前苏联专利SU1650009A3 Method of producing 5-arylalkyl-4-alkoxy-2(5h)furanon

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专利摘要:
The invention relates to 5-arylalkyl-4-alkoxy-2 (5H) furanones, in particular the synthesis of substances L-ly I R. (0) ...., L -0-CR -CH (OK2) -C6H3KEK4, where the oxygen atoms , -C-5 and C-оЈ, respectively, each other are occupied by threo-posit and R - C -C-alkyl, R2 -H, C, -C3-elkil or, at R6, kil or methoxymethyl or ethoxyethyl; Rr - H, C-C {ralkyl, methoxymethyl; R, and R4 (independently) - H, F, C1, Br, C (-C j-alkyl, C 4 -C C-perfluoroalkyl, N0a; R f H or Cj-C e alksh | with the exception of substances with R2 H or CH if R is OH and Rj-Rg. —H, possessing anti-convulsant and antiepileptic activity, which can be used in medicine.The goal is to increase the selectivity of the process with respect to threo enantiomers (tfR, 5S if {8, 5R.) and expansion of the range of target substances. Synthesis is carried out by condensation of compounds of common f-crystals II and III C6H, R3R4. (II) R-CHЈ-C (OR,) CH-C (0) -0-RT (III) with R-g - С-Сф-alkyl with the subsequent hydrolysis of the ether R7-group and, if necessary by transferring the acid to the C-C d-alkyl ester or cis-dihydroxylation of the acid by a catalytic amount of OsO and an oxidizing agent, or the alkaline group or water is removed from the resulting ester to give the compound with R2 - N. If necessary, the latter is treated Compound R2X, where X is a halogen or a lower alkoxy group, a, to give the corresponding substance. Preferably, the condensation is carried out in a dipolar aprotic solvent in the presence of bases (dimethyl sulfoxide and alkali metal hydroxide, quaternary ammonium compound, or a mixture thereof) at 70-140 ° C in an inert gas atmosphere. It is better to use hydroperoxide, alkyl, chlorate or tertiary amine N-oxide as the oxidizing agent. The cis-dihydroxylated step can best be carried out in the presence of a quaternary ammonium base or a quaternary ammonium salt. In this case, selectivity with respect to the treotisomer increases from 35.4 to 56.6%. 5 hp f-ly, 17 tab. o cd &amp;
公开号:SU1650009A3
申请号:SU874202523
申请日:1987-05-04
公开日:1991-05-15
发明作者:Сандер Чэттерьи Шиам；Клессинг Клаус
申请人:Др.Вилльмар Швабе Гмбх Унд Ко.(Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the production of 5-arylalkyl-4-alkoxy-2 (5H) uranones, in which the oxygen atoms C-5 and C- {respectively with each other occupy the threo-boxene.
These compounds possess protivootrezhodnoy and antiepileptic activity. Such compounds, where the C-5 and C-ryo oxygen volumes occupy each other in an erythro-positivity, are not at comparable dosages effective.
The purpose of the invention is to increase the process's seactivity with respect to 15 threo-enantiomers (& G, 5S and & S, 5R) expanding the range of target products.
The method is illustrated by examples where the following abbreviations are accepted: 20
melting scbmp (unadjusted)
Kp - boiling point (uncorrected);
(Z) - decomposition.25
Temperatures are in degrees Celsius.
The pressures are in, bar (mbar), with 1 bar (mbar) 10g (102) Pa.
300 and 75.46 MHz-3C spectra-3-nucleus nuclear resonances were recorded on a Bruckner WH300 nuclear magnetic resonance spectrometer. Dimethyl sulfoxide-Dg (DMSO-D6) was used as a solvent. 35
Chemical shifts & are indicated relative to the signal of tetramethylsilane (internal standard).,
Example 1. Ethyl-3-methoxy-2 (E) butenoate.40
A mixture of 520 g (4 col) of ethyl acetoacetate, 400 ml of methanol and 2 ml of 36% hydrochloric acid (or 1 ml of concentrated sulfuric acid) is heated to 50 ° C. With stirring, a vacuum of 425 g (4 mol) of trimethyl ortho formate is obtained so that the mixture is maintained at a temperature of about 50 ° C. Methyl formate and excess methanol are then distilled off and the residue is divided into fractions through a Vigre column. At 184–186 ° C, 548 g (3, .8 mol) of pure ethyl-3-methoxy-2 (E) -butenoate are distilled.
Yield 95% .55
PRI mme R 2. Ethyl-3-ethoxy 2 (E) - butenoate J
Preparation analogously to example 1 by the conversion of ethyl acetoacetate with TPI
ethyl chloroformate in ethanol with hydrochloric acid as a catalyst.
Exit 84.51. Cr. 191-195 ° C; .
PRI me R 3. Methyl-3-methoxy-2 (E) -pentenoate.
Preparation is analogous to example 1 by conversion of methylyl-3-oxopentaoic acid with trimethyl orthoformate in methanol and sulfuric acid as a catalyst.
Exit 87.7%. Cr 76-78 ° C (20 mbar).
PRI me R 4. Ztil-3-methoxy-2 (E) hexenoate.
Preparation is analogous to Example 1 by the conversion of ethyl 3-oxohexanoate with trimethyl orthoformate in cetanol and sulfuric acid to the catalyst drips.
Yield 95.8%. Cr 87-89 ° C (20 mbar)
EXAMPLE 5 Ethyl-3-methoxy-5 methyl-2 (E) -hexenoate.
Preparation is analogous to Example 1 by converting ethyl 5-methyl-3-oxo-hexanoate with trimethyl orthoformate in methanol and sulfuric acid as a catalyst.
Exits about 50%. Cr 91-97 0 (16-19 mbar).
PRI me R 6. Z-Methoxy-5-phenyl-2 (E), 4 (K) -pentadiene acid,
and With stirring and in the atmosphere of nitrogen, to the mixture and: 53 g (0.5 mol) | 5 benzaldehyde, 100 ml of dimethyl sulfoxd and (0.5 mol) of ethyl 3-methoxy- (E) -butenoate added 1.6 g (0.05 mots) of benacet triethyl ammonium chloride and then a solution of 33, g (0.6 mol) of potassium hydroxide in 35 ml of zoda is instilled. The solution is heated for about 16 hours to 110 ° C, the solution is evaporated, the residue is dissolved in 400 ml of water: and the mixture is extracted with the help of 100 ml of dichloromethane. After acidification with 70 ml of 10 molar hydrochloric acid, the crude product is precipitated from the aqueous phase, which after suction on the suction, 1 washing with water to free it from acid, recrystallizing from this cola and drying at 100 ° C in saiy / ms gives 34.9 g (0.171 mol) of pure product with a melting point of 154-155ES.
Output 34.2%. M.p. according to literary data. 157,5--158вС.
Calculated 3%: C, 70.57; H 5.92.
C, 2H1203 (204.23).
Found,%: С / 0.49 Н 691б.
