• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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    • 专利摘要:
    The novel compound 3-benzyl-3-azabicyclo(3.1.0] hexane may be prepared by selective reduction of the carbonyl groups of 3-benzyl-3- azabicyclo[3.1.0] hexan-2,4-dione, using a complex aluminium hydride reducing agent. It may then be used in the preparation of 2-carboxy-3-azabicyclo [3.1.0]hexane, which has valuable biological properties.
    公开号:SU969158A3
    申请号:SU792783601
    申请日:1979-07-04
    公开日:1982-10-23
    发明作者:Дитрих Коллмейер Вилли
    申请人:Шелл Интернэшнл Рисерч Маатсхапий Б.В. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the method of producing a novel 3-azabicyclo- (3.1.0) -hexane derivative, which can be used as an intermediate in the synthesis of biologically active substances.
    The reduction reaction of ketones. By aluminum hydride agents 1 is widely described in the literature.
    The aim of the invention is to develop a process for the preparation of new compounds with valuable pharmacological properties.
    The goal is achieved by the method of obtaining 3-benzyl-3-azabicyclo 3 .1.0) -hexane, which implies that 3-benzyl-3-azabicyclo (3.1.0) -hexane-2,4-dione is acted upon by a complex reducing agent based on aluminum hydride at a temperature from to the boiling point of the reaction medium, resulting in a selective reduction of carbonyl groups.
    The preferred reducing agents are lithium aluminum hydride and, in particular, sodium bis (2-methoxyethoxy) aluminum dihydride or sodium aluminum diethyl dihydride.
    In addition, the process is carried out at 60 ° C.
    An excess of an aluminum hydride based reducing agent is generally used. Depending on the particular reducing agent used, an excess of up to six times, preferably twice, can be used. Preferably, an excess of 10 dB of 40% is used, for example 20-40%. Any suitable solvent, for example an aromatic hydrocarbon such as toluene or sufir, may be used. Hydride reducing reagents are often supplied as solutions or dispersions in liquid hydrocarbons. Such products can be used directly if the hydrocarbon does not interfere with the flow of the desired reaction, or the hydrocarbon
    25 can be removed. The reduction is preferably carried out by draining the reagents and heating the stirred mixture to moderately elevated temperatures, e.g. 50-120. If necessary, the reagents can be mixed initially at a reduced temperature, for example, and then heated together. The resulting mixture is treated with water or an aqueous solution of an alkali metal base to destroy excess reducing reagent, filtering to remove inorganic salts, and dissolving it is distilled to obtain the crude product required, from which the pure product can be isolated by conventional methods. Alternatively, a phase separation step may be useful. Example 1.A. Preparation of (cis, trans) -1,2-cyclopropanecarbo / nova acid (.17. After removing the moisture, a stirred mixture of 43.3 kg (0.01 g / base) of 56% sodium hydride dispersion in mineral oil in 200 ml toluene is treated with 10–20 ml of mixed UH (1 mol) of ethyl acrylate and 122.6 g (1 mol) of ethyl chloroacetate, followed by the addition of a few drops of ethanol. After an induction period of about 1 hour, stable evolution of gas and heat is started. cooling in an ice bath the remaining ether mixture to maintain temperatures reactions at the level of SO-Be C. After the end of the addition (4 h), the mixture is cooled, washed with water and dried with MgSO4. Distillation gives diethyl cis (trans) -1, cyclopropane dicarbonate, (lA) as a colorless liquid, because boils .78-89 ° C (0.7 Torr). (Value from literature: 50-90 ° C, 1 Torr.) Washing of 190.1 g (1.02 mol) of the product (1A) is provided by adding 116.0 g (2.90 mol) of sodium hydroxide in 780 ml of water at boiling with reflux for 5 hours. After ethanol is removed on a centrifugal evaporator, the remaining solution is acidified with a slight excess of 12N. hydrochloric acid (268 MP, 3.3 mol). The resulting mixture is dispersed to dryness. The solid is extracted with hot ethyl acetate (3) 500 ml). Evaporation of the solvent from the desiccated (MgSO) extracts gives the product (1), mp.108128 s (with evolution of gas). B. 3.