• 专利附录
  • 专利说明
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    • 专利摘要:
    The present invention relates to novel intermediates for use in the production of compounds forming the subject matter of parent Application No. 84302978.6 (Publication No. 0128654). Such intermediate compounds comprise 2,2,5,5-tetramethylcyclopentanone 1,2,2,5,5-pentamethylcyclopentanol 1-methylene-2,2,5,5-tetramethylcyclopentane 2,2,5,5-tetramethylcyclopentylmethanol 2,2,5,5-tetramethylcyclopentanecarboxylic acid
    公开号:SU1494862A3
    申请号:SU843751077
    申请日:1984-06-11
    公开日:1989-07-15
    发明作者:Стефен Ферландер Майкл；Дин Фуллер Вильям；Гудман Муррей
    申请人:Камберленд Пэкинг Корп (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of new asparginic acid derivatives of the general formula
    R
    m
    H N-CH-CO --KH-C-NH-CO-R
    SI, R

    where I am the lowest lykyl or the lowest oxyalkyl,
    R is hydrogen or lower alkyl; and R is branched alkyl C., cycloalkyl C-m lower apkylcycloalkyl, dicyclo- (lower) alkyl, 2,2,4,4-tetramethylthietane or phenyl. These derivatives of formula I can be used as sweeteners in the food industry.
    The aim of the invention is a method of obtaining derivatives of M- (L-aspargkp)
    O4
    -N- (1-acylamino) -alkylamino - new sweeteners with improved properties.
    The invention is illustrated by the following examples.
    Example 1. M- (1.-aspargil) -Y-cyclopentacarbonyl-R-l, t-liamino-eta (I, R-CHi, R -H, K-cyclopentyl).
    A. Dissolve 20 g (0.225 mol) of P-alanine in 400 ml of dimethylformamide, treat 26.8 g (0.250 mol) of chlorotrimethylsilane, and stir the mixture at room temperature until a homogeneous solution is obtained (approximately 45 minutes). In the meantime, 72 g (0.200 mol) of S-benzyloxycarbonyl-ft-benzyl-L-asparginic acid is dissolved in a mixture (1: 1) of dimethylformamide and tetrahydrofuran (880 ml) cooled to -15 C, and treated with 22.4% g (0.200 mol) of N-methylmorpholine and 26.2 ml (0, 200 mol) of isobutyl chloroformate. After an 8-minute activation at -15 ° C, a pre-cooled solution of silyl ether of D-alanine is added to the resulting solution,
    B. Dissolve 2.2 g (5.1 mmol) of the product of Section B in 50 ml of acetonitrile. The solution is diluted with an equal volume of water. Then 2.4 g (5.6 mmol) iodobenzene bis (trifluoroacetate) are added. The reaction mixture is stirred at room temperature in
    35
    then, dropwise, 22.4 ml (0.200 mol) of N-methylmorpholine, providing support for 4 hours (a clear solution forming the reaction temperature -15 ° C. It grows after about 2 hours). The solution is allowed to warm to room temperature (slowly and with stirring) for several hours before acidification to pH 1-2 (while cooling) with an aqueous solution of hydrochloric acid. Chloroform is added, a 4th phase section is added, the aqueous layer is re-extracted with chloroform. The combined organic extracts are washed with 1N. Q hydrochloric acid (three times), with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After evaporation of the solvent at
    is poised
    evaporated, the residue was redissolved in aqueous hydrochloric acid and lyophilized. It is obtained with a quantitative LY- (H-benzyl-oxycarbonyl- / - -6P11zyl-L-aspargCHO-K-1.) 1-diamino-ztan as a hydrochloric acid salt, which is used without further purification.
    G, 2.95 g (5.1 mmol) of the product of section B are dissolved in 50 ml of tetrahydrofuran; 1.5 g (10.6 mmol) of cyclopentane caronyl chloride are added, then 2.5 g (25 mmol; potassium biclbonate and 50 ml of water. The mixture is stirred at
    reduced pressure, oily residue, room temperature. After 2.5 hours, the stream is triturated with ether. The resulting solid is filtered and dried in vacuo. Get 67 g of s benz-1X-carbonyl / 3-benzyl- -b-aspargil-B-alanine with m.p. 158-, which is homogeneous according to those.
    B. Dissolve the product of section A (64 g, 0.150 mol) in 660 ml of dimethylformamide, cool to -15 ° C and treat with 16.5 ml (0.150 mol) of N-methylmorpholine and 19.5 ml (0.150 mol) of isobutyl chloroformate . After activation for 5 min at -15 ° C, add
    shine a sight. But the data from those shows that the reaction is not yet complete, therefore, a second portion of 1.5 g of cyclopentanecarboni, gg chloride (10.6 mmol), 2 g (20 mmol) of potassium bicarbonate is added. The process is repeated after 15 minutes. After 20 minutes, ethyl acetate and water are added, the phases are separated, the aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed twice with 1 M sodium bicarbonate, three times with 2N. hydrochloric acid, then again twice with 1 M bicarbonate nat1D94862
    34 g (0.225 mol) of the ammonium salt of 1-hydroxybene ryazole in the form of a solid product, the mixture peremegt {15 minutes at -15 s. After slowly heating for 4 hours, chloroform is added to room temperature, and the hearth is added, the phases are separated, the aqueous phase is re-extracted with chloroform. The combined organic extracts are washed three times with 1N. hydrochloric acid, three times with a saturated aqueous solution of sodium bicarbonate, with a saturated solution of sodium chloride, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, the solid residue is recrystallized from ethyl acetate (hexane). 50 g of B-benoyloxycarbonyl-p-benzyl-L-aspargyl-G) -alpnilamide are obtained, m.p. 170-171 ° C, which is homogeneous according to those.
    B. Dissolve 2.2 g (5.1 mmol) of the product of Section B in 50 ml of acetonitrile. The solution is diluted with an equal volume of water. Then 2.4 g (5.6 mmol) iodobenzene bis (trifluoroacetate) are added. The reaction mixture is stirred at room temperature in
    within 4 hours (a clear solution is formed after about 2 hours). Solution
    within 4 hours (a clear solution is formed after about 2 hours). Solution
    is poised
    evaporated, the residue was redissolved in aqueous hydrochloric acid and lyophilized. It is obtained with a quantitative LY- (H-benzyl-oxycarbonyl- / - -6P11zyl-L-aspargCHO-K-1.) 1-diamino-ztan as a hydrochloric acid salt, which is used without further purification.
    G, 2.95 g (5.1 mmol) of the product of section B are dissolved in 50 ml of tetrahydrofuran; 1.5 g (10.6 mmol) of cyclopentane caronyl chloride are added, then 2.5 g (25 mmol; potassium biclbonate and 50 ml of water. The mixture is stirred at
    shine a sight. But the data from those shows that the reaction is not yet complete, therefore, a second portion of 1.5 g of cyclopentanecarboni, gg chloride (10.6 mmol), 2 g (20 mmol) of potassium bicarbonate is added. The process is repeated after 15 minutes. After 20 minutes, ethyl acetate and water are added, the phases are separated, the aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed twice with 1 M sodium bicarbonate, three times with 2N. hydrochloric acid, then again twice with 1 M bicarbonate nat1
    and, finally, a sodium chloride solution. Dry over magnesium sulfate. The solution is filtered, evaporated under reduced pressure, the residue is triturated with ether. 1.5 g of N- (N-benzyloxycarbonate-L-benzyl-L-aspargyl) -N-cyclo-pentacarbonyl K-1,1-diaminomethane are obtained in the form of a solid crystalline substance which is homogeneous according to those. The NMR spectrum of the product corresponds to the above structure.
