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    • 专利摘要:
    Novel spiro-oxazolidindiones useful as aldose reductase inhibitors and as therapeutic agents for the treatment of chronic diabetic complications are disclosed. Pharmaceutical compositions containing the novel compounds and a method of treating chronic diabetic complications are also disclosed.
    公开号:SU942597A3
    申请号:SU792803649
    申请日:1979-08-20
    公开日:1982-07-07
    发明作者:Когрен Шнур Родни
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing new chemical compounds, more specifically to methods for producing spirooxazolidinediones of the formula where X is an oxygen or sulfur atom; R., RJ, R - independently of each other, a hydrogen, leo, bromine or fluorine atom. These compounds have the ability to reduce the activity of the aldose reductase enzyme and inhibit the accumulation of sorbitol in the sciatic nerve of the cr and can be used in the treatment of some chronic complications of diabetes such as diabetic cataracts and neurasthenia. A known method of producing N- {3,5 dihalo-phenyl) -6 xazolidinonal N- (3,5-dihalo-phenyl) -thiazolidiOHA-t of the formula hydrogen atom, lower alkyl; halogen; oxygen or sulfur cannot simultaneously mean an oxygen atom if both X are a chlorine atom, which is that a derivative of the formula Xg where B is a hydrogen atom or a lower alB, B, D, and X. have the indicated values are cyclized in in the presence of a base in SO-ZOO C in the medium of solvent p J. N- (3,5-Dihalo-phenyl) -oxazolidinone-4 and N- (3,5-Dihalo-phenyl) -thiazolidinone-4 have biological activity. The purpose of the invention is to obtain new compounds that expand the arsenal of means of action on a living organism. This goal is achieved by a method for producing spirooxazolidinediones of the general formula 1, which is that the compound of the formula t in OCigHs where R-R-iH X have the indicated values, is reacted or phosgene in the presence of a base at a temperature of from -10 to for min with further stirring of the reaction mixture at 20–50 ° C for 12–48 h to form an intermediate compound of the formula NH HOv JL where R. is R--, and X have the indicated values and, by further reaction of the compound of formula III directly in the reaction mixture with phosgene at a temperature of from -10 to +10 ° C for 15-75 minutes, followed by stirring at room temperature for an hour to convert the intermediate product of formula III to the desired product formulas .1; or with a haloalkyl formate with I - carbon atoms in alkyl at a temperature of from -10 to 30 minutes to 2 hours, followed by holding the solution at 50-150 ° C for 1 hour and then keeping the resulting intermediate of formula III at the indicated temperature 2 -6 h with the conversion of the intermediate product of the formula W to the target product of formula 1; or with 1,1-carbonyldiimidazole at 50150С for 30-90 minutes and further aging of the intermediate product of formula W at the indicated temperature of 12-36 h with conversion of the intermediate product of formula III to the target product of formula 1; or with an alkali metal carbonate or ammonium carbonate at 15-50s for 5-24 hours. When reacting with phosgene, triethylamine or another trialkylamine with 1-4 carbon atoms in alkyl is used as the base. The reaction is carried out in an inert organic solvent: diethyl ether, tetrahydrofuran, dimethoxyethane or dioxane. As haloalkyl formate, it is preferable to use ethyl chloroformate and the reaction is carried out in pyridine. The reaction with 1,1 -carbonyldiimidazole is carried out either without a solvent, or in an inert organic solvent such as dioxane, tetrahydrofuran, dimethoxyethane or dimethyl ether. Example 1. 