-Benzyl-3-azabicyclo- (3.1.0) -hexane-2,4-da10n (2). A mixture of 128.1 g (0.984 mol) of the product (1), 100 ml of water and 105.5 g {0.984 mol) of benzylamine is heated at 180 ° C for 2 hours while distilling water. The mixture is then cooled slightly and the warm mixture is slowly fed into 1000 ml of isopropyl alcohol. The mixture is thoroughly cooled and filtered to obtain the uncleaned product (2), mp 90150 ° C. The main by-product is a non-cyclic material formed from the trans-isomer of an acid; Its separation from the product (2) is very difficult. It does not interfere with the subsequent reduction of product 2y, but forms a by-product from which product (3) separates quite easily, stage B (a). B. 3-Benzyl-3-azabicyclo- (3.1.0) hexane (3). a) 142.3 g (0.707 mol) of the product of stage B are added in portions to a cooling ice and a stirred suspension of 105.6 g (1.59 mol) of a dispersion of 57.2% lithium aluminum hydride / mineral oil in 2000 ml of tetrahydrofuran, and the temperature the mixture is kept at the temperature of 15 ° C or below this temperature. The mixture is carefully brought to-boiling point under reflux and boiled at this temperature for 4 hours and then left overnight at room temperature. Over 3 hours, add 200 ml of 50% sodium hydroxide solution and then 150 ml of water. Celite is added and the mixture is filtered to remove inorganic salts. The filtrate is dried with MgSQj, the solvent is distilled off and the residue is distilled in the presence of a few drops of an anti-foam agent of the DowkCorning brand Antifouum A to obtain the product (3), mp.73-74 C (0.01 Torr). b) 63.2% (0.486 mol) of the product () is added in portions to 150 ml of thionyl chloride. The mixture is heated under reflux for one hour, then dispersed. The residue is distilled to obtain cis-1,2-cyclopropanecarboxylic anhydride (Over), T.KIP. 134 ° C (10 Torr). 2.14 g (0.02 mol) of benzylamine is carefully added to 2.24 g (0.02 mol) of the product (Over); the reaction is extremely exothermic. The mixture is heated to 180 ° C for 2 hours. After cooling, the residue is recrystallized from isopropyl alcohol to obtain 3-benzyl-3-azabicyclo 3.1.0) hexane-2, 4-dione as white needles, m.p. -1.90-91 ° C (Zb) The precipitated (О с) solution of 305 ml (1.09 mol) of 70% sodium hydrogen bis- (2-methoxyethoxy) aluminum hydride in benzene, diluted with 600 ml of ether, is treated with 48.7 g of 0.25 mol) of product (Zb) . The mixture was stirred at reflux for 3 hours and heated under reflux for 3 hours. After standing at room temperature for overnight, the excess metal hydride was destroyed by careful addition of cold water. The mixture is filtered after the addition of diatomaceous silica (Celite). The ether layer is separated and the aqueous layer is extracted with ether. The combined organic layers dried MgSQi. The ether and 2-methoxyethanol are distilled off under reduced pressure to obtain the product (3) as an oil. Distillation gives product (3), t; kip. 79-80C (0.01 torr) .10
    D. 3-Azabicyclo- (3.1.0) -hexane (4).
    Catalytic hydrogenation (2.05 g, 10% palladium on charcoal), 40.5 g (0.234 mol) of un-distilled product (3): method (b), in 150 ml of ethanol is carried out using a Parr apparatus (initial pressure 4.5 ati, room temperature) overnight. 20 After filtration of the catalyst, ethanol is subjected to fractional distillation on a 40 cm Vigre column. The product contains identifiable (NMR) amounts of ethanol. -Collect 25 two fractions: bp.104-110 C, 7.78 g, 84% purity and batch 110-114C, 00 g, 94% purity. The relative amounts of product (4) and impurity ethanol in these fractions are determined, ol by NMR analysis.
    E. 3-Azabicyclo- (3.1.0) -hexane hydrochloride (5).
    82.6 g (0.476 mol) of the product (3), method (a), in 100 ml of absolute, e alcohol is subjected to catalytic hydrogenation (4 g, 10% palladium on charcoal) in a Parr apparatus for 5 days at room temperature temperature, and the hydrogen pressure is maintained at 4.5 MPa. The catalyst is separated, 39.7 MP (0.476 mol) of concentrated hydrochloric acid are added and the solution is concentrated under reduced pressure. The last layers of water and ethanol are removed by azeotropic distillation with benzene to obtain the product (5), m.p.1.158-1B1 C. An analytical sample, mp.161-163 s (with evolution of gas), is obtained by grinding The specified product with cold isopropanol.