    D. 1.5 g of the product of section G (0.03 mmol) is hydrogenated in 50 ml of glacial acetic acid on 10% palladium on coal (approximately 0.2 g) at a pressure of 40 psi (2.812 kg / cm 2). overnight. The catalyst is filtered off, washed with glacial acetic acid and the filtrate is lyophilized. The resulting powder is redissolved in water and repeatedly lyophilized again. L-(L-aspargil -) - K-cyclopentacarbonyl-t, 1 is obtained in quantitative yield. -diaminoethane, with a melting point of 220 ° C (aerated). Sweetness 75-100 X sucrose.
    PRI mme R 2. N- (L-acpapgil) - -Y-trimethylacetyl-K-1,1-diaminoethane (Formula I, R-CH, R-H, (CH3) h).
    A. 5.2 g (12 mmol) of N- (N-benzyloxycarbonyl-P-benzyl--b-aspargyl) -K-1,1-diamino-ethane hydrochloric acid salt is obtained, as described in Example 1 (section b), suspended it in 50 ml of water at room temperature. 6 g (60 mmol) of potassium bicarbonate are added, then 1.5 ml (12 mmol) of pivaloyl chloride dissolved in 50 ml of acetonitrile. The homogeneous reaction mixture is stirred for 3 hours at room temperature. According to those data, the reaction is not complete, therefore 0.6 ml of hydrochloric acid and 5 g of potassium bicarbonate are added. The reaction mixture is stirred for another hour. The solution is then diluted with 500 ml of ethyl acetate and extracted three times with 1N. hydrochloric acid, three times with saturated aqueous sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is crystallized from ethyl acetate / hexane. 4.8 g of N- (N-benzyloxycarbonyl- | -benzyl-L-aspargyl) -M tri4862 are obtained.
    methi; il1 etyl- - I, 1-diaminoethane, which is homogeneous according to the data of m. 66-69 s. The NMR spectrum of the product corresponds to the above structure.
    B. Dissolve 4 g of product L-section R with 150 ml of glacial acetic acid and hydrogenate overnight at
    0 40 lb / in (2,812 kg / cm) pressure, 5 g of 10% palladium on carbon. The catalyst is filtered off, washed with glacial acetic acid, and the filtrate is lyophilized. The resulting poroshock is again dissolved in water and repeatedly lyophilized again. It is obtained with a quantitative yield of M- (L-aspargil) - -N-trimethylacetyl-R-1, 1-diaminoethane, mp.150 C. Sweetness 75-100 x sugar0 rose.
    one
    PRI me R 3. M- (L-aspargil) -Y - - (2-norbornancarbonyl) -K-1,1-diaminoethane (formula I, R-CH-, R-H, -norbornyl).
    A. 10.7 g (25 mmol) of N-benzyloxycarbonyl- / 3-benzyl-L- -aspa-rgyl-B-alanylamide (Example 1, section b) are suspended in 200 ml. mixtures (1: 1) of aceto-nitrile: water and 12 g (28 mmol) iodobenzene-bis (trifluoroacetate) were added. The reaction mixture was stirred at room temperature for 4 hours (homogeneous solution was obtained after 2 hours), and then treated with 10 g ( 63 mmol) norbornane-2-carboxyl chloride and 12 g (120 mmol) of potassium bicarbonate. After stirring at room temperature for two hours
    In those shows the completion of the reaction, the product is extracted and treated in the usual manner. After drying over magnesium sulphate, the organic phase is evaporated to dryness under reduced pressure, the residue is crystallized from ethyl acetate / hexane. 10.3 g of S- (H-benzyloxycarbonyl- / 3- -benzyl-L-aspargil) -N - (2-norbornane-Kap6oHmi) -R-1,1-diaminoethane; m.p.
    Q 127-130 ° C, which is homogeneous according to those. The NMR spectrum confirms the above structure.
    B. Hydrogenate 9 g of the product from Section A in the usual way in 200 ml of glacial acetic acid on 10% palladium and carbon. After several lyophilisations from water, N- (L-acnaprHJi) -N - (2-borobanankarbonyl) -R-1,1-
    five
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    - diaminoethane, so pl. 1 77-1 78 s. Sweetness 75-100 X sucrose.
    PRI me R 4, L- (L-aspargil) - -N - (1-adamantanecarbonyl) -K-1, 1-diamino ethane (formula I, R-CH., R-H, R-l- adamantyl).
    A. The process is 8.54 g (20 mmol) of N -benzyloxycarbonylbenzyl-β-pargyl-P-alanyl amide (Example 1, section B) iodobenzene-bis (trifluoroacetate) using the procedure described in Example 3 (section A), The resulting solution is treated with 6 g (30 mmol) of 1-adamantanecarbonyl chloride and 15 g (150 mmol) of potassium bicarbonate, stirred for 4 hours at room temperature. After the usual treatment, a crude product is obtained in the form of an oil, which is purified by chromatography on silica gel, eluting with a mixture (3: 1, volume:: volume) of chloroform / hexane. 2.5 g of N- (N-benzyloxycarbonyl-p-benzyl-b-aspargyL) (1-adamantanecarbonyl) -R-1,1-diaminoethane are obtained in the form of small, which is homogeneous according to those. The NMR spectrum of the product corresponds to the specified structure,
    B. Hydrogenate 2.0 g of product of section A using a conventional method in 50 ml of glacial acetic acid on 10% palladium on carbon. After several lyophilisations from water, K- (L - aspargil) -Y - (1-ad-manthancarbonyl) -R-1,1-diamino-ethane is obtained in quantitative yield; mp.174-175 s. Sweetness 5-15 x X sucrose.
    PRI me R 5. H- (L-aspargil) -C - - (1-methylcyclopropancavol) -R -1,1-diaminoethane (formula I, R-CH ,, R-H, I -1-metsh1Tsiklopropsh1 ).
    A. 10.7 g (25 mmol) of N-benzyloxycarbonyl- / -benzyl-L- -aspargyl-p-alanyl amide are treated (Example 1, section B) iodobenzene-bis- (trifluoroacetate) according to the procedure described in Example 3 ( section a). The resulting solution is treated with 20 g (200 mmol) of potassium bicarbonate, then 3.65 g (35 mmol) of 1-methylcyclopropanecarbonyl chloride and two more aliquots of 2 g each after 3 hours. After completion of the reaction according to TLC, the reaction mixture treated in the usual way. The product is crystallized from ethyl acetate / hexane. 8 g of N- (M ° -benzloxycarbonnp- / b-benzyl- -b-aspargyp) -m - (1-methylcyclopropane-, carbonyl) -K-1,1-diaminoztan are obtained.
    5 0 5
    0 -
    0
    with
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    ry is homogeneous according to those; m.p. 120-123 0, the NMR spectrum of the product corresponds to the above structure.
    B. Hydrate 7 g of the product of section A in the usual way in 200 ml of glacial acetic acid on 10% palladium on carbon. After several lyophilisations from water, L- (L-aspargil) -m - (1-methyl-cyclopropanacarbonyl) -R-1,1-diaminoethane is obtained with a quantitative yield; 134-135 ° C. Sweetness 10-25 X sucrose.
    EXAMPLE 6, N- (L-acpapgyl) -N - - (trimethylcyclohexancarabonyl) -R-1,1-diaminoethane (Formula 1, R-CH, R-H, R-trimethylcyclohexyl).
    A. Cool a solution of 35 g (0.277 mol) of 2,6-dimethylcyclohexane in 200 ml of ether to -78 ° C and treat with a two-fold excess of methyl magnesium bromide solution in ether (2, V M, 198 ml). The mixture is stirred for 3 hours at -78 ° C. The reaction mixture is heated to 0 ° C and carefully quenched with water and brine. The organic layer was separated, dried over magnesium sulfate, and the ether was evaporated under reduced pressure to give 32.2 g of 1.2,6-trimethylhexanol.
    B. A solution of 32.2 g (0.226 mol) of 1,2,6-trimethyl-piclohexanol, 46 g (1 mol) of 98% formic acid and an ice-cooled mixture of 3 ml of 98% formic is added dropwise. acid and 270 ml (4.86 mol) of 90% sulfuric acid; 1 t (the solution then foams rapidly). After stirring for an additional hour, the reaction mixture is poured onto 2 kg of crushed ice and processed as described in Example 10 (Section A). The output of trimethylcyclohexylcarboxylic acid is 29.9 g.