$. Under stirring and in an atmosphere of nitrogen, a solution of 3785 g (26.25 mol) of ethyl 3-methoxn-2 (E) butenoate in 6 l of dimethyl sulfoxide is instilled in turn in 2653 g (25 mol) of benzaldehyde and 926 ml (2.5 mol ) 40% aqueous tetraethylammo hydroxide; and, After heating to 100 ° C, a solution of 1470 g (26.25 mol) of potassium hydroxide is instilled in 1500 ml of water and stirred for 4 hours at 100 ° C. After cooling to approximately 20 ° C, the mixture is poured into 50 l of water and extracted with
9
Found,%: C 60.33; H 4.85; C1 14, / 2.
300 MHz N-nuclear magnetic resonance: 11.8-12.2 (1H, Vg. M. COOH);
8.08 (1H, d, 15/4 16 g "); (1H, d, 1. Hz, H-4); 5.29 (1H,. S, I-2); 3,785 (ЗН, s, OCH5); 7.35-7.75 (4H, t, flavor, protons).
Similarly applied in the application; pax 6 (a, b) and 7 methods of synthesis are obtained by condensation of benzaldehyde or substituted benzaldehydes with 3-alkoxy-2 (E) -al described in examples 1-5
are given in table. one.
In tab. 2 and 3 are analytical and H-NMR spectroscopic
Mix with 10 L dichloromethane. coenoates of C-alkoxy-5- (substituted.) fe The aqueous phase with vigorous stirring-2 (E), 4 (E) -pentadiene acids, is acidified with approximately 3 liters of 33% hydrochloric acid to pH 2 and filter the precipitated crude product through a filter operating under pressure-20 data.
the mixture, washed with water to release the mixture. Benzyl 5- (2-chloro from chloride and sugaat by blowing azophenyl) -3-methoxy-2 (E), 4 (E) -pentadienoate .
In a mixture of 48 g (0.2 mol) 5- (2i after dry purging in vacuum of su- 25 chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadiene acid, 600 ml of acetone and 60 g ( 0.43 mol) potassium carbonate is instilled in with stirring 34.2 g (0.2 mol) of benzyl bromide and heated for 30–16 hours under reflux. After filtering off the inorganic residues, evaporation of the filtrate and recrystallization from tertiary butyl methyl ether, 56.1 g (0.17 mol) of pure
Tom. The filter cake is suspended in 6 liters of ethanol, filtered again.
85 ° C.
Shat to final temperature
Get 3071 g (15.04 mol) of pure
product with so pl. 159-160 ° C.
Yield 60.1%.
Example 7. 5- (2-Chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadioic acid.
3785 g (26.25 mol) of ethyl 3-methoxy 2 (E) -betanoate is converted in a similar manner to
Example 66 in 6 l of dimethyl sulfoxide benzyl ester with m “pcs.
from 3515 g (25 mol) of 2-chlorobenzaldehy-83-86 ° C. yes, 926 ml (295 mol) of 40% hydro-Yield 85%.
tetraethylammonium oxides and 2940 g (26.25 mol) of 50% potassium hydroxide solution and further stirred at 100 ° C for 4 hours. After cooling, diluted with 10 liters of water and extracted with by-products 10 liters of dichloromethane. The aqueous phase is ground into a mixture of 5 liters of 33% hydrochloric acid and 50 liters of water, after which the pH is 3.5–4. The precipitated crude calculated,%: C, 69.41; H 5.21; C1 10.78. 40, 7С109 (328.80).
Found,%: C 69.42; H 5.08; C1 10.9.
Example 35 Ethyl 5- (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadi-45 enoate.
O- A mixture of 31 g (0.13 mol) of 5- (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) -penO- A mixture of 31 g (0.13 mol) of 5- (2 - chlorophenyl) -3-methoxy-2 (E), 4 (E) -pendicular after filtration, washing with hydrotadiene acid, 400 ml of acetone, up to relieve chloride and about 36 g (0.26 mol) of potassium carbonate and khoi purge in 20 l of ethanol, the suspension — SQ g (0.13 mol) of iodoethane is heated, again sucked off under suction, refluxed for 8 hours until refluxed, then dry purged and dried until it is cooled, filtered and evaporated. 85 C at 20 mbar. neither filtrate absorbs oily
crude product in 100 ml of n-pentane, from - - with Insoluble potassium iodide is filtered, the filtrate is evaporated and demolished at 45 ° C and 20 mbar. Obtain 33.3 g (0.125 mol) of pure ethyl ester with so pl. 49-51 ° C.
Get 5045 g (2151D mol) of the pure product with tsh, 202 ° C.
Yield 84955%.
Calculated,%: C 60.39; H 4.65; , C1 14.85.
S, JN (4S103 (238.67).
are given in table. one.
In tab. 2 and 3 are analytical and H-NMR spectroscopic
K-aloxy 3-alkoxy-5- (substituted.) Phenyl-2 (E), 4 (E) -pentadiene acids data.
Calculated,%: C 69.41; H 5.21; C1 10.78. , 7109 (328.80).
Found,%: C 69.42; H 5.08; C1 10.9.
Example 35 Ethyl 5- (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadiene.
O- A mixture of 31 g (0.13 mol) of 5- (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadiene acid, 400 ml of acetone, 36 g (0.26 mol) of carbonate potassium and g (0.13 mol) of iodoethane are heated to reflux for 8 hours at reflux. After cooling, filtering and evaporation, the filtrate absorbs oily
Yield 96%.
Calculated,%; From 63.05 $ H 5.67} C1 13, / - 9.
C 4H15C10a (266.73). Found,%: C 63.3 /; H 5.69; SP 13.3.
Ј. With stirring, instilled into a mixture of 35 l of butanol, 2386 g (10 mol) of 5- (2-chlorophenyl) -3-methoxy 2 (E), 4 (E) -pentadienic acid, 2073 g (15 mol) of potassium carbonate and 16 , 6g (0.1 mol) of potassium iodide at 56 ° С 1635 g (15 mol) of bromoethane and stirred for an additional 24 hours at 566С.
After cooling and filtering off the inorganic components, the filtrate is washed with 2 times 10 liters of water and the butanone phase is evaporated. 2348 g (3.80 ml) of ethyl ester are obtained, which crystallizes on cooling. Thin layer chromatography and infrared spectrum show identity with the product described in item a.
T „pl. 45 ° C. Yield 88%. PRI me R 36. Methyl-5 (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentandane.
A mixture of 23.9 g (0.1 mol) of 5- (2- to orphenyl) - 3 methoxy-2 (E), 4 (E) -pentadienic acid, 500 ml of acetone per 30.4 g (0, 22 mol of potassium carbonate is mixed with 9.5 ml (0.1 mol) of dimethyl sulfate with stirring and heated for 4 hours under reflux. After cooling and filtration, the filtrate is evaporated, the crude product is dissolved in 100 ml of chloroform, washed twice with 30 ml of water, the chloroform phase is evaporated and recrystallized from isrpropanol — water. After drying at 50 ° C / 20 mbar, 22.18 g (87.8 mmol) of pure methyl ester with mp. 50-52 ° C.I