    Example 2. A. Cis and trans ethyl ethyl cyclopropane-1, 2-dicarboxylates.
    A 50-liter glass reactor, equipped with a stirrer, a separating head, a thermocouple socket, and a refrigerator, is filled with nitrogen. Sodium hydride (6360 g, 50% in asla, 132.5 M) is charged and washed three times with 60 dry toluene (5, 2.5 and 3 liters), and the solvent is successively removed through a filter tube. Following the addition of dry toluene (6 L), a portion (1 L) of ethyl chlorine mixture is introduced., 65
    acetate (16.2 kg, 132.5 M), ethyl acrylate (13.25 kg, 132.5 M, stabilized by the addition of 0; 02% hydroquinone) and dry toluene (12 l). The slurry is intermatized and absolute ethanol (3 ml) is added as initiator to minimize the induction period. The reaction starts after an hour.
    The use of cooling with a mixture of isopropanol-solid carbon dioxide leads to a decrease in internal temperatures of t d. The addition of the raw material (ether toluene mixture) is continued at such a flow rate so that the temperature of the bottom of the wasp is 10–20 ° C in the case of using a cooling bath from -20 to 40 ° C. The total addition time is 11.5-hours and after another 2 hours, the reaction is essentially complete.
    After stirring overnight, the contents are cooled before and a solution of glacial acetic acid (1.5 liters, 26 M) in toluene (3 liters) is slowly added, bringing the pH to about 6. This mixture is then slowly added with vigorous stirring - a liter jar containing water (12.5 l), crushed ice (10 kg) and concentrated hydrochloric acid (4.5 l).,
    Acidity is maintained throughout this operation. For transfer purposes use an additional 25 liter portion of water. The phases are separated - and the organic layer is washed with demineralized water (10 L). The combined aqueous solution is re-extracted with toluene (5 L). Toluene is distilled off on a centrifugal evaporator at 60 s / 25 mm Hg. to obtain a crude product (27.9 kg, cis / trans ratio 75:25).
    Distillation in a Claisen apparatus gives a mixture of cis- and trans-diethylcyclopropane-1, 2-dicarboxylates, b.p. 75-90 With at 0.5-1 mm Hg (18.08 kg, cis / trans ratio 72:28); yield 73%, based on the starting esters.
    B. Anhydride cyclopr-6-dan-1,2-dicarboxylic acid (6).
    A mixture of diethylcyclopropane-1,2-dicarboxylates (28.3 kg, cis / trans ratio 72; 28, 152.5 m), formic acid (70 l of 98% product, 1818 M) and concentrated sulfuric acid (610 ml 98 % product, 11.2 m) is brought to a boil under reflux with stirring in a 100-liter glass reactor. Ethyl formate is distilled off. The reaction is stopped and allowed to cool overnight. Sodium formate (1.7 kg, 25 M) is added to neutralize the sulfuric acid catalysts, and the monobaric acid is distilled off into a vacuum on a centrifugal evaporator. At this stage, the crude mixed acids containing sodium sulfate, weighing 22.7 kg. The crude acids are dissolved in B acetic anhydride (40 L) for 40-50 s and dehydration cyclization is carried out by adding this solution to the stirred acetic angiote (10 L), aged etc. This took 1.5 hours and the reaction was completed for another 1 hour at 125-140 ° C. After cooling to insoluble material (sodium sulfate), it is removed by filtration through a pad of celite. Acetic acid and excess acetic anhydride are removed by centrifugal evaporation in a vacuum. Distillation in a Claisen apparatus after the distillation of the light-boiling fractions gives the product (b), as a boil, 105-120 0 at 0.2-1.0 mm Hg (10.4 kg, 92.9 M), which is easy crystallizes on cooling, mp 60-55 ° C. The yield according to the stages of acidolysis and dehydration is 85% based on the cis component of the cyclopropane ether. VAT residue has a weight of 5.19 kg and consists of polymeric trans-anhydride. B. 3-benzyl-3-azabicyclo- (3.1.0) hexane-2, 4-dione (7). A stirred 16-liter reaction flask was charged with product (6), 3.37 kg, 20, 1M, and the temperature was increased to 75 ° C. The heating is stopped and benzylamine (3.22 kg, 30.1 M) is carefully added. The temperature rises over