    B, Carefully add 29.9 (0.176 mmol) of product from Section B
    To an excess (65 ml) of thionyl chloride. The mixture is stirred overnight at room temperature. Thionyl chloride is distilled off under reduced pressure. 25.5 g of trimethylcyclohexanecarbonyl chloride are obtained, which is used without further purification.
    G, 10.7 g (25 mmol) of N-benzyloxycarbonyl- / i-benzensht-L- -aspargyl-D-alanylamide are treated (example 1, section B, iodobenzene-bis- (trifluoroacetate) according to the procedure described in example 3 (section A). Half a day, the solution is treated with 20 g (220 mmol) of potassium bicarbonate and 6.15 g (30 mmol) of trimethylcyclohexancarbonyl chloride, and after 30 minutes with a second portion (3 g). After 3 h (according to the reaction is completed) the reaction mixture is worked up in the usual manner.The product is crystallized from ethyl acetate / hexane to give 8.6 g of N- (N-benzyloxycarbonyl- / 5-benzyl--b-aspargil) -M - (trimethylcyclohexancarbonyl) -K-1,1-diaminoethane, which is homogeneous with respect to AaHHbr t. The JT-GR spectrum of the product corresponds to the indicated structure.
    E. Hydrate 8 g of the product of section G (in the usual way) in 200 ml of glacial acetic acid on 10% palladium on carbon. After several lyophilisations from water, L- (L-aspargil) -N-trimethylcyclohexanecarbonyl-R--1,1-diaminoethane is obtained in quantitative yield, Sweetness 25-50 x X sucrose.
    Example. N- (L-acapapyl) -N - - (1,1-dicyclopropylacetyl) -K-1,1-diamino-ethane (formula 1, R-CH, R -H R-dicyclopropylmethyl).
    A. 116 g (0.325 mol) of methyltriphenylphosphonium bromide is suspended in 600 ml of dry ether cooled to -10 ° C and treated with a solution of n-butyl lithium in hexane (2.2 M, 175 ml). The mixture is stirred for 5 min before adding the solution 35.6 g (0.325 mol) of dicyclopropyl ketone in 100 ml of ether, previously cooled to 0 ° C. The suspensions are allowed to warm to room temperature and stirred for another 2 hours. 1000 ml of water is added (first in small portions) and the mixture is stirred to dissolving the precipitate. The organic layer is separated, washed with water, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure. The residue containing solid triphenylphosphine oxide, which is separated from the oil, is moistened with a small amount of ether. The combined ethereal (organic residues) are fractionated. 6.5 g of dicyclopropyl ethylene are obtained; bp 130 ° C / 760 mm, which is pure according to gas chromatography (GC).
    B. Dissolve 19 g (0.176 mol) of dicyclopropylethylene in 100 ml of dry tetragilrofuran in a three-neck flask.
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    in atmps (leu nitrogen and treated with borane-tetrahydrofuran in tetrahydrofuran (1M, 210 ml). The mixture is stirred at room temperature for an hour before adding (with caution) 60 ml of 3N sodium hydroxide (foaming is possible). When adding It is finished, 60 ml of aqueous 30% hydrogen peroxide are added dropwise at a rate sufficient to maintain the boiling point. After the addition is complete, the mixture is refluxed for another 30 minutes, cooled, the aqueous layer is saturated with sodium chloride. The layers are separated. The organic layer is dried over sulfate. magnesium, evaporated under reduced pressure. 2.2-Dicyclopropylethanol, which is pure according to GC (product can also be distilled) i bp 99 ° C / 25 mm, is obtained with a quantitative yield.
    B. Dissolve 16 g (0.127 mol) of the product of Section B in 300 ml of ether, add the solution to a mixture of 60 g of potassium dichromate dissolved in 120 ml of concentrated sulfuric acid, and 600 ml of ice water. The reaction mixture, which immediately becomes dark, is stirred for one hour at room temperature. The organic layer is then separated, washed three times with water, dried over magnesium sulfate and the ether is distilled off under reduced pressure. The residue is distilled. 10.3 g of 1,1-dicyclopropylacetic acid are obtained, b.p. 130-141 ° C / 25 mm, which is clean according to GC.,
    D. Dissolve 10 g. (0.071 mol) of section B product in 25 ml of dry tetrahydrofuran and treat with excess (25 ml) of thionyl chloride. After stirring the mixture at room temperature for one hour, conversion into the acid chloride according to GC is complete. The solvent and the thionyl chloride are distilled off under reduced pressure. 1,1-Dicyclopropylacetyl chloride, which is used without further purification, is obtained in quantitative yield.
    D. Process 8.54 g (20 mmol) of N-benzyloxycarbonyl | -benzyl-b-aspargyl-B-alanylamide (example 1, section B) with iodobenzene bis (trifluoroacetate) according to the procedure described in example 3 (section A). Received in re
    111D9
    As a result, the solution is treated with 16 g (160 mmol) of potassium bicarbonate, then 4.7 g (30 mmol) of 1,1-dicyclopropylacetyl chloride is added dropwise. Almost a precipitate forms. The reaction mixture was stirred at room temperature for one hour, then water and chloroform were added. Separate the phases and flush the organic layer (three times) with an aqueous saturated sodium bicarbonate solution. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The solid residue is recrystallized from ethyl acetate. 6.5 g of l4- (N - -benzyloxycarbonyl-benzyl-L-ac-pargyl) -N - (1,1-dicyclopropylacetyl) -R-1,1-diamino ethane are obtained, which is homogeneous according to TLC, t .pl. ZOO-ZOI C, NMR spectrum of the product corresponds to the above structure.
    E. Hydrogenate 4 g of the product of section D in the usual way in 200 ml of glacial acetic acid on palladium on coal. After several lyophilisations, the residue is crystallized from water / ethanol / water. 1.0 g of N- (L-acnapyl) is obtained. -Y - (1,1-dicyclopropipacetyl) -R-1,1-diaminoethane; t.pp. 209-210 С Sweetness 500-700 x sucrose.
    Example N- (L-aspargil; - -N - (2,5-dimethylcyclopentacarbonyl) -K-1,1-diamnoethane (formula I, R-CHj, R-H, R-dimethylcyclopenents).
    , A, Dissolve 16 g (0.7 mol) of metallic sodium in 500 ml of absolute ethanol in an argon atmosphere while cooling, necessary in dp to maintain the temperature below 70 ° C. The solution is cooled and added dropwise; 54.3. g (0.362 mol) of distilled diethylmalonate (with cooling, if necessary), then one portion of 85 g (0.348 mol) of 2,5-dibromhexane, the reaction mixture is stirred overnight at room temperature, then boiled under reflux 2 hours. The mixture is concentrated to about half the volume under reduced pressure, 500 ml of water are added and the mixture is extracted three times with 200 ml of ether. The combined extracts are dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is fractionated in vacuo. 35 g of 2,5-dimethylcyclopentane-1,1-d-ssarboxylic diethyl ether are obtained.
    12
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    acid, which is homogeneous according to TLC.
    B. 35 g (0.145 mol) of product of section A is added to a solution of 55 g of potassium hydroxide in 300 ml of absolute ethanol. The mixture is refluxed overnight. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in 500 ml of water. The aqueous solution is extracted with 200 ml of ethyl acetate, acidified to pH 1 (conc. HC) and extracted three times with 200 ml of ether. The combined extracts blink 1 n. hydrochloric acid and dried over sodium sulfate. The solution is evaporated under reduced pressure, the remaining space is triturated with pentane to cause crystallization. The product is filtered and dried under vacuum. 10.5 g of 2,5-dimethylcyclopentane-1,1-dicarboxylic acid are obtained, which is homogeneous according to GC.