Exit 87.8,%.
Calculated,%: C, 61.79; H $ 5.18 C1 14, 03.
C “H, 9S103 (252.69).
Found,% g C 61.30; H 5.07; C1 13, /.
Similarly as described in the examples 34-36 methods were obtained are listed in the table; 4 esters of 3-alkoxy-5-phenyl-2 (E), 4 (E) -pentadiene acid, the results of the elementary
the analyzes of the latter are listed in Table 5.-ns / M-g - H 5.008 (1H, s, H-5),
0
n 5
d «45
0
five
50
EXAMPLE 64 threo-5- (2-Chorphenyloxymethyl) -4-methoxy-2 (5H) -furanone.
Below are the various options for the implementation of the osmium tetroxide-oxidized oxidation of 3-alkoxy-5-phenyl-2 (E), 4 (E) -pentadienic acid derivatives to threo-4-alkoxy-5-phenyloxymethyl-2 (5H) - furanos.
Q. To a mixture of 48.0 g (201 mmol) of 5- (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) of pentadienic acid, 400 ml of water and 400 ml (566 mmol) of 20% With aqueous stirring and cooling to 0 ° C, 50 ml of a 0.02 M solution of four osmium oxides in acetone or tertiary butanol and 56 ml (403 mmol) of 70% is added with aqueous hydrochloride. tertiary butyl hydroperoxide aqueous solution. After 6 hours of stirring at 0 ° C, it is left for 0 days at 0-5 ° C and after this the hydroperoxide is reduced by stirring with a 10% aqueous solution of sodium sulphite. The pH of 2S is adjusted by addition of 1 molar sulfuric acid crystallize out. The latter is suction filtered on suction (IOS1 g 42.3 mmol), Filtrate i is extracted 3 times with 100 ml of chloroform and the extract is washed with 50 ml of 1-molar hydrochloric acid to free from quaternary ammonium salts. The extract contains a mixture of threo-5- (2-chlorophenyl) -4,5-dioxy-3-methoxy-2 (E) -pentenoic acid and (2-chlorophenyloxymethyl) -4-methoxy-2 (5H) -fura- nona. The cycle is closed by evaporation and, after recrystallization from ethyl acetate, 18.12 g (71.2 mmol of pure threo-5- (2-chlorophenyloxy-imgtil) -4-methoxy-2 (5H) -furanone) are obtained. 149-151 0.
The output in terms of converted source product of 45.1%.
Calculated,% i C 56.59, H.4.35 C1 13.92.
C42KU ClO (254.67).
Found,%: C 56.2 /; G1 14, C.
H 4S35S300 1Hz N-nuclear magnetic resonance: 7-7, / (4H, n, aromatic protons); 5.96 (1H, #, .1Сц / н - 5.5 Hz, Oi-QH) 5.440 (1H, d, ..3 Hz, H-3); 5.225 (1H, dd,
5.008 (1K, s, H-5); 3,923 (3H, s, OCH3).
75.46 MHz-13 C — nuclear magnetic resonance (breaking of the wide spectral band): C-2 (1 / 2.530); C-3 (90.268); C-4 (180,229); C-5 (79.872) C- (x (66, 721), Cdg, - "(138,409); SAP-up to 6 (130, 650, 129, 571, 129, 421, 129, 032 and 1 127, 265); OCH, (60,071) .J
Coordination of C signals was provided by a far resonance spectrum and controllable spectrum pulses, as well as SFORD experiments.
S. To a solution of 26.7 g (100 mmol) of ethyl 5- (2-chlorophenyl) -3-methoxy-2- (E), 4 (E) -pentadienoate in 450 ml of acetone was added 6.5 F (25 mmol) of tetraethylammonium acetate tetrahydrate and boiled under stirring and while cooling to 0 ° C in turn 25 ml of a 0.02 molar solution of osmium tetroxide in tertiary butanol and 23.6 ml (170 mmol) of a 70% native solution tertiary butyl hydroperoxides. Leave for 12 days at 4 ° C, add 200 ml of dichloromethane and 140 ml of a 10% aqueous solution of sodium sulfite, stir until hydroperithexy disappears, separate the organic phase, extract the aqueous phase 2 times with 100 ml of dichloromethane and wash the combined organic phases with an aqueous solution of sodium chloride. The organic phase contains a mixture of threo-ethyl-5- (2-chlorophenyl) -4,5-dioxy-3-methoxy-2 (E) -pentenoate and threo-5- (2-chlorophenyloxymethyl) -4-methoxy- 2 (5H) -furanone. A loop closure is added by evaporation and, after recrystallization from tertiary butyl methyl ether, 19.4 g (76.2 mmol) of pure product with m.p. 149-151 ° C, which is identical in terms of thin-layer chromatography and infrared spectrum to the product obtained in Example 63 a. : k Yield / 2.6%.
&. Similar to variant o, however, instead of ethyl ester, benzyl-5 (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadienoate is used.
The yield of threo-5- (2-chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone after recrystallization from ethanol is 67.5%. Mp 149-151 ° C.
1. In a solution of 26, 7 g (100 mmol) ethyl-5- (2 chlorophenyl) -3-methoxy-2 (B),
j Ш
15
20 25 30 35 40 45
cn
five
4 (E) -pentadienoate and 360 ml of acetone are added with stirring 10 ml of a 0.02 molar solution of osmium tetroxide in tertiary butanol and a solution of 14.9 g (110 mmol) of N-methylmorpholine-N-hydroxy hydrate in 30 ml water and stirred for 4 days at room temperature. The excess, N-oxide is reduced by mixing with 5.2 g (50 mmol) of sodium sulfite dissolved in 50 ml of water, the P4 is adjusted to 4 with help of 1 molar sulfuric acid, the acetone is distilled off in vacuo, and the remaining aqueous mixture is extracted 2x200 ml of dichloromethane. The extract is washed with dilute sulfuric acid and water to free N-methyl morpholine and, after drying on anhydrous sodium sulfate, concentrated in vacuo. 18.13 g of threo-5- (2-chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone are crystallized. Evaporation of the filtrate and recrystallization from ethyl acetate gave the remaining 1.20 g of pure product.
Yield 19.33 g (75.9 mmol), i.e. 75.9%.
but. As in option 1, but the reaction is not carried out in acetone, but in the 2-phase system butanone is water and instead of 110 mmol 160 mmol of N-methylmorpholine-N-oxide is introduced,
Yield / 6.2%.
at. As with option Ј, however, in a two-phase system dichloromethane is water.
The yield is 66.7%.
