The method of obtaining derivatives of 1-oxa-3,8-diaza-4-oxo-spiro- [4,5]-decane

 

(57) Abstract:

The inventive compound of General formula I is subjected to interaction with (C1-C21) -alkylbis ester of acrylic acid in the liquid medium at room temperature aromatic hydrocarbon in the presence of a catalyst of General formula II at a temperature of 30 to 150°C., followed by separation of the desired product of General formula III. 6 C.p. f-crystals, 1 table. The structure of formulas 1,2,3: .

The invention concerns a method of obtaining derivatives oxa-3,8-diaza-4-oxo-Spiro(4,5)decane-compounds that can be used as light stabilizers for polymers or as intermediates in obtaining synthetic additives.

A method of obtaining compounds of General formula

which includes a multiple change of the reaction medium during the reaction and therefore requires additional extraction and distillation [1].

The closest is the method of obtaining these compounds, including the interaction of the compounds of General formula II

R where R1is hydrogen, alkyl with alkanoyl;

R2and R3are together with the carbon atom pyrocondensation cycloalkanes with (about[2].

Additive phase transfercallpeer though and promotes faster and more complete reaction, however, the drawback of its use is a strong environmental pollution, since the phase catalyst in the processing of reaction mixtures fed to the waste water. The use of phase transportationfrom increases the fraction of organics in the waste water and thus increased environmental pollution. If you use the most effective Quaternary halides of ammonium or phosphonium as phase transportationfrom, it increases the fraction of organics in the waste water, and also prevents the introduction of wastewater in biological settling the installation, as Quaternary ammonium salts and phosphonium have bactericidal properties and can't peredayutsya in biological sucks installation. Daily water must therefore be corrected with high costs as a special waste.

The aim of the invention is the development of receipt of such compounds with high yield and reduction of a long process, in addition to eliminating the disadvantages associated with environmental pollution and due to the fact without the most expensive remedy when utilizator the compounds of formula III.

R

This invention relates to a method of producing 1-oxa-3,8-diaza-4-oxo-Spiro(4,5)-decane-compounds of formula 1

where R1is hydrogen, (C2-C4) alkyl, (C2-C30-alkanoyl;

R2and R3- taken together with the carbon atom to which they are attached, form pyrocondensation (C5-C12-cycloalken;

R4- (C1-C21) alkyl, by reacting compounds of General formula II

C1-C21) alkylbis ester of acrylic acid in the liquid medium at room temperature aromatic hydrocarbon in the presence of a catalyst at 30-150aboutWith, as a catalyst used as a compound of General formula III.

R where R1, R2and R3defined above, M is alkali metal, in the amount of 1-10 mol.% regarding the compounds of General formula II.

It is preferable to use as the aromatic hydrocarbon toluene or xylene; as a catalyst for lithium, sodium or potassium salt of the compounds of formula II; as a catalyst sodium salt of the compounds of formula II.

The catalyst was prepared in the reaction mixture in situ before the introduction of (C1-C21) Olkiluoto ether and the-(5,1,11,2)-heneicosan.

AND (C1-C21) acrylic ester of acrylic acid is a lauric ester of acrylic acid.