    B. Heat 10.5 g (56 mmol) of product of Section B to 230 ° C in a stream of argon for 1.5 hours. The residue is dissolved in tetrahydrofuran, discolor (Norit A) and the solvent is distilled off under reduced pressure. The residual oil crystallizes on standing. 6.3 g of 2,5-dimethylcyclopentacarboxylic acid (mp. 45 ° C), which is pure according to GC, are obtained.
    D. Dissolve 6.3 g (48 mmol) of the product. Section B in 100 ml of a mixture (1: 1, v / v) of tetrahydrofuran and thionyl chloride. The mixture is stirred for an hour at room temperature. The solution is evaporated under reduced pressure. 2.5-dimethylcyclopentanecarbonyl chloride is obtained with a quantitative yield, which is used without further purification.
    D. 8.6 g (20 mmol) of N-benzyloxycarbonyl- / 5-benzyl-L- -aspargsh1-B-alanylamide are treated (Example 1, section B) with iodobenzene-bis- (trifluoroacetate) using the procedure described in Example 3 (Section A). The resulting afternoon solution is treated with 20 g (200 mmol) of potassium bicarbonate, then 4.8 g (30 mmol) of 2,5-dimethylcyclopentanecarboxylic chloride, added dropwise over 5 minutes. The product precipitates almost immediately. Stirring is continued for another 2 hours at room temperature. Reaction
    3
    The mixture is processed in a conventional manner. The product crystallizes during the drying of the final extracts over sodium sulfate, the no3Tot-fy solution is heated to boiling, filtered hot and washed with sodium sulfate in ethyl acetate. The filtrate is evaporated under reduced pressure and the residue is crystallized from ethyl acetate / hexane. 6.1 g of N- (N-benzyloxycarb nyl-fi-benzyl-L-aspargyl) -H -2,5- (d methylcyclopentanecarbonyl) -1,1-di are obtained. - aminoethane, which is homogeneous according to those of mp. 193-195 The NMR spectrum corresponds to the marked structure of the product.
    E. 5.5 g of the product is hydrogenated in a conventional manner in 200 ml of glacial acetic acid on 10% palladium on carbon. After several lyophilisations from water, the solid residue is recrystallized from ethanol / water. 2.6 g of N- (L-acapargyl) -N- - (2,5-dimethylcyclopentanecarbonyl) -R-1,1-diaminoethane are obtained; mp 208-209 С Sweetness 300-400 x sucrose.
    PRI me R 9. N- (L-acnapr -ui) -N - (2,2,5,6-tetramethylcyclopentane-carbonyl) -R-1,1-diamino ethane (formula I, R-CH, I -N, 2,5,5-tetraJch
    methylcyclopentyl).
    A. Add 144 g (3.0 mol) of 50% dispersion in sodium hydride oil to a three-liter three-neck flask equipped with a reflux condenser, mechanical stirrer, and nitrogen inlet. A moderate stream of nitrogen is passed through the flask. Load 1.5 liters of dry tetrahydrofuran. At the same time, 53.6 g (0.64 mol) of cyclopentanone in 350 ml of dry tetrahydrofuran and 285 MP (3.0 mol) of dimethyl sulfate in 120 ml of the same solvent are added to the stirred suspension in small portions (20-40 ml) to a stirred suspension: to maintain a slight evolution of hydrogen. The reaction mixture is cooled, keeping the temperature below 40 ° C. After the addition has been completed (several hours), the reaction mixture is heated under reflux for 2 hours. After cooling, 100 ml of tertiary butano are slowly added to destroy excess hydride, then 1 liter of water (first Caution). The reaction mixture is then boiled for 2 hours with a condenser to dissolve the excess dimethyl sulfate. Cool




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    Separate the layers, wash the organic layer with a saturated sodium chloride solution, and dry over sodium sulfate. The solvent is evaporated under reduced pressure, the residue is fractionated in vacuo. Get 59 g of 2,2,5,5- -tetramethylcyclopentanone, b.p. 55 ° C / 20 mm.
    B. Process a solution of 30 g (0.215 mol) of 2,2,5,5-tetramethylcyclopentanone in 50 ml of ether under a nitrogen atmosphere with 100 ml of a 3 M solution of methylmagnesium bromide. The reaction mixture is stirred overnight at room temperature, then 65 ml of a saturated solution of ammonium chloride in water is added dropwise. The mixture is stirred for 10 minutes, the ether solution is decanted, the solid residue is triturated with ether. The ether extracts are dried over sodium sulfate and evaporated under reduced pressure. 30 g of crude 1,2,2,5,5-pentamethylcyclopentanol are obtained, which is used without further purification.
    B. Dissolve 30 g of the crude product of Section B in 150 ml of pyridine. The solution is cooled to 0 ° C and treated by adding dropwise 20 ml of thionyl chloride (0.28 mol). The temperature is maintained below 5 ° C. The reaction mixture is stirred overnight, filtered, ether and water are added. Separate the phases. The organic phase is washed twice (200 ml each time) with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure. 10.8 g of 1-methylene-2,2,5,5-tetramethylcyclopentane, which is pure according to GC, is obtained.
    G. Dissolve 10.8 g (78 mmol) of the product of section B in 100 ml of dry tetrahydrofuran and process in nitrogen atmosphere 1 M borane-tetrahydrofuran in 100 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature and treated with 40 ml of 3N. an aqueous solution of sodium hydroxide, then 40 ml of 30% hydrogen peroxide is added dropwise at a rate sufficient to maintain a low boil. The mixture was heated under reflux for an additional hour, and sodium chloride was added to saturation. The mixture was cooled to room temperature with stirring. The phases are separated, the organic phase is dried over sulfur.
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    151
    sodium hydroxide and evaporated under reduced pressure. A crude 2,2,5,5-tetramethylcyclopentylmethanol is obtained with a quantitative yield, which is used without further purification.
    D. Dissolve the product of section G in 300 ml of ether and add 45 g (0.15 mmol) of potassium dichromate to 90 ml (1.7 mol) of concentrated sulfuric acid and 450 ml of water to the solution. The mixture is stirred at room temperature for 3 hours. The phases are then separated, the organic layer is washed with a saturated solution of sodium chloride and dried over sodium sulfate. The solvent is evaporated under reduced pressure, the residue is distilled in vacuo. 6.6 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid are obtained.


    you, which is homogeneous according to GC.
    E, Dissolve 6.5 g (38 mmol) of product D in 100 ml of tetrahydrofuran and treat by adding dropwise 21) ml of thionyl chloride (270 mmol). The solution is boiled for 2 hours under reflux, evaporated under reduced pressure, the residue is distilled in vacuo. 4.8 g of 2,2,5,5-β-tetramethylcyclopentane carbonate chloride are obtained, b.p. 65-75 C / 4 mm.
    G. Process 10.7 g (25 mmol) N-Benzyloxycarbonyl-p) -benzyl-1-aspargyl-B-alanyl amide (Example 1, section B) iodobenzene-bis- (trifluoroacetate) according to the method of Example 3 (Section A ), The resulting solution is evaporated almost to dryness under reduced pressure
    they add water and a large
    current of concentrated hydrochloric acid. The mixture is again evaporated to dryness. The solid residue is dissolved in 20 ml of 4.4 M HC1 / (Ioxane. The solution is evaporated to dryness, the residue is again dissolved in dioxane (100 ml) and lyophilized. 10.2 g of NN-benzyloxycarbonyl-β-benzyl- (L- aspargyl) -E-1,1-, -diaminoethane as a hydrochloric acid compound, which is homogeneous according to those.