G. A mixture of 23.6 g (80 mmol) of secondary butyl 5- (2-chlorophenyl) g-3-methoxy-2 (E), 4 (E) -pentadienoate, 200 ml butanone, 15 ml A 0.02-molar solution of osmium tetroxide in tertiary butanol, 1 /, 6 g (160 mmol) of N-methylmorpholine-M-hydroxide is added to 50 ml of water for 7 days at room temperature. After the addition of 100 ml of dichloromethane, it is kneaded with 100 ml of a 2% aqueous solution of sodium sulphite, the organic phase is separated and washed with 2 times with 100 ml of 0.5 molar hydrochloric acid and 5 times with 100 ml of water. Organic phase contains a mixture of threo-sec-butyl-5- (2-chlorophenyl) - 4,5-dihydroxy-3-methoxy-2 (E) -pentenoate and threo-5- (2-chlorophenoxymethyl) - 4-methoxy-2 ( 5H) -furanone. Addition of 0.1 / ml of 32% hydrochloric acid and evaporation of the organic phase completes the ring closure and, after recrystallization from ether, 10.66 g (4199 mmol) of threo-5- (2 chlorophenyl oxymethyl) - 4-to-toxic 2 (.5Н) - furan.
Yield 52.3%.
Instead of the secondary complex ester, the corresponding methyl, isopropyl or tert-butyl esters can be used.
Analogously to the method described in example 64 of the method Q, by oxidation of the derivatives of 3-alkoxy-5-phenyl-2 (E), 4 (E) -penadiadienic acid described in examples 6-63, derivatives of threo-g4-alkoxy-5-phenyloxime- Tyl-2 (5H) -furanone listed in Table. 6; in tab. 7 shows the results of elementary analyzes; Table 8 shows the spectroscopic data of H-nuclear magnetic resonance
Example89. threo-5- (2-Chlorophenyloxymethide) 4-methoxy-5-methyl-2- (5H) -furanone.
ABOUT . A mixture of 28 g of ethyl 5- (2-chlorophenyl) 3-m etoxy-4-methyl-2 (E), 4 (E) -pentadienoate (crude product from example 61), 250 ml of tetrahydrofuran and 50 ml. water is mixed with 25 ml of a 0.02 molar solution of tetra x sy osmi
ten
15
20
25
(82 mmol) 1, 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMRI). In the meantime, a solution of 10.5 g (82 mmol) of 4-methoxy-5-methyl-2 (5H) -furanone in 80 ml of tetrahydrofuran is dripped, stirred for 30 minutes and a solution of 11.84 g (82 mmol) is dropped in chlorobenzaldehyde & in 50 ml of tetrahydrofuran. While stirring for 16 hours, bring the temperature to 0 ° C, hydrolyze by instillation with 50 ml of water and adjust the pH to 5.5 with 2 molar hydrochloric acid. The organic phase is separated and evaporated, the aqueous phase is extracted with 3 times 100 ml of ether. The evaporation product and ether phases are combined, washed with water to remove DMRI, dried over sodium sulfate and evaporated. The residue is partitioned into 400 g of silica gel using chloroform - methanol 98: 2 as a solvent by column chromatography. fractions with the coefficient RЈ (chloroform - methanol 95: 5) -0.37 after evaporation and recrystallization from tertiary butyl methypester ether - dichloromethane give 5.3 g (19.7 mmol) of pure threo-5- (2 in t-butanol and 10 , 7 g of chlorate nat- 30 hlorfensh1oksimetil) -4-mztoksi-5-methyl35
Re and heat for 4 days with stirring until reflux. 25 ml of a 0.02 molar solution of four osmium oxides and 10.7 g of sodium chlorate are added again and the mixture is refluxed for another 3 days under reflux. In spite of incomplete oxidation process. After cooling and adding 100 ml of dichloromethane, the inorganic components are washed out with water, the dichloromethane phase is dried on sodium sulfate, evaporated and recrystallized from ethyl acetate. This gives 1.463 g of pure threo-5- (2-chlorophenyloxymethyl) -4 methoxy 5-methyl -2 (5K) g furaion with m.p. 181-184 ° C. Thin-layer chromatography (DC) on F 254 silica gel with chloroform - methanol 95; 5 gives
, 37i
Calculated% J C 58.11, And 4s88j
13,15
45
C1
C1
C H13C104 (268.69). Found%: C 57352 | H.4,67;
50
12.9.
ЈG. Under stirring and cooling to -77 ° C in a nitrogen atmosphere, 50 ml of a 1.64 molar solution of p-butyl lithium in hexane and 10 ml are instilled into a solution of 3 g (82 mmol) diisoproplaminate in 150 ml of tetrahydrofuran; 52 g
2 (5H) - Ј urance with m.p. 192-194 ° C, which is identical with thin-layer chromatography and infrared spectrum. obtained according to example 89a product.
Calculated%: C 58.11 s- H 4.88, - C1 13.19.
. (268.69) about
Found%: C 58.05 | H 4.81; C1 13.21. ,
Fractions with R, -, 48 after evaporation and recrystallization from toluene give 2.64 g (9.84 mmol of pure erythro-5- (2-chlorophenyloxymethyl) -4-methoxy-5-methyl-2 (5H) -furanone mp 153-155 ° C.
Calculated,% .- C 58.11; H 4.88; C1 13.19.
C13H43C10 (268.69).
Found,%: C 58502, - H 4.87; CI 13 ..
Example 90 threo-5- (2-Chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone.
When cooled to -70 ° C under agitation and in a nitrogen atmosphere zakapy-,
vnivoptopylamine ml (327 mmol) and 500 ml of anhydrous tetrahydrofuran are added to a solution of 200 ml 1.64-mol
0
five
(82 mmol) 1, 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMRI). In the meantime, a solution of 10.5 g (82 mmol) of 4-methoxy-5-methyl-2 (5H) -furanone in 80 ml of tetrahydrofuran is dripped, stirred for 30 minutes and a solution of 11.84 g (82 mmol) is dropped in chlorobenzaldehyde & in 50 ml of tetrahydrofuran. While stirring for 16 hours, bring the temperature to 0 ° C, hydrolyze by instillation with 50 ml of water and adjust the pH to 5.5 with 2 molar hydrochloric acid. The organic phase is separated and evaporated, the aqueous phase is extracted with 3 times 100 ml of ether. The evaporation product and ether phases are combined, washed with water to remove DMRI, dried over sodium sulfate and evaporated. The residue is partitioned into 400 g of silica gel using chloroform - methanol 98: 2 as a solvent by column chromatography. fractions with the coefficient RЈ (chloroform - methanol 95: 5) -0.37, after evaporation and recrystallization from tertiary butylmethyl ether - dichloromethane, give 5.3 g (19.7 mmol) of pure threo-5- (20 chlorofenshoxymethyl) -4- mztoksi-5-methyl5
about
five
0
2 (5H) - Ј urance with m.p. 192-194 ° C, which is identical with thin-layer chromatography and infrared spectrum. obtained according to example 89a product.
Calculated%: C 58.11 s- H 4.88, - C1 13.19.
. (268.69) about
Found%: C 58.05 | H 4.81; C1 13.21. ,
Fractions with R, -, 48 after evaporation and recrystallization from toluene give 2.64 g (9.84 mmol of pure erythro-5- (2-chlorophenyloxymethyl) -4-methoxy-5-methyl-2 (5H) -furanone mp 153-155 ° C.
Calculated,% .- C 58.11; H 4.88; C1 13.19.
C13H43C10 (268.69).
Found,%: C 58502, - H 4.87; CI 13 ..