Suitable compounds of the formula II are, for example, 2-butyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2-pentyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)- decane, 2-out-of pentyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo - Spiro-(4,5)-decane, 2-hexyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2-heptyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)- decane, 2-ISO-heptyl-7,7,9,9-tetramethyl-1-oxa-3,8-di - Aza-4-oxo-Spiro-(4,5)-decane; 2 nonyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo - Spiro-(4,5)-decane, 2-ISO-nonyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5) - decane, 2-undecyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2-phenyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2-(4-chloro-phenyl)-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo - Spiro- (4,5)-decane, 2-ethyl-2,7,7,9,9-pentamethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2-propyl-2,7,7,9,9-pentamethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5) -decane, 2-ISO-propyl-2,7,7,9,9-pentamethyl-1-oxa-3,8-diaza-4-oxo-Spiro- (4,5)-decane, 2-butyl-2,7,7,9,9-pentamethyl-1-oxa-3,8-diaza-4-QA - with-Spiro-(4,5)-decane, 2-ISO-butyl-2,7,7,9,9-pentamethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)- decane, 2-pentyl-2,7,7,9,9-pentamethyl-1--pentamethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2,2,7,7,9,9-HEXAMETHYL-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-decane, 2,2,7,7, 8,9,9-heptamethyl-1-oxa-3,8-diaza-4-oxo-Spiro(4,5)-decane, 2,2-diethyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5) -decane, 2.2-dipropyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5)-de - Cana, 2,2-dibutil-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-Spiro-(4,5) -decane, 2-ethyl-2-pentyl-7,7,9,9-tetramethyl-1-oxa-3,8-dia - for-4-oxo-Spiro-(4,5)-decane, 2.2-dibenzyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo - Spiro-(4,5)-decane, 2,2,4,4-tetramethyl-7-oxa-3,13-diaza-14-oxo-despero-(5,1,4,2)-tet - radican, 2,2,4,4-tetramethyl-7-oxa-3,14-diaza-15-oxo-despero-(5,1,5,2)-pentadecane, 2,2,4,4-tetramethyl-7-oxa-3,20-diaza-21-oxo-despero-(5,1,11,2)heneicosan, 2,2,7,7,9,9 - HEXAMETHYL-1-oxa-3,8-diaza-4-oxo-8-Aza - Teal-Spiro-(4,5)- decane, 2,2,4,4-tetramethyl-7-oxa-3,14-diaza-15-oxo-3-acetyl-despero-(5,1,5,2) -pentadecane, 2,2,4,4-tetramethyl-7-oxa-3,20-diaza-21-oxo-3-acetyl-despero- (5,1,11,2)-heneicosan.

As Olkiluoto ester of acrylic acid using methyl ester of acrylic acid, ethyl ester, acrylic acid n-butyl ester of acrylic acid, isobutyl ester of acrylic acid, tert-butyl ester of acrylic acid, 2-etelemetry ester of acrylic acid, oktilovom ester of acrylic acid, lauric ester of acrylic acid, myristyl is you, ethyl ester of methacrylic acid n-butyl ester of methacrylic acid, isobutyl ester of methacrylic acid, tert-butyl methacrylic acid, lauric ester of methacrylic acid, cyclohexyloxy methacrylic acid, allyl ester of methacrylic acid, 2-ethoxyethyl ester of methacrylic acid, 2-multilinearity methacrylic acid, methyl ester of crotonic acid, ethyl ester of crotonic acid, 1,4-potentialities, 1,6-hexanediamine, 2-ethyl-2-hydroxymethyl-1,3-propandiol-triacrylate, dietilenglikoluretan, pentaerythritol-triacrylate, pentaerythritoltetranitrate, ethylenglykolether, 1,4-potentialtheorie, 1,6-hexanediamine - acrylat, detranscendentalized, triethyleneglycoldinitrate, tripropyleneglycol, trimethylolpropane - trimethacrylate, 2,2,6,6-tetramethylpiperidine-4-yl-ester of acrylic acid, crotonic acid 2,2,6,6-tetramethylpiperidine-4-yl-ester, methacrylic acid - 2,2,6,6-tetramethylpiperidine-4-yl-ester. Especially preferred of the compounds II is 2,2,4,4-tetramethyl-7 - oxa-3,20-diaza-21-oxo-despero-(5,111,2)-GE - naksan and lauric ester of acrylic acid.

The catalyst was prepared by vzaimodeistvie can be used after removal of the solvent in the form of isolated solids or without removal of the solvent in the form of a suspension or solution.

Especially preferable to use the catalyst obtained in situ. To the reaction mixture, which consists only of a solvent and the compounds of formula II are added to the alkali metal in the amount of 1-10 mol.%, regarding the compound (II).

Received in accordance with the invention the compounds of formula I are used primarily as light stabilizers, for example, polyolefins, in particular polyethylene and polypropylene, ethylene-propylene copolymers, and others.

Mainly received in accordance with the invention compounds are used for stabilizirovannye polypropylene, low-molecular and high-molecular polyethylene, ethylene-propylene copolymers, polyvinyl chloride, polyester, polyamide, polyurethane, polyacrylonitrile, S, terpolymer acrylic ester, styrene and Acrylonitrile, copolymers of styrene and Acrylonitrile or styrene and butadiene, in particular for polypropylene, polyethylene, ethylene-propyleneamine or S, such as for example rubber, and also for lubricating oils. Then they are also suitable for stabilizirovannye varnishes.

Use obtained in accordance with the invention compounds as light stabilizers, introducing them may be introduced these stabilizers.