6-Chloro-4-cyano-4-trimethyl. Silyloxy-4H-2, 3-Dihydrobenzpyran. A mixture of 6-chloro-4H-2, 3H-dihydrobenzopyran-4-one (.20.0 g, 0.11 mol), trimethylsilyl cyanide, and 3.0 g, 0.13 mol) and zinc iodide (0.2 g in 50 ml the ether is stirred for 18 hours. The solution is decolorized with charcoal, filtered and evaporated under vacuum to form an orange oil, which, with the addition of pentane, gives crystalline 6-chloro-4-cyano-4-trimethylsilyloxy-4H-2, 3-dihydrobenzopyran , 26.4 g, m.p.b7-b9 ° C. Example 2. Ethyl-6-chloro-4-hydroxy-4H-2, 3-dihydrobenzpyran-4-carboximidate, saturated solution of 6-chloro-4-t1 1ano -4-trimethylsilyloxy-4H-2, 3 dihydrobene pyran (273.0 g, 0.97 mol) in 2.0 l of ethanol is cooled before and dry hydrogen chloride is supplied to it for 40 minutes. At mild exotherm, the mixture becomes homogeneous. After 16 h at A ° C, volatile substances are removed under vacuum, a semi-solid residue is formed. Rubbing into powder in 800 ml of diethyl ether and then filtering gives a solid material which is divided between 3.8 l of chloroform and 500 ml of saturated sodium bicarbonate. The organic layer is washed with an additional amount (500 ml) of saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated under vacuum, resulting in the formation of solid ethyl 6-chloro-4H-2, 3-DIHYDROBenzopyran-carboxymidate , 193.0 g C. Trituration with ether gives a material with mp. 12 -12b ° C. Example 3. 6-Chloro-spiro CtH-2, 3-dihydrobenzpyran (jS) oxazolidin3 -2, (- dione. A mixture of ethyl 6-chloro-oxy-H-2,3-dihydrobenzpirancarboximidate COO g, 1.95 mol ) and. triethylamine TsOO g, 3.96 mol) in 13 l of dry tetrahydrofuran with phosgene (1818 g, 18, + mol) rinsed at such a rate as to maintain the temperature below 27 C. Mixing is continued while feeding phosgene, the temperature is allowed to reach 20C and maintain its such for +8 hours. Analysis by thin layer chromatography shows a point in R 0.57 and the absence of a point in Rr 0.29 (1: 1, chloroform: ethyl acetate, on silica gel). (The material with R 0.29 is the starting imidate, whereas the material with Rr 0.57 is the intermediate ethoxyoxazoline-2-it from example b). The mixture is then poured into 13 liters of crushed ice with stirring, and phosgene and carbon dioxide are then released. The biphasic mixture is neutralized with 1.7 l of 50% sodium hydroxide solution to pH 7. Next, sodium carbonate (g 2.0 mol) is added and the mixture is stirred for 16 hours at 20 ° C. The product is isolated using the following extraction procedure: 12 L of ethyl acetate is added to the mixture and, after shaking, the aqueous layer is removed. The organic phase is washed twice with 12 l of a 7% aqueous solution of sodium bicarbonate. The combined aqueous layers are acidified to pH 1 with cooling to 10-15 ° C by addition of concentrated g 6 hydrochloric acid. The aqueous layer was extracted three times with 12 L of ethyl acetate. The combined organic phase is washed with 12 l of saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under vacuum to a solid residue; 392 g (79%), so pl. 191-195 ° C. Recrystallization from toluene gives 6-chloro-spiro-E4H-2, 3-dihydrobenzpyran (t.Soxazolidin3-2, t-dione with mp 19b-198 ° C; Rp O, (1: 1, SSCC: EtOAc on salicylic acid.) Example 4, 6-Chloro-spiro 4H-2, 3-dihydrobenzpyran (+, 5) oxazolidin3-2, 4-dion. A mixture of ethyl 6-chloro-4-hydroxy-2H-2, 3- dihydrobenzpyran - + - - carboxy-imidate (5.0 g, 0.019 mol) and 1.1-carbonyldiimidazole (3.7 g 0.023 mol) are heated in 5 ml of dioxane to a temperature of 90 ° C, which is maintained for 16 hours. Analysis of the reaction mixture using thin-layer chromatography after 1 h shows the point Rr 0.57 (1: 1, chloroform: ethyl acetate, After cooling the mixture is diluted with 100 ml of ethyl acetate and washed twice with 100 ml of 1N hydrochloric acid. The organic layer is extracted twice with 100 ml of saturated sodium bicarbonate solution. The basic layer is acidified 6N hydrochloric acid is added to pH 1 and extracted three times with 100 ml of ethyl acetate.The latter organic layer is washed with hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated under vacuum to a solid residue; 1.20 g (25%), so pl. 189-191 0. Recrystallization from toluene gives 6-chloro-spiro C + H-2,3-dihydrobenzpyran (,) oxazolidin3-2, 4 dione, m.p. 192-193C. Example 5-6-Chloro-spiro4H-2, 3-Dihydrobenzpyran (4.5) oxazolidine -2, C-dione. A mixture of ethyl chloroformate (2.00 g, 2.82 mol), ethyl 6-chloro-4-hydroxy-4H-2, 3 dihydrobenzpyran-4-carboximidate (1.69 g, 1.5b mmol) and pyridine (5 ml) interact at 0 ° C for 1 h, then warm to room temperature and reflux for k h. Concentration under vacuum and extract
    the fusion described in Example 3 gives 6-chloro-spiro ftH-ZjS-flHrHflpo-benzopyran (5, Oxazols jn -2, 4-dione with a yield of 10%, mp. 195198 ° С.