    3. Dissolve 6.6 g (15 mmol) of the product of section G in 150 ml of dry tetrahydrofuran and treat with 3.1 g (15 mmol) of 2,2,5,5-tetramethylcyclopentanecarbonyl chloride (section E), then 4.2 ml (30 mmol) of triethylamine. The reaction mixture is stirred for 1 hour at room temperature.
    sixteen
    0
    five
    five
    round, add ethyl acetate. The product is processed in the usual way. Crystallization from ethyl acetate / hexane gives 6.0 g of NN-benzyloxycarbonyl- (3-benzyl- (L-aspartic) -Y- (2, 2.5-5,5-tetramethylcyclopentanecarbonyl) -R-1,1-diaminoethane. which is homogeneous according to TLC; mp.122-125 ° C, the NMR spectrum corresponds to the above structure.
    I. 5.5 g of the product of Section 3 is hydrogenated in the usual manner in 200 ml of glacial acetic acid on 10% palladium on carbon. After lyophilization (several times) from water, the solid residue is crystallized from ethanol / hexane. Obtain 2.0 g of N- (L-aspargil) -M - (2,2,5,5-tetramethylcyclopentanecarbonyl) -K-1,1-diaminoethane, t.1.171-172s. The compound is homogeneous according to high performance liquid chromatography under pressure (HPLc). Conditions: Likhrosorb RP-18,
    5 linear gradient 24–33% of acetonitrile in 0.01 M of triethylammonium phosphate, pH 4.5, flow rate 1 ml / min, retention time 12.31 minutes. Sweetness 800-1000 x sucrose.
    Example 10. M- (l-aspargil) - -N - (2,6-dimetiJ: cyclohexancarbonyl) -R-1,1-diaminoethane, (formula I, R-CH3, R-H,, 6-dimethylcyclohex- forces).
     A. Suspend 286 g (0.80 mol) of methyltriphenylphosphonium bromide in 1500 ml of ether and process 500 ml (0.80 mol) of 1.6 M n-butyl lithium in ether, then 50.4 g (0.40 mol) of 2.6 -dimethylcyclaxanone according to the procedure described in Example 7 (section L). The crude product is dispersed. 24 g of 1-metnpsn--2,6-dimethylcyclohexane are obtained, bp 146-154 0/760 mm.
    B. Dissolve 24 g (0.10 mol) of the product of section A in 50 ml of dry tetrahydrofuran and treat under nitrogen at 250 mp 1 M borane-tetrahydrofuran in tetrahydrofuran. The reaction mixture is stirred overnight at room temperature, treated with 20 MP 3 N, an aqueous solution of sodium hydroxide, added dropwise (possibly foaming), then 20 ml of 30 "-aqueous hydrogen peroxide is added dropwise. The mixture was heated under reflux for 30 minutes, sodium chloride was added to saturation and cooled to room temperature.
    0
    171
    rituration with mixing. The phases are separated, the organic layer is dried with sodium sulfate and evaporated under reduced pressure. 2,6-Dimethylcyclohexyl methanol is obtained in a quantitative yield. The product is purified by fractionation in vacuo, bp. 187-210 С / / 760 mm.


    -R-1,1-diaminoet, which is homogeneous, according to TLC, mp 1A6-50 ° C. The NMR spectrum of the product corresponds to the above structure,
    E. Hydrogenate 4 g of the product L in the usual manner in 150 ml of glacial acetic acid on 10% palladium on carbon. After several lio
    B. Dissolve 20 g (0.14 mol) of npo-4Q filiation from the water; solid of section B is crystallized in 300 ml of ether, and the residue from ethanol / water to obtain 0.8 g of N- (L-acapargyl) - N - (2,6-dimethylcyclohexanecarbonyl) -K-1,1-dia noethane. Sweetness 150 - 200 x
    30 g (0.30 mol) of potassium dichromate in 175 ml of concentrated sulfuric acid and 900 ml of water in an ice bath are added to the solution. A mixture of heat-5 sucrose.
    to room temperature and permeate. Example 11. L - (L-aspargil) - stirred for two days. The phases are separated; the or -N-N- (2,2,5,5-tetramethylcyclopentanecarganicutto phase is washed with water, the bonyl is dried); K-1,1-diamino-2-oxyethane (formula I, R, H, R 2,2,5,5-20-tetramethylcyclopentyl).
    A. Dissolve 5.0 g (25.6 mmol) of O-benzyl-B-serine in 50 ml of dimethyl ned magnesium sulfate and evaporate under reduced pressure. The residue is fractionated. Obtain 16.7 g of 2,6-dimethyl shlohexanecarboxylic acid, which is pure by GC, b.p. 145-148 ° C.
    D. Dissolve 16.7 g of the product, stir 25 times at room temperature B in 100 ml of tetrahydrofuran and treat with excess (30 ml) of thionyl chloride at room temperature. After stirring at room temperature.
    until a homogeneous solution is obtained (approximately 1 hour). At the same time, 9.14 g (25.6 mmol) of N-benzyloxycarbonyl temperature was dissolved and the hg-benzyl-L-aspartic acid was distilled off within one hour.
    excess thionyl chloride and solvent under reduced pressure. 2,6-Dimethyl-cyclohexanecarbonyl chloride is obtained with a quantitative yield, which is used without further purification.
    in a mixture (1: 1) of dimethylformamide and uranium tetrahydrof, cooled to, is treated with 2.81 ml (25.6 mmol) of N-methyl morpholine, then 3.32 ml (25.6 mmol) of isobutyl chloroformate.
    D. Treat 10.7 g (25 mmol). After a 10-minute activation, the addition of N -benzyloxycarbonyl- -b-benzyl-L- -aspargyl-B-alanylamide (example 1, section B) with iodobenzene-bis- (trifluoroacetate) the method described in example 3 (section A). The resulting solution is treated with 20 g (200 mmol) of potassium bicarbonate, then: 6.1 g (35 mmol) of 2,6-dimethyl cyclohexanecarbonyl chloro 40 are added dropwise.
    P-cooled solution of O-benzyl-B-serine silyl ether, then (dropwise) 2.81 ml (25.6 mmol) of N-methylmorpholine is maintained, ensuring the reaction temperature is kept at -15 ° C. The solution is allowed to heat up to which temperature (slowly and with stirring)
    , - „,. within 4 h before acidification to
    yes for 2 min The reaction mixture is pH 1-2 (with cooling), using stirring for 3 hours at room temperature, hydrochloric acid. The solution is added, it is treated with conventional halogen-chloroform, the phases are separated and reused.
    bom The difference is that the product crystallizes from the final extracts over sodium sulfate, so the solution is heated to a boil, filtered hot and washed with sodium sulfate in ethyl acetate. The filtrate is evaporated under reduced pressure and the residue is crystallized from ethyl acetate. Obtain 4.5 g of N- (N-6eH3HnoKCH-carbonyl- / 1-benzsh1-b-aspargil) -Y - - (2,6-dimethylcyclohexanecarbonyl) -diam noethane. Sweetness 150 - 200 x
     sucrose.
    formamide, treated with 3,053 g
    (28.1 mmol) chlorotrimethylsilane. Mixture
    until a homogeneous solution is obtained (approximately 1 hour). 9.14 g (25.6 mmol) of N-benzyloxycarbonyl / -benzyl-L-aspartic acid are dissolved simultaneously.
    in a mixture (1: 1) of dimethylformamide and uranium tetrahydrof, cooled to, is treated with 2.81 ml (25.6 mmol) of N-methyl morpholine, then 3.32 ml (25.6 mmol) of isobutyl chloroformate.
    P-cooled solution of O-benzyl-B-serine silyl ester, then (dropwise) 2.81 ml (25.6 mmol) of N-methylmorpholine is kept, ensuring that the reaction temperature is maintained at -15 ° C.
    extract the aqueous layer with chloroform. United Organic Extracts
    three times blink 1 n. hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the solid residue is crystallized from ethyl acetate / hexane. 11.0 g of N-benzyloxycarbonyl-A-benzyl-L-aspargnol-O-benzyl-B-serine are obtained, mp 107-108 C, which.
    nineteen
    is homogeneous according to TLC, the NMR spectrum of the product is consistent with its structure.