Example 90 threo-5- (2-Chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone.
When cooled to -70 ° C under agitation and in a nitrogen atmosphere zakapy-,
vnivoptopylamine ml (327 mmol) and 500 ml of anhydrous tetrahydrofuran are added to a solution of 200 ml 1.64-mol p13
a n-butyl lithium solution in hexane 84 g (655 mmol) of 1, 3-dimethyl-3,4,5,6 tetrahydro-2 (1H) -pyrimidinone and a solution of 37.4 g (32 / mmol) of 4-methoxy-2 (5H) -furanone in 300 ml of tetrahydrofuran. The mixture is stirred at -55 ° C for 30 minutes, a solution of 46 g (327 mmol) of 2-chlorobenzaldehyde and 5.8 ml of water is instilled in 100 ml of tetrahydrofuran and stirred for an additional 16 hours while gradually heating to 0 ° C. After hydrolysis with 200 ml of water, setting the value to 5 with 2 molar hydrochloric acid and after separating the phases, the organic phase is evaporated, the aqueous phase is extracted 2 times with 300 ml of ether, the ether phase is combined washed 3 times with 300 ml of water and evaporated. An oily, crude product consisting of a mixture of the threo and erythro isomers becomes crystalline after trituration with carbon tetrachloride. Repeated fractional recrystallization from ethyl acetate gives 41.5 g (163 mmol) of pure threo-5- (2-chlorophenyloxymethyl) -4-methoxy-2 (5H) furanone with m.p. 140-145 ° C and 35 (DC, silica gel F 254; chloroform - methanol 95: 5). The product from the point of view of nuclear magnetic resonance and infrared spectrum thin-layer chromatography is identical with the product obtained in Example 64.
From the mother liquors of crystallization, 5.0 g (20 mmol) of pure erythro-5- (2-chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone with m.p. 159-161 ° C (ethyl acetate) and, 45.
Calculated,%: C 56.59; H 4.35; C1 13.92.
С, гН „С104 (254,67).
Found,%: C 56.80; H 4.50; C1 13.9.
300 MHz N-nuclear magnetic resonance: 7.27-7.6 / (4H, t, flavor, protons); 6.205 (1H, d, 1i / nL 5.0 Hz, tf-OH) $ 5, DU (III, s H-3); 6.292 (1H, dd; 1sc / m-5 2.7 Hch, tH d, H-S); 3.73, (SQ, s, OCHj).
Another concentration of stock solutions gives another 18.7 g (73 mmol) of a crystal mixture of threo- and erythro-isonomers, which is no longer separated.
Example 91. 4-Ethoxy-2 (5H) -furanone.
0009 4
A mixture of 34.2 g (300 mmol) of 4-methoxy-2 (5H) furanone, 5200 ml of ethanol and 30 mmol of sodium ethylate is stirred in an autoclave under a nitrogen atmosphere for 24 hours at 120 ° C. After cooling, the filtrate is filtered over 100 g of silica gel, the filtrate is evaporated and distilled 2 times at 10 mbar through a Bigre column. 21.6 g (169 mmol) of 4-ethoxy-2 (5H) -furaconone are obtained with 135-137 ° C.
Yield 56%.
Example 92. 4-Propox-2 (5H) -furanone.
Preparation analogously to example 91 of 4-methoxy-2 (5H) -furanone and propa10
15
nola. Cr40 143-145 S.
0
Yield 39%.
Calcd., 7; C, 59.14; H 7.09
0 С7НШ03 (142,16).
Found,%: C 59.18; H 7.36. Examples 93-105. Similarly to the methods mentioned in examples 89 and 90, the remaining threo-4-alkoxy-55 oi-OKCH-W- (substituted.) Fecalcyne} -2 (5H) -furanones are obtained and the accompanying erythroisomers are separated from them.
Name, melting points and determined by thin layer chromatography
0 on silica gel F254 Rr-values are given in table 9, analytical data - in table. 10 and spectroscopic data of H-nuclear magnetic resonance in Table. eleven.
Example 106. Threo-4-Ethoxy-5-methoxy- (2,4-dichlorophenyl) -methyl | -2 (5H) -furanone.
A mixture of 3.0 g (9.9 mmol) of threo-5- (2,4-dichlorophenyloxymethyl-4-ethoxy-2 (5H) -furanone, 50 ml of butanone, 9.23 g (mmol) of silver (I) oxide and 5 ml (80 mmol) of iodomethane are heated for 24 hours under stirring until refluxing, filtered, evaporated and the oily crude product is recrystallized 2 times from ether-petroleum ether to give 3,03 g (6.4 mmol) threo -4-ethoxy-5-methoxy- (2,4-dichlorophenyl) -methyl-2 (5H) -furanone with mp 110-114 ° C.
five
0
five
Yield 64.6%.
Calculated,%: C 53.02; H 4.45; C1 22.35.
C 4H14Cle04 (317.18).
Found,%: C 53.16; H 4.60; C1 22.4.
300 MHz N-core. magnetic resonance: 7.45-, 7 (3N, t, aromatic protons); 5.40 (1H, of, 1ts-3 / n-5
0.88 Hz, H-3); 5.05 (1H, dd, 1 „/ nG 3.10 Hz, H-5); 4.86 (1H, d, Hrf) 4.1 (H, AVH-system, 4-OCH "-); 3,20 (ЗН, в, -ССИ,); 1.31) (GH, ICH / oclle-
7.07 Hz, CH3) .3
Example 107. threo-methoxy-5-methoxymethoxy- (2 chlorophenyl) -metcpG-2 (5H) -furanop.
A mixture of 12.7 g (50 mmol) of threo-5- (2-chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone, 100 ml of dimethoxymethane, 1.7 g (20 mmol} of lithium bromide, and 0, 95 (5 mmol) of p-toduol sulfonic acid hydrate is heated for 4 days during refluxing under reflux. Evaporated, mixed with 50 ml of dimethyl methane, washed with water to free from bromide and p-toluene-sulphonic acid, the organic phase is evaporated and recrystallized the crude product, 2 times from methanol, gives 10.68 g (37.75 mmol) of a methoxy methyl ester with mp 14t-i43 ° G.
Exit 71 ,.
Calculated,%: C 56.29; And 5, About C1 11.87.
C, 4% C105- (298.73).
Found,%: C 56.62 H H SJOj C1 11.9.
300 MHz — N-nuclear magnetite resonance: 7 3-756 (4n, ms aromatic protons); 5, -47 (1H, d, 1c „s / Ts.6 0.88 Hz, H-3); 5, (1H, d, Hw / H.ff -2.63 Hz, NOO; 5.09 Hz (1H, dd, H-5) S 4., 55 and 4S42 (2H, AB - system $ - $ &; - 7.08 Hz, 0-CH2-0); 3.94 (ZI, s9 4-OCHj) 3.20 (ZN, st W-OCH8),
Example 108. threo-4-methoxy
5-methoxethoxymethoxy- (2-chlorofaei) ketil-2 (5H) -furanone.
A solution of 10.2 g (40 mmol) of ipeo-5- (2-chlorophenyloxy-methyl) -4-methoxy-2 (5H) -furanone in 250 ml of dagx srmetane is mixed in turn with. 27 mL (238 mmol) methoxyethoxymethyl r; 40 ml (234 mmol) of ethyldiophenyl amine and heated to reflux for 30 hours. After cooling, the mixture is washed with a total of 260 ml of 1 molar hydrochloric acid and 2x50 ml of water, dried over an aqueous sodium sulfate, evaporated, and the oily, crude product is recrystallized 2 times from ethanol. Poluugayug 9.86 g (28.8 mmol of methoxyethoxymethyl ether with a melting point of 102–104 ° C.
Yield 72%.