    Example 6, b-Chloro-ETOXI-, spiro 4H-2,3-dihydrobenzpyran C, 5) oxazolinZ-2-one.
    A solution of ethyl-6-chloro-α-ethoxy- | H-2, 3-dihydrobenzpyran - “- car-6-moxy-imidate, 15 g (4.00 mmol) in 60 ml of tetrahydrofuran is cooled to 0 ° C and stirred. At that, phosgene is served for 5 minutes. After 30 minutes, the thin layer chromatography of the reaction showed a new point with Rr 0.57 (1: 1, chloroform: ethyl acetate, salicylic acid) and the absence of starting material with RP 0.29. The mixture is poured into 90 ml of an ice-water mixture and extracted twice with 50 ml of ethyl acetate. The organic layer is washed twice with 30 ml of a 5% aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated under vacuum to an oily liquid (0, b51 g), which crystallizes at a low temperature from an ether-hexane mixture to 0.350 g ( 3U), mp. SE-PO C. This ethoxyoxazoline is also obtained from using ethyl chloroformate in pyridine with yield 62. using ethyl chloroformate in pyridine with yield 62I.
    Example 7. 6-Chloro-spiro 9H-2,3-dihydrobenzpyran (4,5) oxazolidin3-2, 4-dione.
    A mixture of 6-chloro-4-ethoxy spiro, 3-dihydrobenzpyran (4,5) oxazolin -2-one (100 mg, 0.355 mmol) and sodium carbonate (88 mg, 0.710 mmol in 2 ml of a mixture (1: 1) of tetrahydrofuran and water stirred for 16 h. After adding 10 ml of ethyl acetate and 10 ml of water, extraction was performed as described in Example 3, which gives 6-chloro-spiro 4H-2,3-dihydrobenzpyran (4.5 L) xazolidine -2, 4-dione, 63 mg (70), mp 192-195s.
    Examples 8-15. In a manner similar to that shown in Example 1, compounds are prepared using the corresponding ketones together with 6-chloro-4H-2, 3-Dihydrobenzpyran-4-one, presented in Table L. All compounds were isolated as oils after washing with sodium bicarbonate solution and brine, dried over magnesium sulfate, followed by evaporation under vacuum. The structure of the compounds is determined by NMR and / or thin layer chromatography on salicylic acid.
    N (i. 0 $ 1 ((Ne) 5
    The product is stored at room temperature (20 ° C), cooled to 4 ° C.
    PRI me R 22. Spiro 4H-2,3-dihydrobenzpyran (4.7 oxazolidine -2, 4-dione.