    B, Dissolve 10.0 g (18.72 mmol) of Section A product in 100 ml of drmethylformamide, cooled to -15 ° C, and treated with 2.05 ml (18.72 mmol) of N-methylmorpholine, and then 2, 43 ml (18.72 mmol) of isobutyl x 1; orformate. After 4 minutes of activation, 3.13 g (20.5 mmol) of 1-hydroxybene-triazole ammonium salt is added in VI 1448.
    de solid and stirred the mixture for 30 min at -15 s. After heating to room temperature with stirring, chloroform and water were added for 4 h, the phases were separated, the aqueous phase was re-extracted with chlorine
    by form. The combined organic phases are 20 in the usual manner in 150 ml of ice-cream, washed three times with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate solution (three times), saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the solid residue is crystallized from ethyl acetate / hexane. 7.4 g of N-benzyloxycarbonyl- - | L-benzyl-L-aspargyl-O-benzyl-P-sernlamide are obtained (mp. 150 C ), which is homogeneous according to TLC. The NMR spectrum of the product corresponds to the specified structure,
    B. Dissolve 5.33 g (10 mmol) of product B in 10 ml of acetonitrile and dilute the solution with an equal volume of water. Then 4.8 g (11.2 mmol) iodobenzene-bis (trifluoroacetate acetate) are added. and stir the reaction mixture at room temperature for 5 hours. The solution is evaporated under reduced pressure, the residue is redissolved, in 4 n. anhydrous HC1 / di-ocean and lyophilized solution of Semi35 "oi
    acetic acid on 10% palladium on carbon. After lyophilization and reliofilization, several times are obtained from water with a quantitative yield of K- (L-aspargil) -Y- (2,2,5,5-tetramethylcyclopentanecarbonyl) -K-1,1-diamine-2- hydroxyethane (m.p. 174-176 C, with decomp.). Sweetness 500-400 x sucrose.
    PR and ME 12. H- (L-aspargil) - -N - (2,2, 5,5 - tetramethylcyclopentane-carbonyl) -S-1,1-diaminoethane (formula I, RH, R-CH3 to -2,2,5,5-tetra methylcyclopentyl),
    A. 1.70 g (5 mmol) of benzyloxycarbonyl- / 3-benzyl-L-aspartic acid is dissolved in 100 ml of tetrahydrofuran, the solution is cooled to -15 ° C and treated with 0.5 ml (5 mmol) of N-methylmorpholine . After 10 minutes of activation at -15 ° C, a pre-cooled solution of 0.75 g (6 mmol) of hydrochloric acid L-alanine amide and 50 ml of dimethylformamide, then 0.66 ml (6 mmol) of N-methylmorpholine is added. The solution is allowed to warm to room temperature and stirred overnight. Water and chloroform are then added, the phases are separated, the aqueous phase is re-extracted with chloroform. The combined organic phases are washed three times with 1N, hydrochloric acid, saturated sodium chloride solution and dried over magnesium sulfate. The solution is filtered, the filtrate is evaporated under reduced pressure, and the residue is crystallized from ethyl acetate / hexane. 2.0 g of N -benzicloxarbonyl- / - -benzyl-b-aspargyl-P-alanylamide are obtained.
    40
    45
    With a quantitative yield, hydrochloric acid N- (N-benzyloxycarbonyl- - P) -benzyl-b-aspargyl) -K-1,1-diamino-2-hydroxyethane is used, which is used without further purification.
    G; Dissolve the product of section B in 50 ml of tetrahydrofuran, add 3.30 ml (30 mmol) of N-methylmorpholine, then 3.1 g (16 mmol) of 2,2,5,5-tetramethylcyclopentanecarbonder chloride. The mixture is stirred for 4 hours at room temperature. Ethyl acetate and water are added and the phases are separated. The aqueous phase is re-extracted with ethyl acetate.
    Q 4862 20
    The combined organic phases are washed twice with 1 M sodium bicarbonate solution, three times with 2N. hydrochloric acid, twice - again with 1 M sodium bicarbonate, then with a saturated solution of sodium chloride and dried over magnesium sulfate. The solution is filtered, the filtrate is evaporated under reduced pressure, the residue is crystallized from ethyl acetate / hexane. 4.0 g of N- (K-benzyloxycarbonyl- - L-benzyl- (L-aspargil) -H -2,2,5,5-tetramethylcyclopentanecarbonyl) are obtained. -1 .1- Diamino-2-hydroxyethane (mp. 90-93 C), which is homogeneous according to TLC. The NMR spectrum of the product corresponds to the structure shown.
    D.Gidrir gTot 3.8 g of product section0
    0 in the usual way in 150 ml of ice -
    5 „oi
    acetic acid on 10% palladium on carbon. After lyophilization and reliofilization, several times are obtained from water with a quantitative yield of K- (L-aspargil) -Y- (2,2,5,5-tetramethylcyclopentanecarbonyl) -K-1,1-diamine-2- hydroxyethane (m.p. 174-176 C, with decomp.). Sweetness 500-400 x sucrose.
    PR and ME 12. H- (L-aspargil) - -N - (2,2, 5,5 - tetramethylcyclopentane-carbonyl) -S-1,1-diaminoethane (formula I, RH, R-CH3 to -2,2,5,5-tetra methylcyclopentyl),
    A. 1.70 g (5 mmol) of benzyloxycarbonyl- / 3-benzyl-L-aspartic acid is dissolved in 100 ml of tetrahydrofuran, the solution is cooled to -15 ° C and treated with 0.5 ml (5 mmol) of N-methylmorpholine . After 10 minutes of activation at -15 ° C, a pre-cooled solution of 0.75 g (6 mmol) of hydrochloric acid L-alanine amide and 50 ml of dimethylformamide, then 0.66 ml (6 mmol) of N-methylmorpholine is added. The solution is allowed to warm to room temperature and stirred overnight. Water and chloroform are then added, the phases are separated, the aqueous phase is re-extracted with chloroform. The combined organic phases are washed three times with 1N, hydrochloric acid, saturated sodium chloride solution and dried over magnesium sulfate. The solution is filtered, the filtrate is evaporated under reduced pressure, and the residue is crystallized from ethyl acetate / hexane. 2.0 g of N -benzicloxarbonyl- / - -benzyl-b-aspargyl-P-alanylamide are obtained.
    0
    five
    0
    five
    ten
    15
    211494862
    (m.p.180-180,), which is homogeneous according to TLC. The NMR spectrum of the product corresponds to the specified structure,
    B. Dissolve 1.0 g (4.4 mol) of the product of section A in 25 ml of acetonitrile, dilute with an equal volume of water and treat with 2.13 g (5 mmol) iodobenzene-bis- (trifluoroacetate). After stirring the solution at room temperature for 5 hours, the product is treated according to the procedure of Example 17 (section B); the sulfate N- (N-benzyl-hydroxycarbonyl- | -benzyl-b-aspargyl) -S-1,1-diaminoethane is obtained with a quantitative yield. which is used without further purification.
    B, Dissolve the product of section B in 100 ml of tetrahydrofuran, add 1.1 ml (10 mmol) of N-methyl morpholine, then 1.25 g (6.5 mmol) of 2,2,5,5-α-tetramethylcyclopentanecarbonyl chloride. yes and stir the mixture for 5 hours at room temperature. Ethyl acetate and water are then added, the phases are separated, the aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed twice with a 1 M solution of sodium bicarbonate, then with an aqueous solution of sodium chloride and dried with magnesium sulfate. The solution is filtered, the filtrate is evaporated under reduced pressure, the residue is crystallized from ethyl acetate / hexane. Half 20
    25
    thirty
    22
    A. Suspend 20 g (0.194 mol) of th-aminoisobutyric acid in 400 NU of tetrahydrofuran, treat the solution with phosgene in toluene (3 M, 160 ml). The mixture is heated overnight at 65 C. The resulting clear solution is evaporated under reduced pressure. re-dissolved in tetrahydrofuran and again evaporated. The N-carboxyanhydrile of oi-aminoisomelaic acid is obtained in the form of a dense oil which is used without further purification.