The compounds of formula I and their aforementioned mixture can also be applied in the presence of other additives. They are known and belong, for example, to the group aminoacridine compounds, VU-absorbents and antioxidants such as 2-(2' -hydroxyphenyl)-benzotriazole, 2-hydroxybenzophenones, 1,3-bis(2' - hydroxybenzoyl)benzenes, esters of salicylic acid, esters of cinnamic acid, esters of optionally substituted benzoic acids, steric broken amines, the diamide of oxalic acid.

The applied amount received in accordance with the invention compounds of formula 1 is 0.01 - 5 wt.% the artificial compounds, 20 to 80 wt.% stabilizatory concentrates and 0.02 - 5 wt.% the varnishes.

Comparative example A (according to the method according to the patent Germany 3 524 543). to 91.1 g (0.25 mol) 2,2,4,4-tetramethyl-7-oxa-3,20-diazide-Spiro- (5,1,11,2)-heneicosan-21-she's in 100 ml of toluene is heated to 80aboutC. Then added to 0.30 g (0,013 mol) of sodium, 1.5 g of trietilenglikole ammonium and 76.5 g (0,30 mol) lauryl-acrylate (technical mixture of about 55-58%12-ether and about 37-40%14-ether), and the mixture is stirred 4 h at 80aboutC. Then the initial mixture is stirred three times with 100 ml of water and the solvent is distilled off from the organic phase. Get 168 g prodregister-(5,1,11,2)-heneicosan-21-it.

Comparative example Century.

Similarly, comparative example A, but with 1.5 g of chloride tetrabutylphosphonium (instead of chloride of triethylenediamine).

Get 167 g of the product (light yellow viscous liquid) with a residual content of 1.1 wt.% 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-geneico - Zan-21-it.

P R I m e R 1. to 91.1 g (0.25 mol) 2,2,4,4-tetramethyl-7-oxa-3,20-diaza-despero-(5,1, 11,2) -heneicosan-21-she's in 100 ml of toluene is heated to 80aboutC. Then add 3.0 g (0,008 mole) sodium 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro- (5,1,11,2)-heneicosan-21-it ("amide sodium") and 76.5 g (0,30 mol) of laurelcrest and the initial mixture is then stirred 4 h at 80aboutC. the mixture is stirred three times each time with 100 ml of water and the solvent is distilled off from the organic phase.

Obtain 171 g of the product (colorless viscous liquid) with a residual content of 0.9 wt. % 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-geneico - Zan-21-it.

P R I m m e R 2. Analogously to example 1, but using 5.0 g (0,013 mol) of sodium salt of 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-heneicosan-21-she as the catalyst source and the mixture is stirred for only 2 h at 80aboutC.

Obtain 171 g of the product (colorless high is 21 she is.

P R I m e R 3. Analogously to example 1, but using 1.0 g (of 0.003 mole) of sodium salt of 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-heneicosan-21-she as a catalyst, and the mixture is stirred for 1.5 h at 120aboutC.

Get 166 g of the product (colorless viscous liquid) with a residual content of 1.3 wt. % 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-geneico - curtain-21-it.

P R I m e R s 4-6. Analogously to example 1, but instead of toluene using o-xylene as solvent.

P R I m e R 7. (this example shows the use of the obtained catalyst).

To to 91.1 g (0.25 mol) 2,2,4,4-tetramethyl-7-oxa-3,20-diazaspiro -(5,1,11,2)-heneicosan-21-she's in 100 ml of o-xylene added 0.18 g (0,008 mole) of sodium and the mixture is heated under reflux until the sodium is completely react (approximately 1 hour). Then the reaction mixture is cooled to 80aboutTo add a 76.5 g (0,30 mol) of laurelcrest and the mixture is stirred 4 h at 80aboutC. the mixture is Then three times each time with 100 ml of water washed, and the solvent is distilled off from the organic phase.

Get 168 g of product with a residual content of 0.4 wt.% 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-Gena - Kazan-21-it.

P R I m e R 8. Synthesis of cat is she and 9.2 g (x 0.40 mole) of sodium stirred in 500 ml of toluene for 24 h at boiling temperature under reflux. Then the initial mixture is subjected to hot filtration, and the solvent is removed from the filtrate. Get 150,9 g (98% of theory) of the catalyst in the form of a white solid with a melting point of 235aboutC.