the course of an hour before and at this point 2 kg is charged. Heating is resumed to maintain the temperature for 155-165 seconds while simultaneously distilling water at a low temperature; Nitrogen using a Dean-Stark trap. The addition of benzylamine is completed after 2 1/4 h and the reaction is brought to 175-180 ° C. for an additional 1.5 h. The reactor contents are allowed to cool and are added, with stirring, to isopropanol ( 12.5 liters). After cooling to 10 ° C, the product is isolated by filtration. Air drying gives the product (7), 5.44 kg, 27, 1M, so pl. 93-95 s, which is a yield of 90% by product (6). G. 3-Benzyl-3-azabicyclo- (3.1.0) hexane (8). A glass-lined, 250-liter, core-type stirred reactor is purged and filled with nitrogen. Then over load. sodium bis- (2-methoxyethoxy aluminium dihydride (63 kg, 61.5 l, 75% w / v in toluene, 212.5 M) and dry (azeropic) toluene (25 l). and all this is brought to 60 ° C. The product (7) (17.1 kg, 85 M) is dissolved in dry toluene at (85 L) and added to the reducing agent without external heating for 3.5 h. The temperature rises from to. this time. The reaction is brought to rest for half an hour at a .. After cooling down, Sodium hydroxide solution (8.5 kg, 212.5 M) in water (80 liters) is slowly introduced. After the first 1.5 liters is introduced, hydrogen evolution ceases and temperature is easily regulated at 15 -25 ° C with water cooling; total alkaline addition time is 1.5 hours. The organic layer is washed with demineralized water (30 L) and the combined aqueous layers are re-extracted with toluene (10 L). The solvent is distilled off on a centrifugal evaporator to give crude product (15.48 kg). Distillation in the Claisen apparatus gives the product (.8), bp 95-100 C at 0.2-0.5 mm Hg (13.57 kg, 78.4 M), at the exit of 92%. D. 3-AzabI1daclo-C3.1.0) -hexane (9). 5% palladium on carbon (250 g) is suspended with methanol (1.2 l), which is cooled to .. A 10-liter autoclave made of stainless steel. with a core-type mixer, load product (8), 2.6 kg, 15.0 M, a catalyst slurry and an additional portion of methanol (.4 L). The reactor is closed, rinsed three times with nitrogen, twice with hydrogen and, finally, the pressure of hydrogen is adjusted to 18 MPa. After 4 hours, the pressure was adjusted to 28 MPa and maintained at this level overnight. After a 21 h conversion of the starting material is 95%. An additional 4 h of reaction (a total of 25 h) gives the complete disappearance of the product (8). The catalyst was removed by filtration and washed with methanol. The toluene-methanol azeotrope is distilled. The product (9) is obtained with a yield of 95%. All this time provides an atmosphere of nitrogen. Formula of the invention. Method of producing 3-benzyl-3-azabicyclo- (3.1.0) -hexane, characterized in that 3enzyl-3-azabicyclo 3 .1.0) -hexane-2, 4-dione is reduced complex an aluminum hydride agent at a temperature from to the boiling point of the reaction medium. 2. The method according to claim 1, characterized in that lithium aluminum hydride is used as a complex aluminum hydride agent.
    996915810
    sodium bis (2-methoxyethoxy) aluminum-Sources of information
    dihydride ,. sodium aluminium diethyldi-dihydride- taken into account in the examination RID.1. Taylord N. Recovery com3. The method according to claim 1, about the aphids of tea-plex metal hydrides. M.,
    u and with the fact that the process is carried out with Eed-inostr. Lit., 1959, p.17b60-110 С .5 177..
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining 3-benzyl-3-azabicyclo- (3.1.0) -hexane, characterized in that 3-benzyl-3-azabicyclo <3.1.0) -hexane-2,4-dione is reduced with a complex aluminum hydride agent at a temperature from 0-5 ° C to the boiling point of the reaction medium.
    [2]
    2. The method of Pop. 1, characterized in that lithium aluminum hydride, sodium bis- (2-methoxyethoxy) aluminum- are used as a complex aluminum hydride agent
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    法律状态:
    优先权:
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