    B. Dissolve the product of section A in 200 ml of tetrahydrofuran, cool to -20 ° C and treat with excess ammonia-shaped gas. The solution is allowed to slowly warm to room temperature and then evaporated to dryness under reduced pressure. The solid residue is extracted with ethyl acetate in a Soxhlet extractor for 3 hours. The resulting solution is filtered and the product is allowed to crystallize. 10 6 -aminoisoutiramide are obtained in the form of a solid crystalline product (m.p. 1.115-118 C), which is homogeneous according to TLC. The NMR spectrum of the product corresponds to the specified structure.
    B. Dissolve 24.2 g (67 mmol) of N-benzyloxycarbonyl-benzyl-L-asparginic acid in 300 ml of dry dimethylformamide, solution 40
    give up to -20 ° C and treat 14.5 g
    1.3 g of N- (No. -Benzilloxycarbonone- (71 mmol) dicyclohexylcarbodiim- - | L-benzyl-L-aspargyl) -N - (2,2,5,5-tetramethylcyclopentanecarbonyl-5-1,1- - diaminoethane (mp. 129-131 C), which is homogeneous according to TLC. The NMR spectrum of the product corresponds to the indicated structure.
    G, Hydrate the product of section B in the usual way in 50 ml of glacial acetic acid on 10% palladium on carbon. After lyophilization and several repeated lyophilisations, (L-acnapyl) (2,2,5,5-tetramethylcyclopentanecarbonyl) -5-1,1-diaminoethane is obtained from water in quantitative yield. (mp. 174-176 C, with decomposition). The compound is homogeneous according to HPLc (conditions - see, example 14, retention time 10.27 minutes). Sweetness 600 - 800 x sucrose.
    PRI and MER 13. N- (L-acnaprHn) 45
    Yes. After 30 minutes of activation at this temperature, a pre-cooled solution of 6.9 g (67 mmol) of ob-aminoisobutyramide in 125 ml of dimethylformamide is added. The mixture is allowed to warm to room temperature. After stirring for two days, the mixture is evaporated to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel, eluted with a successive gradient of chloroform / hexane 3: 1 (v / v), chloroform, and then chloroform / methanol (95: 5, v / v). After 50 elution, 10.0 g of N-benzyloxycarbonyl-benzyl-L-acnapyl-about-aminoisobutyramide is obtained, which is homogeneous according to TLC. I The TR spectrum of the product corresponds to the indicated structure.
    55
    -N - (cyclopentanecarbonyl) -2,2-diaminopropane (formula I, R is hcclopentyl).
    0
    five
    4862
    0
    five
    0
    22
    A. Suspend 20 g (0.194 mol) of y-aminoisobutyric acid in 400 NUT of tetrahydrofuran, treat with growth | thief phosgene in toluene (3 M, 160 ml). The mixture is heated overnight at 65 ° C. The resulting clear solution is evaporated under reduced pressure, redissolved in tetrahydrofuran and again evaporated. O-aminoisobutyric acid N-carboxyanhydrile is obtained in the form of a dense oil, which is used without further purification.
    B. Dissolve the product of section A in 200 ml of tetrahydrofuran, cool to -20 ° C and treat with excess ammonia gas. The solution is allowed to slowly warm to room temperature and then evaporated to dryness under reduced pressure. The solid residue is extracted with ethyl acetate in a Soxhlet extractor for 3 hours. The resulting solution is filtered and the product is allowed to crystallize. 10 g of 6-aminoisobutyramide are obtained in the form of a crystalline solid (i.e. 1.115-118 ° C) which is homogeneous according to TLC. The NMR spectrum of the product corresponds to the specified structure.
    B. Dissolve 24.2 g (67 mmol) of N-benzyloxycarbonyl-β-benzyl-L-β-aspartic acid in 300 ml of dry dimethylformamide, the solution is cooled.
    (71 mmol) dicyclohexylcarbodiimi-
    Yes. After 30 minutes of activation at this temperature, a pre-cooled solution of 6.9 g (67 mmol) of ob-aminoisobutyramide in 125 ml of dimethylformamide is added. The mixture is allowed to warm to room temperature. After stirring for two days, the mixture is evaporated to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel, eluted with a successive gradient of chloroform / hexane 3: 1 (v / v), chloroform, and then chloroform / methanol (95: 5, v / v). After elution, 10.0 g of N-benzyloxycarbonyl-β-benzyl-L-acnapgyl-about-aminoisobutyramide are obtained, which is homogeneous according to TLC. I TR spectrum of the product corresponds to / specified structure.
    G. Dissolve 5.0 g (11 mmol) of npd-duct of section B in 30 ml of acetonitrite, the solution is diluted with a rapid volume
    water and treated with 5.16 g (12 mmol) iodobenzene-bis- (trifluoroacetate). The reaction mixture is stirred for 7 hours at room temperature until completion of the reaction (according to TLC). The solution is evaporated under reduced pressure, the residue is dissolved in 100 ml of dioxane and 3 ml of concentrated hydrochloric acid, lots and lyophilized. Repeat the process. Succinate N- (N-benziloxycapaponyl-p -benzyl-T - (aspargil) -2,2-di-aminopropane is obtained with a quantitative yield, which is used without further purification,
    D. Dissolve the product of section G in 100 ml of tetrahydrofuran and treat with 2.5 g (24 mmol) of triethylamine, then 1.75 g (13.2 mmol) of cyclopentane carbonyl chloride. The reaction mixture is stirred at room temperature for 5 hours and filtered. The filtrate is evaporated under reduced pressure. The residue is purified by chromatography on silica gel. The H- (K-benzyloxycarbo-NIL-1-benzyl-L-aspargyl) -y-Cyclopentanecarbonyl) -2,2-diaminopropane is obtained, which is homogeneous according to TLC, NMR spectrum of the product corresponds to the specified structure
    E, Hydrogenate the product of section L in the usual manner in 100 ml of glacial acetic acid on 10% palladium on carbon. After lyophilization and several repeated lyophilisations, water is obtained with a quantitative yield of L- (L-aspargil) -N - (cyclopentane-carbonyl-2,2-diaminopropane). Sweetness 50-100 X sucrose.
    Example 14. N- (1-aspargil) - -N - (2,2,5,5-tetramethylcyclopentane carbonyl) -K-1,1-diaminopropane, (compound I,, CH j, ,, 2,5,5 - tetramethylcyclopentyl).
    A, Dissolved in 50 ml of dimethylformamide, 5.0 g (48.5 mmol) of D- (ib-amino-n-butyric acid, treated with 6.15 ml (48.5 mmol) of chlorotrimethylsilane. The mixture is stirred 1 h at room temperature. Simultaneously 15.73 g (45.1 mmol) of N-benzyloxycarbonyl-3-benzyl-L-asparginic acid are dissolved in 50 ml of dimethylformamide, cooled before treatment and 4 , 84 ml (44.1 mmol) of N-methylmorpholine, then 5.72 ml (44.1 mmol) of isobutyl chloroformate. After 10 minutes of activation, a pre-cooled silyl solution is added.