    A mixture of ethyl 4-hydroxy-4H-2,3-dihydrobene pyran-4-carboximidate (5.50 g, 24.9 mmol) and triethylamine (5.03 g, 49, 7 mmol) in 50 ml of tetrahydrofuran at saturate phosgene gas for 30 minutes. Immediately after the start of the supply of phosgene, a solid precipitate is formed. The mixture is stirred for 16 hours at. Under these conditions, i-oxazolidinedione is obtained directly without isolation and hydrolysis of the oxazoline intermediate. The reaction mixture is poured onto 200 ml of crushed ice and extracted with ethyl acetate. Spiro E LN-2,3-dihydrobenzpyran (A, 5 oxazolidin1-2, 4-dione is isolated from this organic phase as described in example 3, yield 5b, mp 168-170 ° C. Example 23. 6- Fluoro-spiro, 3-dihydrobenzpyran {k, S) oxa zolidin -2j -dione. 6-Fluoro-spiro, 3-dihydrobenzpyran (4.5 ° Cazolidin3-2, -dione is prepared in a manner similar to that described in the example from ethyl-6-fluoro-4-hydroxy-H-2, 3-DIGIDrobenzpyran-β-carboxyimidate with yield 3%. The exception is that the mixture is heated to a temperature of 100 ° C, which is maintained for 1 hour, mp 177.5180 ° C after recrystallization from toluene. Example 2. 6-Bromo-spiro yn-2,3 -dihydrobenzpyran (, S) oxazolidinZ-2, 4-dione 6-Bromo-spiro 4H-2,3-. Dihydrobenz pyran (4,5) oxazolidine -2, -dione is prepared in a manner analogous to that described in the example of ethyl- 6-bromo-4-hydroxy-H-2,3-dihydrobenz iran-4-carboximidate with an output of 38. An exception is that the mixture is heated to a temperature of 100 ° C, which is maintained for 0.5 hours, mp IBS-ISI C after recrystallization from toluene. Spiro, 3-dihydrobethothiran C, 5 oxazolidine 1-2 4-dione. Spiro kH-2,3-dihydrobenzthiopyr (J, 5) oxazolidine -2, -dione is prepared in a manner analogous to that described in the example from ethyl-α-hydroxy H-2, 3-Dihydrobenzthiopyran-4-carboximidate, yield 5. An exception is that the mixture is kept for 7.0 hours at 100 ° C; mp 165-167 ° C after recrystallization of toluene. Example 26. 6-Fluoro-spiro tH-, 3-dihydrobenzthiopyran C, 5) oxazolidinZ-2, -dione. 6-Fluoro-spiro LH-2,3-dihydrob nz thiopyran (5) oxazolidinZ-2, -dione is obtained in accordance with the method described in the example from ethyl-6-fluoro-oxy-4H-2,3 -dihydrobenzthiopyran-4-carboximidate with the yield of C}%. The difference is that the tzzo mixture is incubated for 48 hours at SO, so pl. 193-19, after recrystallization from toluene. 7 Example 27. (- - $ - chloro-spiro H-2,3-dihydrobenzpyran (, S-) oxazolidine -2, L-dione. Racemic 6-chloro-spiro L4H-2,3-dihydrobenzpiran C,) - oxazolidineJ -2, t-dione (32.0 g, 0.126 mol) and cinchonidine (37.1 g, 0.126 mol) were dissolved by heating in 290 ml of anhydrous ethanol. After cooling the solid material, the adduct C of oxazolidinedione and cinchonidine was isolated by filtration, 28.0 g (81). The filtrate is concentrated under vacuum to a solid residue, which is divided between 500 ml of ethyl acetate and tOO ml of 1N hydrochloric acid solution. The organic layer is washed additionally with tOO ml of 1N hydrochloric acid solution, 200 ml of brine, dried over magnesium sulfate, filtered, and concentrated to 150 ml. Liquid L-amphetamine (10, 13 g, 0.075 mol) is added to this organic solution. The copious precipitate that forms is isolated by filtration, washed with ether and dried under vacuum to form the adduct (-) - oxazolidinedione-L-amphetamine, 1.85 g (60%); Co (l 36, mp. 171- 17 p.15.80 g of this adduct are divided between 300 ml of ethyl acetate and 200 ml of hydrochloric acid solution. The organic layer is washed with an additional 200 ml of hydrochloric acid solution, 100 ml of brine, dried over magnesium sulfate, filtered and evaporated in vacuo to a colorless solid residue; 9.5 g C yield rg7; 8S); Cotafto - 60.58 °; m.p. 201-202, 5c. Recrystallization from toluene gives C-) -6-chloro-spiro 1., 3-dihydrobenzpyran (, 5) oxazolidin3-2, -dione, 8,203 g; m.p. 200-200, 161 ,. Example 28. The cleavage of 6-chloro-spiro CN-2,3-Dihydrobenzpyran (,, 5) oxazolidine -2, C -dione. 6-Chloro-spiro 4H-2,3-dihydrobenzpyran C.SV oxazolidin3-2, -dione (1.00 g, 3.93 mmol) and cinchonidine (1.16 g, mmol) are dissolved in alcohol than ethanol. After precipitation, the adduct is collected and recrystallized from ethanol, so pl. 206-. 