;

(ii) processing the bearer of indolin polymer n is sites, where the carrier is hydroximino, at a temperature of from 50 to 120°C, in an inert atmosphere, during the time from 14 hours to 11 days, a derivative of salicylaldehyde formula

where R4means hydrogen, hydroxy, trichloromethyl, trifluoromethyl, formyl, C1-C4-alkyl, halogen, C1-C4-alkoxy, nitro, and x is 1 or 2,

getting connection endosonography formula (I) and

(iii) releasing the connection endosonography formula (I).

2. The method according to claim 1, where hydroxytrol is hydroxymethylprednisolone resin, the resin Wang'a, the resin GMPW-PAGE, resin GMFB-BGA, resin GMFB-MBHA or combinations thereof.

3. The method according to claim 1 where the use of a resin with a granule size of about 100-200 mesh or about 200-400 mesh.

4. The method according to claim 1, where the use hydroxymethylprednisolone resin or resin Wang'with a granule size of approximately 100-200 mesh, with high load.

5. The method according to claim 1, further comprising a step for carrying indolin the polymer carrier by

(i) processing connection aminoindane formula

where R1means C1-C18-alkyl, each of R2and R3independently mean C1-C4-alkyl, succinic anhydride;

(ii) adding subsequently, to the mixture hydroxypoly, diisopropylcarbodiimide and dimethylaminopyridine with formation of a suspension of polymer granules and

(iii) the shaking of the suspension of the granules of the polymer with the receipt of the bearer of indolin polymer carrier.

6. The method according to claim 1, further comprising receiving the bearer of indolin the polymer carrier by

(i) shaking excess hydroxypoly with an excess of succinic anhydride at a temperature of about 60-120°within about 24-48 hours for the connection resin and succinic acids;

(ii) subsequent laundering excess of succinic anhydride and

(iii) processing the resin, combined with succinic acid, 1-hydroxybenzotriazole and DICK at approximately 0-60°and in an inert atmosphere and aminoindoles formula IV

where R1means C1-C18-alkyl, each of R2and R3independent means1-C4-alkyl.

7. The method according to claim 5, further comprising the stage of obtaining the connection aminoindane by restoring the derived nitroindoline formula

where R1means C1-C18-alkyl, each of R2and R3independently mean C1-C4-alkyl.

8. The method according to claim 6, additionally which includes the stage of obtaining the connection aminoindane by restoring the derived nitroindoline formula

where R1means1-C18-alkyl, each of R2and R3independently mean C1-C4-alkyl.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

The invention relates to new derivatives of galantamine General formula I:

where R1-R5, G1-G3and W have the meanings indicated in the claims, and the invention relates to a method for producing these compounds, medicinal product and the method of its production

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds, and more specifically to 5-formyl-substituted indoline spirobenzopyrans with general formula 1 where R1, R2 - Alk or c-Alk; R3 -CHO or NO2 group (electron-acceptor substitute), with photochromic properties. The invention also relates to the method of producing 5-formyl substituted derivatives of indoline spirobenzopyrans with formula 1. Spirobenzopyrans, which have electron-acceptor substitutes in the pyran part of the molecule, are subjected to direct selective formylation in position 5 in a trifluoroacetic acid medium with urotropine (hexamethylenetetramine) at boiling point of the mixture in an inert atmosphere for 1-1.5 hours. The obtained 5-formyl-substituted spirobenzopyrans are photochromic compounds are photochromic and can be used for making new photochromic materials (recording devices or information storage; photo-switching activity of biological objects and polymer matrices, complex formation; information security media, maps, special document protection equipment) or as advanced initial compounds for further synthesis of a large number of new photochromic objects.

EFFECT: wider field of application of the compounds.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) or to its salt or ester in which radicals and symbols have the values presented in claim 1. These compounds are ACC inhibitors.

EFFECT: production of compounds to be applied as a therapeutic agent for various ACC-related disorders such as bacony liver, hyperlipidemia, obesity and diabetes.

13 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) given below or pharmaceutically acceptable salts thereof:

[where: each of X, Y, Z and W independently denotes a methane group which optionally contains substitutes selected from a group of substitutes α, or a nitrogen atom (except when all elements X, Y, Z and W denote a methane group which optionally contain substitutes selected from the group of substitutes α); A denotes -(C(R3)(R4))m1-; B denotes -O-; D denotes -C(O)-; m1 equals 0; Q denotes a methane group or a nitrogen atom; R denotes a group of formula (II)

, where R6 denotes a lower alkyl group; R7 and R8, together with the nitrogen atom with which they are bonded, form a 5-6-member nitrogen-containing aliphatic heterocyclic group; and where the group of substitutes α includes the following substitutes. Group of substitutes α: halogen atom, hydroxyl group, lower alkyl group, alkoxyl group (said group can be substituted with a cycloalkyl group), amino group, mono- or disubstituted lower alkylamino group, aryl group (said group can be substituted with a halogen atom, a -SO2CH3 group), aryloxy group (said group can be substituted with a halogen atom), heteroaryl group, where 'heteroaryl group' denotes a 5- or 6-member monocyclic saturated or unsaturated group containing 1-2 heteroatoms selected from an oxygen atom or a nitrogen atom (said group can be substituted with an alkoxyl group, alkyl group). The invention also relates to a histamine 3 receptor antagonist, histamine 3 receptor inverse agonist, a prophylactic or medicinal agent, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having histamine H3 receptor antagonist or inverse agonist action.

15 cl, 57 ex, 1 tbl

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