    Q

    0 5
    five
    of D-o6-amino-n-butyric acid ester, then a second equivalent of 4.84 ml (44.1 mmol) of N-methylmorpholine. The solution is allowed to warm to room temperature, stirred for 4 hours and then acidified to pH 1 -2 aqueous hydrochloric acid. Chloroform is added, the phases are separated, the aqueous layer is re-extracted with chloroform. The combined organic phases are washed three times with 1N hydrochloric acid, saturated with sodium chloride and dried with magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is crystallized from ethyl acetate / hexane. 13.3 g of N-benzyloxy-carbonyl-benzyl-L-aspargyl-B-o-amino-n-butyric acid are obtained (t, mp, 150-152 s), which is homogeneous according to TLC and NMR - the product spectrum corresponds to the specified structure,
    B, Dissolve 10.0 g (22.6 mmol) of the product of section A in 50 ml of dimethylformamide, cool before and treat with 2.48 ml (22.6 mmol) of N-methylmorpholine, then 2.93 ml ( 22.6 mmol) isobutyl chloroformate. After 4 minutes of activation at -15 ° C, 3.84 g (24.9 mmol) of 1-hydroxybenzotriazole ammonium salt is added as a solid. The mixture is stirred for 45 minutes at -15 ° C, then allowed to warm to room temperature slowly, with stirring, over 4 hours, diluted with water and chloroform. The phases are separated, the aqueous phase is re-extracted with chloroform. The combined organic extracts are washed three times with 1N. hydrochloric acid, three times with a saturated solution of sodium bicarbonate, with a saturated solution of sodium chloride and dry, with magnesium sulfate. The solvent is evaporated under reduced pressure and the solid residue is recrystallized from ethyl acetate / hexane. 7.5 g of benzyl-oxycarbonyl- - A - benzyl-L-aspargyl-Bc-amino-n-butyramide (m, mp 170-171 ° C), which is homogeneous by TLC, are obtained. The NMR spectrum of the product corresponds to the specified structure.
    B. Dissolve 5.0 g (11.3 mmol) of the product of Section B in aqueous acetone triple (1: 1 by volume, 100 ml) and treat 5.85 g (13.6 mmol) of iodobenzene bis (trifluoroacetate ), The reaction mixture is stirred for 5 hours at room temperature and evaporated to dryness under reduced pressure. The residue is redissolved in 50 ml of dioxane, an excess of concentrated aqueous hydrochloric acid is added, the solution is re-evaporated several times and, finally, lyophilized from dioxane ,. N- (M-benzyloxycarbonyl-benzyl-L-aspargyl) -R-1,1-diaminopropane is obtained with a quantitative yield, which is used without further purification.
    D. Dissolve the product of Section B in 25 ml of tetrahydrofuran and treat 2.56 g (13.6 mmol) of 2.2.5.5-α-tetramethylcyclopentanecarbonyl chloride, then 3.46 ml (24.9 mmol) of triethylamine. The mixture is stirred at room temperature and the reaction is monitored by TLC. Upon completion of the reaction (after about 5 hours), ethyl acetate and water are added. The phases are separated, the aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed twice with 1 M aqueous sodium bicarbonate, three times with 2N. hydrochloric acid, saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is recrystallized from ethyl acetate / hexane. Get 4.4 N- (N-benzyloxycarbonyl-p-benzyl-L-aspargil) -N - (2,2,5,5-those tramethyl-cyclopentanecarbonyl) -K-1,1-diaminopropane, which is homogeneous according to TLC. I GR spectrum of the product corresponds to the specified structure.
    D. Hydrate 4.0 g of the product of section G in the usual way in 100 ml of glacial acetic acid on 10% palladium on carbon. After lyophilization and several repeated lyophilisations from water, N- (L-acpapgyl) -N - (2,2,5,5-tetramethylcyclopentanecarbonyl) -K-1,1-diaminopropane (m.p. 164 C, with decomposition). Sweetness 200-300 x sucrose.
    As mentioned above, the synthesized compounds can be used to make sweeteners in the food industry (for use in food, chewing gum, beverages, etc.).
    In addition, these compounds provide a high degree of sweetness.
    five
    0
    five
    0
    five
    0
    five
    0
    five
    These are of particular interest because of the amino acids produced, but not peptides, because of which the degree of safety they provide is much higher than that of any of the known synthetic sweeteners.
    The compounds obtained by the proposed method are highly stable. They can be used over a wider pH range than compounds such as L-aspargyl-L-phenylalanine methyl ester, referring to the dipeptide sweetener. Under high temperature conditions, they also remain stable.
    The resulting compounds are not organic in the amounts used for sweetening. The degree of sweetness depends on a number of factors, the most important of which is the nature of the acylating group R, the precursor of carotelic acid. Generally preferred are branched, massive hydrophobic groups, but most preferred are cycloalkyl and heterocycloalkyl groups containing alkyl substituent groups adjacent to the carbonyl group. For example, the cyclopentyl group contains geminal dimethyl substituents at the 2nd and 5th positions of the ring (see table). The substitution at the 3rd and 4th positions of the ring is usually not
    gives a high level of sweetness.
    t
    Although the degree of sweetness of the compounds obtained according to the invention, in comparison with sucrose (counting weight by weight) largely depends on the substituent R, all these compounds provide advantages as sweetening agents due to the fact that all their decomposition products are compatible with human physiology, namely, acetic acid and amino acids, as well as due to their high stability both in solid form and in solution. In addition, the compounds according to the invention when used with other sugars, such as to saccharin, the undesirable bitter aftertaste of other sweeteners is eliminated.
    Therefore, the compounds obtained by the proposed method can be
    used to sweeten various types of edible materials.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining N- (L-acpapgil) - -M- (1-acylamino) -alkylamines of General formula I
    R
    NZM-CH-CO-T H- -NH-CO-R
    CH-i R
    with
    where R is lower alkyl or lower oxyalkyl,
    R is hydrogen or lower alkyl; and R is branched C-alkyl, Cg-Cycloalkyl, lower alkylcycloalkyl, dicyclo (lower) alkyl, 2,2,4,4-tetramethylthietane or phenyl, characterized in that the wire t interaction protected amino acids of the formula
    X-NH-CH-COOH
    sn shit
    where X is an amino protecting group such as benzyloxycarbonyl, and Y is a carboxyl protecting group such as benzyl,
    with an amino acid derivative of the formula
    H N-C-COOZ
    R
    where R and R have the above values,
    Z is hydrogen or carboxyl protecting group to form a compound of formula
    R
    X-NH-CH-CO-NH-C-COOZ SNg R GOOD
    the protecting group Z is removed to obtain a compound of the formula
    R X-MH-CH-CO-NH- (f-COOH
    CH2
    soo
    R
    which is treated with am1 to obtain the corresponding amide of the formula
    R
    X-NH-CH-CO-NH-C-COMH, I I
    CH
    coo
    R
    where X, y, R and. R have the indicated meanings
    the amide obtained by the Hoffman rearrangement is converted into the corresponding mono-acyl-gran) hemdiaminoalkane salt of the formula
    R
    X-NH-CH-CO-NH-C-NnV II 3
    CH2 R
    so-z
    where R, R, X and Y have the indicated meanings, A is an anion,
    reacting this salt with an acid chloride of the formula where R has the indicated meanings to obtain the corresponding protected derivative of the formula
    R
    x-NH-cH-co-NH-C-NH-COR
    CHi R
    coo
    50
    wherein the protecting groups X and Y are removed.
    sweeteners for sweeteners - what is hemodyaminoal
    R
    H jN-CH- (p-NH- CO-I
    R
    CH, CO.
    CHjClljN
    R
    200-300
    31
    a) Sweeteners occur from b-aspargil-K-hemdiaminoalkanes, unless otherwise indicated
    b) Regarding sucrose
    c) Origin of 1, -aspargsh1-8-1,1-diaminoethane
    Compiled by L.Ioffe A.Makovska Editor Tehred M.Didyk Proofreader E.Lonchakova
    Order 4136/58
    Circulation 352
    VNIIPI State Committee for Inventions and Discoveries at 1 CST of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
    ,, K ..,. B ... w.H.B. . .but..-.......,..... .
    Production and publishing plant Patent, Uzhgorod, st. Glrina, 101
    1494862
    32 Continuation of the table
    Subscription
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    同族专利:
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    KR910000406B1|1991-01-25|
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    EP0128654A2|1984-12-19|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/503,853|US4571345A|1983-06-13|1983-06-13|1,1-Diaminoalkane derived sweeteners|
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