207 ° C. This solid material is partitioned between 50 ml of ethyl acetate and -50 ml of 1N hydrochloric acid. The acidic 119 phase is extracted with 50 ml of ethyl acetate. The combined organic layers are washed with 50 ml of brine, dried over magnesium sulfate, filtered and evaporated under vacuum to a solid, which is recrystallized from toluol; 288 mg (57); m.p. taZ-TEU C, recrystallizing it from toluene gives (+) -6-chloro-spiro 4H-2,3-dihydrobenzpyran (k, S) oxazolidin3 -2, -dione, 200 mg (0); m.p. 2QO-201.5 ° C; Cc jE ° -. + 60.55 °. From the first ethanol stock solution, also, the largest amount of) -adduct is obtained in the form of crystals after it is separated during the night. After filtration, this mother liquor is partitioned between 50 ml of 1N hydrochloric acid and 50 ml of ethyl acetate. The oxazolidinedione thus obtained is recrystallized twice from toluene, with the result that 6-chlorospiro 4H-2, 3-dihydrobenzpyran (1.5) oxazolidin3-2, dione, 143 mg of C29 is formed; m.p. 199-200 ° C; Co; E4- ° - 61 ,. Example 29. The cleavage of 6-chloro-spiro 4H-2, 3-Dihydrobenzpyran (4,5 oxazolidine 3-2, - 4-dina. 6-Chloro-spiro + N-2,3-Dihydrobenzpiran (,) oxazolidine - 2, V-di (1.00 g 3.95 mmol) and L-amphetami (26k mg, 2.00 mmol) is dissolved in hot ethyl acetate. Dried crystals collected after cooling (E mg, mp. 1b5 -1b8 s), recrystallized from ethyl acetate; 221 mg, mp 171-173 0; W3 | tOH — 32.7 °. The splitting of the adduct and the isolation of (-) - oxazolidinedione is carried out in accordance with exemplary accordance with 198- 20 ° C; C About 27; 53 mg, mp. - 60.83 ° C., Example 30. Spirooxazolidine dions obtained in co In accordance with the previous examples, the ability to reduce or suppress the activity of the aldose reductase enzyme is tested. This uses material that is a partially purified aldose reductase enzyme obtained from the calf's eye lens. The results obtained for each compound at a concentration of 10m are expressed in percent of activity suppression enzyme. 7 Suppression of enzyme activity by compounds of formula 1 are presented in Table 3. Example 31. Spirooxazolidinediones, prepared in accordance with the examples given, are tested for their ability to reduce or suppress accumulation of sorbitol in the sciatic nerve in rats that have been injected with streptozotocin (i.e. diabetic patients). In this study, the amount of sorbitol that accumulates in the sciatic nerve is measured 27 hours after diabetes of a rat. Compounds are applied orally at doses that are indicated after 4.8 and 2k hours after the application of streptozotocin. The results are given as a percentage of inhibition for each compound compared with the case when the compound was not used (i.e. for untreated animals, where, in general, the amount of sorbitol increased from 50-100 to / 00 mm / g of tissue after 27 hours) In this experiment, values below 20 do not always have experimental and statistical meaning. The suppression of sorbitol accumulation in the sciatic nerve of rats with compounds of formula 1 is given in the table. The activity of new compounds of formula 1 as agents for regulating complications in chronic diabetes can be determined using several standard biological or pharmacological experiments, including the measurement of the ability to: suppress the activity of the enzyme isolated aldose reductase; reduce or completely eliminate the accumulation of sorbitol in the sciatic nerve of a rat that has been given a strong dose of streptozotocin (i.e. diabetes); reduce the already high level of sorbitol in the sciatic nerve and lens of the eye in rats with chronic diabetes caused by administration of streptozotocin; to prevent or reduce the formation of galactite in the lens of the eye in rats with acute disruption of galactite synthesis; inhibit the formation of cataracts and reduce the degree of turbidity of the crunch; eyes in rats with chronic disruption of the process of galactite synthesis. New spiro-sazolidin-2, 4-diones are used as inhibitors
    aldose reductase, being therapeutic agents in the treatment of complications of chronic diabetes, such as cataract, neurasthenia, and retinal disease (retinitis). Treatment consists in preventing or alleviating the aforementioned complications. Compounds of formula 1 may be attached to -. Various methods are used, including oral and parenteral. In general, these compounds are administered in doses of 1-500 mg / kg of patient body weight per day, preferably 125 mg / kg per day. However, some dose changes may be necessary depending on the condition of the patient and the specific compound that is being used for treatment. The appropriate dose is determined on a case by case basis.