0
S
0
five
0
Calculated%; C, 56.07; H 5.59; C1 10.34.
I19C306 (342.78). Found,%: C 55, / X; H 5.60; C1 10.2.
Examples 109-24. The methods of etherification and lere-acetalizationatd described in examples 106-108 are given in table. 12 derivatives of ethers and acetals of the described ipeo-4-alkoxy-5- (substituted.) Phenylsimetry-2 (5H) -furapones. Analytical data are summarized in Table. 13.
To determine the anticonvulsant and antiepileptic activity, the substances according to the invention of male mice (MP1) with a body weight of 20-25 g are subjected to nepefen current of 50 Hz and 50 mA for 0.2 s through Comeal-erectrog. (HSЈ Schock - device of irritation Ј type 207) Caused by electric shock maximum convulsion (MEG) sucks out of the topical limb of the hind limbs, clonic convulsions and the warmth of consciousness. For the criterion of activity, suppress convulsions of razbibachtsikh M1z1shts soedtneni 3-: formuli I before the h with experiments have free access to feed and water. received adequate, obgemy agar. Cherch t-h after administration, a test was carried out for an action against MES.
In tab. Figures 14 and 15 show the results of MES-Tast at dosages of 150 mg of compounds I per 1 t of body weight compared with other antipyretic drugs - (indicated in (c s / cent) of those animals that received ilFS- the test was protected from extensor convulsions, 100%) ", In table. 16 as AU 50, the magnitude of the reduced dosage of compounds I and conventional anti-epileptic drugs, which in the MES-theot 1 hour after administration, could pop stote s. 50% animals from cramps pr ibayuschh mhppts. (the predlozhenie DB 50-values and trust limits (5% probability oiOgsh) conducted by Lich-field and Wulcoxor, respectively, with 4, 5 groups of ANIMALS BY 8-10% of the SIV
, on one quit dose.
During the described animal CR experiments, the symptoms of behavioral changes and toxicity for the nervous system (motility, muscle tone, respiration rate, body temperature, and general condition) were observed for animals during the gsec period, during the experiment (up to 4 hours). At a dosage of 100 mg / kg, all tested compounds could not detect any symptoms of toxicity to the nervous system.
S tab. 17 shows the lower limit dosages of conventional anticonvulsant agents that, when administered by mouth, caused symptoms of toxicity for the nervous system in mice.
For all compounds I, with a dosage of up to 300 mg / kg administered by mouth, no mortality was established. Approximate toxicological studies of the substances in Examples No. 64,65,79 and 81 in rats at a dosage of up to 1000 mg / kg when injected 1 through the mouth did not show any improvement in animals.
Studies have shown a good anticonvulsant effect and a wide therapeutic range of compounds I.
As can be seen from the data of Table 15, the anticonvulsant effect of erythroisomers is zero in all the indicated cases.
The manufacture of pharmaceutical dosage forms of the compounds of formula I.
A.Tablets.
For the manufacture of tablets of 25 ° C, which, depending on the desired strength of action, contain 5-100 mg of the active substance, g are used:
Substance according to the invention 200 4000
Cellulose powder
Corn starch
Colloidal flint
acid
Magnesium stearate
Milk sugar
The active substance and excipients are mixed until uniform and are pressed into tablets of 250 mg and 9 mm in diameter in the usual way. If required, tablets are provided with a film coating.
B. Capsules.
For the manufacture of capsules, which, depending on the required strength of dey2000, 1200
80 20 to 10
0
five
0
five
0
five
0
five
0
five
The compounds contain 5-100 mg of the active substance, will be used, g;
Substance according to the invention 50010000
Cornstarch 2000 Colloidal silicic acid300
Magnesium stearate 50
Cellulose powder Up to 20,000 Substances, in the form of fine powder, are mixed until uniform and packaged into a hard gelatin capsule of size 2 in an amount of 200 mg per capsule. V. Juice.
For the manufacture of juice with an active substance content of 0.035-0.7% by weight, depending on the strength of action, g are used:
Substance according to the invention Propylene glycol
Glycerin Methylcellulose Sodium Cyclamate Saccharin Ndtri Um Gchennaya water
35-70 20000 20000 1000 500 50
Up to 100,000 The active substance is ground finely and kneaded until homogeneous in a solution of auxiliary substances. G. Candles:
For the manufacture of candles weighing 3 g each, containing 5-100 mg of active substance per candle, depending on the required strength of action, g are used:
Substance according to the invention 50-1000 colloidal silicic acid60
Lecithin150
Cured fat Up to 30,000 Finely ground active substance is kneaded until a homogeneous state into the melt of auxiliary substances and poured into candles with a specific e-grade of 3 g.
Thus, the application of the proposed method allows to increase the selectivity of the process relative to the threo isomer, increasing its yield to 56.6% instead of 35.4% of the prototype, as well as expanding the range of target products by obtaining new ones; compounds of formula I.