P R I m e R 9. To the 94.5 grams (0.25 mole) 2,2,3,4,4-pentamethyl-7-oxa-3,20-diazadispiro-(5,1,11,2)-heneicosan-21-it is 100 cm3toluene (abs.) added 0.18 g (0,008 mmole) of sodium and the mixture was heated up until the sodium does not react (approximately 1 hour). Next, the reaction mixture is cooled to 80aboutTo add 72 g (to 0.29 mol) of lauryl-acrylate and the mixture is stirred for 4 h at 80aboutC. the mixture is Then washed three times with water to 100 ml and the solvent is distilled off from the organic phase.

Get 166,1 g (98,8%) of the product (white solid with so pl. 64-68aboutC).

P R I m e R 10. The process is carried out analogously to example 9, but using instead of 2,2,3,4,4-pentamethyl-7-oxa-3,20-diazide - pyro(5,1,11,2)-heneicosan-21-she of 101.5 g (0.25 mole) of 3-acetyl-2,2,4,4-tetramethyl-7-oxa-3,20-diaza-despero-(5,1,11,2)-heneicosan - 21-he.

Get 165,5 g 95.4 percent of the product. The data given in the table.

1. The METHOD of OBTAINING DERIVATIVES of 1-OXA-3,8-DIAZA-4-OXO-SPIRO-[4,5]-DECANE General formula I

< / BR>
where R1is hydrogen, C1-C4-alkyl, C25-C12-cycloalken;

R4- C1-C21-alkyl,

by reacting compounds of General formula II

< / BR>
where R1, R2and R3have a specified value,

with C1-C21-alkylbis ester of acrylic acid in the liquid medium at room temperature aromatic hydrocarbon in the presence of a catalyst at 30 - 150o, Characterized in that the catalyst is used as a compound of General formula III

< / BR>
where R1, R2and R3have the specified values,

M is alkali metal,

in quantities of 1 to 10 mol.% regarding the compounds of General formula II.

2. The method according to p. 1, wherein the aromatic hydrocarbon is toluene or xylene.

3. The method according to p. 1, characterized in that the catalyst used lithium, potassium or sodium salt of the compounds of General formula II.

4. The method according to p. 1, characterized in that the catalyst used sodium salt compounds of General formula II.

5. The method according to p. 1, wherein using the catalyst obtained in the reaction mixture in situ before the introduction of C1-C21-Olkiluoto ester of acrylic acid.

6. The method according to the-despero-[5,1,11,2]-heneicosan.

7. The method according to p. 1, characterized in that C1-C21-alkilany ester of acrylic acid is a lauric ester of acrylic acid.

 

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22 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl- and heteroarylsubstituted diasaspiropyridine derivatives of formula (I) to its pharmaceutically acceptable acid- or base-additive salt wherein A represents a radical of formula (II) wherein each k, l, m, n independently represents an integer equal to 0, 1, 2, 3 or 4, provided (k+1) and (m+n) are equal to 2, 3, 4 or 5; wherein one of -CH2-fragments can be substituted by atom O; and wherein one of -CH2-fragments can be substituted by an oxo group; X represents CH or N; R3 is specified in a group consisting of hydrogen, C1-5alkyl and C3-6cycloalkyl; each R4, R5 is independently specified in a group including hydrogen, halogen, oxo, C1-3alkyl and C1-3alkyloxy; p represents an integer equal to zero, 1, 2 or 3; q represents an integer equal to zero, 1, 2 or 3; each Y1, Y3, is independently specified in a group including a single bond and O; Y2 represents saturated or unsaturated C1-6hydrocarbon radical with a straight chain; B is specified in a group including phenyl optionally substituted by the number of the substitutes R6 each of which is independently specified in halogen; and wherein r represents an integer equal to zero, 1 or 2; alkyl represents a saturated hydrocarbon radical with a straight and branched chain containing said number of carbon atoms; wherein said radical can be optionally substituted by one or more carbon atoms or more radicals specified in a group including halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl; and halogen represents fluorine, chlorine, bromine or iodine. Also, the invention refers to a pharmaceutical composition based on the compounds of formula I as an active ingredient for preparing a drug for preventing and/or treating mental disorders, including but not limited to anxiety, eating behavior disorder, affective disorders, such as bipolar disorders and depression, psychosis, such as schizophrenia, and sleeping disorders; obesity, diabetes; sexual disorders and neurological disorders; to a method for preparing a pharmaceutical composition, and to using the compounds of formula I for preparing the drug.

EFFECT: there are prepared and described new compounds possessing melanin-concentrating hormone (MCH), particularly MCH-1 antagonist activity.

19 cl, 4 ex, 7 tbl

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