    The compounds can be used as such or in a mixture with acceptable from a pharmaceutical point of view carriers as a single dose or as several doses. Compliance-25 count;
    Pharmaceutically acceptable carriers are inert solid diluents or fillers, sterile aqueous solutions and various non-toxic organic solvents.
    Pharmaceutical compositions resulting from the mixing of spirooxazolidin-2,4-dione and the pharmaceutical-acceptable carrier are used in various forms such as tablets, powders, pills, syrups and injection solutions. These pharmaceutical compositions, if necessary, may contain additional ingredients such as fragrances, carriers, or excipients. Thus, for dental use, tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, can be used together with various dispersing materials, such as starch, preferably potato, or tapioca starch,
    alginic acid and some silicate complexes. together with the bond. agent such as polyvinylpyrrolidone, glucose, gelatin and acacia. In addition, lubricants such as magnesium stearate, lauryl, sodium sulfate and talc are often used in the manufacture of tablets. Solid compositions of the same type can
    also used as fillers for light and heavy gelatin capsules. Preferred materials for this are lactose or milk sugar, as well as polyethylene.
    high molecular weight glycols. If elixirs or suspensions are used for dental use, they mix the active ingredient with various deodorizing or flavoring agents, coloring materials and, if necessary, emulsifying or suspending agents, along with diluents, such as water, ethanol, propylene glycol, for parenteral use, solutions can be used stirooxazolidin-2, -diones in sesame or peanut oil or in water
    solution of propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts of alkali or alkaline-earth metals. If necessary, such
    the aqueous solutions are supplemented with a buffer solution or a liquid diluent, which before addition is converted into an isotonic solution with the aid of a saline solution or a glucose solution. Said aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous solutions which are used in the said use of the compounds according to the invention can easily be obtained by known methods. In addition, spirooxazolidin-2, -dione can be applied topically, using an appropriate optometry solution and applied as drops in the eye. glycerin or mixtures thereof.
    Table. one
    8r
    Cl
    Cl
    HCHj 0
    Cl
    21N
    0.90
    ColiDiethyl Simple
    ether is honorable
    99
    0.79
    Also
    890.90 Ethyl acetate
    (T.p.68-71 C)
    58
    0.90
    18 SZO)
    98-101
    86
    Note. The results of the repeated experiment are given through a skew.