权利要求:
Claims (6)
[1]
1. Method for preparing 5-arylalkyl-4-alkoxy-2 (5H) -furanones of general formula I
OR, H,
HRs Oh
where the oxygen atoms of C-5 and respectively each other occupy a critical position and where RJ is C-C-alkyl |
RY atrm hydrogen, C (-C3-alkyl or residue
CH
R7
where R is C-Su-alkyl, ethoxye.til
, or methoxyethyl 5 Ry - hydrogen atom, Cd-Su-alkash
or methoxymethyl;
IR, and Rjj- independently of each other - a hydrogen atom, fluorine., Chlorine or bromine, C., -CZ alkyl, C4-C3-perfluoroalkyl or nitro-rpynnaj
R is a hydrogen atom or a kil, with the exception of compounds of formula I, where R is a hydrogen atom or methyl, if R.J is methyl n R and Rg are hydrogen atoms,
based on benzaldehyde and alkeneic acid derivative5 characterized in that in order to increase the selectivity of the process for expanding the range of target products, benzaldehyde of general formula II. /
R,
w-sn-o
where R to R $. have the indicated values s are stereoselectively condensed with the lower alkyl ester of 3-alkoxy-2 (E) olkenose acid of general formula Ili 45
R5-H2C
-O-o-r:
about
where R f and Rg- have the indicated meanings; R 7 - C-C-alkyl, with hydrolytic cleavage by hydrolysis of the residue R-p
and the resulting substituted 2 (E) 9 4 (E) - pentadienoic acid of general formula IV
RP H H
Rz v
R-C & O, 0 4 4, v R5
where Rp R,; ,, Kfi RЈ. have indicated
meanings
if necessary, transfer the ester of the general formula V
RiC H Nh
Cs
-0-rg
where Ra is C1-C-alksht or C-Sed-aralkil,
The half ester of the general formula V, directly, compound IV is subjected to cis-digroxing by the action of a catalytic amount of OsQq. and an oxidizing agent and from the obtained ester of Z-alkoxy-4j5 (threo) -hydroxy-5-D, K4-substituted) fet-sh- (E) -pentene acid of general formula VI / -
thirty
RiO H
0
five
0
where R is the poison and the R & - have the indicated, meaning-,
cheni |
R.J; is a hydrogen atom or is R s
alcohol B | OH is cleaved, the water from the position is 1s k and the compound of formula 3 is isolated where Rg is a hydrogen atom, or, if necessary, is reacted with compound R2-X where R has the ordered values with the exception of the hydrogen atom9 and X is a halogen atom, or a lower alkoxy group, if X is H is cleared and the compound of the general formula 1} gdg R. is isolated, it has the indicated value, except for the hydrogen atom.
[2]
2 "The method according to claim 1, distinguished by the fact that the condensation is carried out in a dipolar aprotic solvent medium in the presence of basic
t
[3]
3. The method according to p. 2 about tl and h-1c and the fact that as a dipolar aprotic solvent use dimethylsuperoxide, and as the base is an alkali metal hydroxide, a quaternary ammonium base or mixture.
[4]
A. The method according to claim 1, differing from that the condensation is carried out in an inert gas atmosphere at 70-140 ° C.
[5]
5. Method 1, characterized in that, as the oxide, the solvent, alkyl hydroperoxide, chlorate or tertiary amine M-oxide is used.
[6]
6. The method according to claim 1, wherein cis-dihydroxylation is carried out in the presence of a quaternary ammonium base or a quaternary ammonium salt.
Table 1
23
1650009
At yields below 50% of the reaction condition, we process and recrystallize are not yet optimized.
TK & Face2
ten
12
13
14
15
sixteen
17
18
nineteen
20
21
22
23
24 Continued tabl, 1
C1 14.03 (14.3) G1 14.03 (13.7) C1 13.29 (13.5) C1 14.85 ((5.5) Vg 28.22 (28.0) Vg 28.22 (30.5) F 8.55 (7.9) F 20.94 (10.6) F 20994
F 20.94
N 5.62 (5.35) N 5.62 (5973)
C1 14.03 (14.5) C1 25.96 (.15.7)
25
Calculated (found)
165000926
Continuation of table 2
Table3
37 Isopropyl 5- (2-chlorophenyl) 3-methoxy-g. (E) -pentadiene
38vtor-5ut1 Sh-5- (2-hporpenyl) 3-mathoxy 2 (E), 4 (E) -pentadienoate
39 tert-Butyl-5- (2-chlorophenyl) -3-methoxy-2 (E), 4 (E) pentadienoate
40Heat-3 methox 5tphenyl-2 (E) 9 4 (E) pentadienoate
41 Ethyl 5- (2-chlorophenyl) -3-ethoxy-2 (K) 5 4 (E) -pentadienoate
42 Ethyl 5- (4 chporpenyl) -3-methoxy-2 (E), 4 (E) -pentadienoate
43 Ethyl 5- (2-bromofecyl) 3-methoxy 2 (E) 5 4 (E) -pentadieno, am
44 Ethyl 5- (2-phtophenyl) -3-methoxy-2 (E) 4 (E) -pentadkenate
45 Ethyl 5- (2-trifluoromethyl-phenyl) -3-labels si-2 (E), 4 (E) -pentadiene
46 Ethyl-5 (3-trifluoromethylfesh "t) -3-methox 2 CE), 4 (E) -pentadiene
47Extl-5- (4-trifluoromethyl-1 1-sh) -3-methox 2 (E), 4 (E) -specten alkenate
48 Ethyl-3 methoxy-5 - (. Met1Sh-phenip |) - 2 (fi), 4 (H) -pentadienoate
49Etsh1-5- (2 chloro-5-g ethylphenyl) 3-methox 2 (5), 4 (E) pentadienoate
50 Ethyl 5- (2,3-dichlorophenyl) -3-methoxy-2 (E), 4 (E) -pentadiene
51 Ethyl 5- (2,4-dkkhlorfeniet) -3-methoxy-, 2 (E), 4 (E) -pentadionoate
52 Etkl-5- (2,4-dichpfrenil) 3-ethoxy 2 (E)} 4 (E) -peredienoate
Continuation
T b l to c and a
55-58 (pentane) 41-42
(isopropanol (mash, extracts) 34.
(evaporation) .79-31. (methanol). 52-53 (isopropanol 45-45 (pentane) 46-48
(isopropacol) 75
(ethanol) 46-47 (ethanol) 42G44, (ethanol) 53-54 (ethanol) 76-78 (ethanol) 110-1J1 (ethanol) 81-83
(isopropacol) 64-67 (isoproganop)
1650009
30 Continuation of table 4
31
165000932
Continuation of table.5
Calculated (found).
65treo-4-methoxy-5-phenyloxy-methyl-2 (5H) -furanone
66treo-5- (2-Hporfennloxymethyl) -4-ethoxy-2 (5H) -furanone
67treo-5- (4-Chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone
68treo-5- (2-Bromophenyloxymethyl) 4-methoxy-2 (5H) -furanone
69 threo-5- (3-bromophenyloxymethyl) 4-methoxy-2 (5H) -furanone
70treo-5- (2-Fluorophenyloxymethyl) -4-methoxy-2 (5H) -furanone
71treo-4-methoxy-5- (2-trifluoromethylphenyloxymethyl) -2 (5H) -furan
72treo-4-methoxy-5- (4 trifluoromethyl phenyloxymethyl) -2 (5H) -furanone
73treo-4-methoxy-5- (4-trifluoromethylphenyloxymethyl) -2- (5H) -furanone
Table
a 46157
G49 (dicloromethane)
g 59
c.24114-116
(isopropanol) 5 47148-150
(dkhlormethane) g 85162-164
(dichloromethane) 50167-168
(acetone / ethano g 87130-133
(dichloromethane) S 62 166-167
(ethanol / water) $ 27,128-129
(ethanol-water) "G 28 171,
(methanol)
33
1650009
34 Continuation of table 6
Table 7
Calculated (found).
Continuation of table 7
Tablczav
37
s - synglet bs - extended singlet; d is a doublet; dd - double doublet t - triplet, m - multiplet.
1650009
38. Continuation of table 8
39
1650009
threo-4-methoxy-5- (2-methylphenyloxymethyl) -2 (ZN) -furanone
94
threo-4-methoxy-5- (3-methylphenyloxymethyl) -2 (5H) -furanone
Erythro-Isomer
95 threo-4-methoxy-5 -. (4-methylphenxy-methyl) -2 (5H) -furanone
Erythro-Isomer i
threo-5- (3-Fluorophenyloxymethyl) -4methoxy-2 (5H) -furanone threo-5- (4-Fluorophenloxymethyl) -4
methoxy -2 (3N) -fou he
Erythro-Isomer
98 threo-5 (3-Chlorophenyloxymethyl) -4-methoxy-2 (5H) -furanone
Erythro-Omer
99 threo-5- (2-Xporpenyloxymethyl-4-propoxy-2 (5H) -furanone
Viewer Isomer
100 threo-5- (4-bromophenyloxymethyl) -4-methoxy-2 (5H) -furanone
Viewer Isomer
101 threo-4-methoxy-5- (4-nitrophenyloxymethyl) -2 (5H) -furanone
40 Ta blitz 9
0.45
(acetone-toluene 1: 1) 0.39
(toluene-zopropanol)
0.45
0.45
(toluene-acetone 1: 1) 0.47
0.30 (СНС13Н .ОН
5: 5)
26
(СНС1, Н3ОН
98: 2)
26
0.41
(toluene-acetone 1: 1) 0.45
0.39
(SNSSCH3OH 98:.) 0.39
0.46 (toluene-acetone 1: 1.) 0.49
0.42 (toluene174-176 (isopropanol)
127-130 (dihpormetan- /
pentane)
139-141
(toluene)
148-151,5
(isopropanolpentane)
143-147. (isopropanol)
123-126; (dichloromethanepentak)
141
(toluene-tert-butylmethyl
ether)
141-143 (toluene - tert-butylmethyl
ether)
150-152
(chloroformpentane)
121-126
(chloroformpentane)
103-105
(SCC)
147-149 (ethyl acetate) 157-158 (CC14 - ethyl acetate)
149-150 (ethyl acetate) 226-228 (isopropanol)
94C 1H,., Oy 234.25 (eritro
95C, 3H, vOv 234.25 (erythro:
96С, гН „FO, 238,22
97 C (Ya.N „70„ 238.22 (eritro:
98C,., H "C10" 254.67 (erythro;
, 282,73 (erythro:
0 С, гН „ВгО“, 299,13 (eritro:
Continuation of table 9
Table 10
43
Calculated (found).
165000944
Prolongation of table 10
Table 11
45
d is a doublet; s is a singlet; bs - extended singlet; .dd - double doublet; t is a triplet; m - multiplet
Table 12
i
109treo-4-methoxy-5-methoxy- (phenyl) -methyl -2 (5H) - furanone
110treo-4-methoxy-5- methoxy- (2-chlorophenyl) -methyl 7-2 (5H) furanone
111treo-4-methoxy-5-methoxy- (234-dichlorophenyl) -methyl -2 (5H) -furanone
112treo 4-methoxy-5-methoxy- (2,5-dichlorophenyl) -metshG | -2 (5U-furanone
11 3 threo-4-methoxy-5-methoxymethoxy- (ZI) -furanone
114treo-4-methoxy-5-methoxymethoxyphenyl) methyl -2 (5H) -furanone
115treo-4-methoxy-5-Ј methoxymethoxymethyl} -2 (5H) -furanone
116treo 4-methoxy-5-methoxymethoxymethylJ-2 (5H) -furanone
117treo-4-methoxy-5-Ј methoxymethoxymethyl -2 (5H) -furanone
118treo-4-methoxy-5-Ј methoxymethoxymethyl -2 (5H) -furanone
119treo-4-methoxy-5-methoxymethoxy - I-
methyl} -2 (5H) -furanone
1650009
46 Continuation of table 11
-
-
- 91-95 (ether-heptane)
118-120 (ether-pentane)
124-125
(ether-petroleum ether)
95
(ether-petroleum ether)
93-96 (methanol)
142-145 (methanol)
102-104 (methanol).
141-144 (ethyl acetate)
144-146 (ethanol)
160-161 (ethanol)
130 (methanol)
47
1650009
121
122
120 threo-4-methoxy-5- (methoxyethoxymethoxy- (2,4-dichpophenyl) -methyl | -2 (5H) -furanone
threo-5-p; 2p-dimethoxyethoxy- (2-chlorophenyl) -metshG} -4-methoxy-2 (5H) -furanon threo-g5-Ј1 - This is silropoxy- (2-chlorophenyl) methyl 4-methoxy-2 (G) -furanone
123treo-4-methoxy-5-methoxy- (2-fluorophenyl) -methyl -2 (5H) -furanone
124treo-4-methoxy-5-Јmethoxy- (2-bromophenyl) -metshG - 2 (51H) -furanone
Calculated (found).
48 Continuation of table 12
104-107 (ethanol)
131-134 (ethanol)
106-108 (ether-pentane)
106-108 (ether)
123-125 (ether-methanol
Table 13
Table 14
100 79 100 75
100 70
100
100
80
60
100
60
90
100
90
50
70 100
BEFORE
80 100
37,
62,
25
90,100
62, 100
37,
12,
30 100
70
40 100 100 100 100
10,100
70 100
70 100 100 100 100 100
100
51
165DO) 9

100 100
too
100 100 100 100 100 100 100
Obtained by the method prototype
50 60 60 60
52 Continuation taol.14
Table 15
with
0 0 0 0 0 0 0 0
19.75 (17.10-22.81)
69.0 (63.07-75.49)
73.5 (63.86-84.60)
23.5 (23.38-27.10)
53
Substance
Carbamazepine1.00
Diazepam 40
Diphenylhydantoin100
Ethosuximide500
Pentaveronal50
Luminal60 Valopropic acid 350 Compound I
examples 64-124All 100
1650009
54 Continued by ta.b
3U
Table 17
T
Vine, oral administration, mg / kg

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同族专利:

公开号 | 公开日

PT84824A|1987-06-01|

AT59386T|1991-01-15|

DK226287A|1987-11-06|

AU7246687A|1987-11-12|

HUT48228A|1989-05-29|

EP0247320A3|1989-06-14|

NO871845D0|1987-05-04|

EP0247320A2|1987-12-02|

ZA872867B|1987-11-25|

NO171273B|1992-11-09|

CN1016868B|1992-06-03|

AR247203A1|1994-11-30|

FI871946A|1987-11-06|

CS274728B2|1991-10-15|

KR870011122A|1987-12-21|

JPH0764835B2|1995-07-12|

CA1270256A|1990-06-12|

NO171273C|1993-02-17|

CS313687A2|1990-11-14|

EP0247320B1|1990-12-27|

EG18151A|1992-08-30|

AU596175B2|1990-04-26|

MX27046A|1994-01-31|

FI871946A0|1987-05-04|

HU206105B|1992-08-28|

CN87103274A|1988-01-20|

DK226287D0|1987-05-04|

US4855320A|1989-08-08|

YU46422B|1993-10-20|

DK166725B1|1993-07-05|

NO871845L|1987-11-06|

PT84824B|1989-12-29|

YU77687A|1988-08-31|

KR950001790B1|1995-03-02|

JPS6322087A|1988-01-29|

ES2003293A6|1988-10-16|

DE3615157A1|1987-11-12|

DD260699A5|1988-10-05|

DE3767029D1|1991-02-07|

NZ220188A|1989-10-27|

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法律状态:
2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20050505 |

优先权:

申请号 | 申请日 | 专利标题

DE19863615157|DE3615157A1|1986-05-05|1986-05-05|5-ARYLALKYL-4-ALKOXY-2-FURANONE, INTERMEDIATE PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS THERAPEUTIC ACTIVE SUBSTANCES|

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