    Connection example
    Table 3
    Table
    Percentage of inhibition at dose, mg / kg
    15
    Dindionov General formula 1:
    "-N
    where X is an oxygen or sulfur atom;
    R. - R - is, independently of each other, a hydrogen, chlorine, bromine or f-fopaj atom, characterized in that. compound of general formula II:
    where R and X have the indicated meanings,
    is reacted with phosgene in the presence of a base at a temperature of from -10 to within 15-75 minutes with further stirring of the reaction mixture at 20-50 for 12-A8 h to form an intermediate compound of the general formula III: where Rj and X have the indicated meanings, and further reacting the compound of formula III directly in the reaction mixture with phosgene at a temperature of from -10 to for 15-75 minutes, followed by stirring at room temperature for an hour to convert the intermediate product of formula III into oh Formula 1 product; or with a haloalkyl formate with carbon I-atoms in alkyl at a temperature of from -10 to within 30 minutes - 2 hours, followed by holding the solution at 50-T50 ° C for 1 hour and then keeping the resulting intermediate -. a standard product of formula III at a given temperature of 2–6 hours with the conversion of an intermediate product of formula III to a target product of formula 1; or with 1,1-carbonyldiimidazole at 50 to 150 s for 3090 min and further exposure of the intermediate product of formula W at the indicated temperature of 12-36 h with conversion of the intermediate product forg mules III to the target product of formula 1; or with an alkali metal carbonate or ammonium carbonate at 1550 C for 5-24 hours. Sources of information, taken into account during the examination 1. Patent of the USSR No. 23300, cl. C 07 O-abz /, 1969.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of dindion production of spirooxazole general formula 1:
    Where
    X is an oxygen or sulfur atom;
    independently from each other, a hydrogen atom, chlorine, bromine or φ-fopa;
    characterized in that about. the compound of General formula P:
    subjected to interaction with phosgene in the presence of a base at a temperature of from -10 to + 10 ° C for 15-75 minutes with further stirring of the reaction mixture at 20-50 ° C. within 12-48 hours with the formation of the 'intermediate compound of General formula III: ·
    19 942597 where R ^ - Rj and X have the indicated meanings, 10 and the further interaction of the compounds of formula III directly in the reaction mixture with phosgene at a temperature of from -10 to + 10 ° С for
    15-75 minutes, followed by stirring at room temperature for 15 hours for 12-48 hours to convert the intermediate of formula Sh to the target product of formula 1; or halo-, idalkilformiatom with 1-4 carbon atoms in the alkyl sort 20 at a temperature of from -10 to + 15 ° C for 30 min - 2 hours, followed by aging the solution at 50-150 ° C for 1 hour and further 'exposure to the resulting intermediate; a product of the formula Sh at the indicated temperature for 2-6 hours with the conversion of the intermediate of the formula Sh to the target product of the formula 1; or with 1,1-carbonyldiimidazole at 50-150 ° C for 3090 min and further exposure of the intermediate product of formula Sh at the indicated temperature for 12-36 hours with the conversion of the intermediate product of forgula M to the target product of formula 1; or with an alkali metal carbonate or ammonium carbonate at 15 ~ 50 C for 5-24 hours.
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    BE878311A|1980-02-20|
    DE2953954A1|1982-09-02|
    IL58076A|1982-07-30|
    LU81613A1|1980-04-21|
    PL130686B1|1984-08-31|
    FR2440949B1|1981-06-12|
    HU179746B|1982-12-28|
    IT1123536B|1986-04-30|
    AU535170B2|1984-03-08|
    FR2440949A1|1980-06-06|
    YU199979A|1983-06-30|
    AT366689B|1982-04-26|
    FI792567A|1980-02-22|
    EG14639A|1985-03-31|
    NL7906318A|1980-02-25|
    AU5009279A|1980-02-28|
    GB2033904B|1982-08-04|
    FR2440950A1|1980-06-06|
    PH18091A|1985-03-20|
    JPS55129288A|1980-10-06|
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    GB2028318A|1980-03-05|
    IL58076D0|1979-12-30|
    SE447116B|1986-10-27|
    ZA794379B|1980-08-27|
    FR2442851B1|1983-06-17|
    FI65255C|1984-04-10|
    FI65255B|1983-12-30|
    CA1121361A|1982-04-06|
    JPS5943954B2|1984-10-25|
    JPS6011915B2|1985-03-28|
    US4200642A|1980-04-29|
    FR2442851A1|1980-06-27|
    IE48932B1|1985-06-26|
    GB2033904A|1980-05-29|
    JPS55129279A|1980-10-06|
    AR225614A1|1982-04-15|
    PT70086A|1979-09-01|
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    IN152416B|1984-01-07|
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    JPS55129280A|1980-10-06|
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    GB2028318B|1982-08-04|
    FR2440950B1|1981-06-12|
    IE791592L|1980-02-21|
    IT7925182D0|1979-08-20|
    ATA560579A|1981-09-15|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/935,199|US4200642A|1978-08-21|1978-08-21|Spiro-oxazolidindiones|
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