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    • 专利摘要:
    The invention relates to a process for the preparation of an azetidine-3-carboxylic acid of the formula I: <CHEM> or a salt thereof, wherein R1 represents a hydrogen atom, a C1-6 alkyl or C3-8 cycloalkyl group or a group phenyl-CH(R3)- wherein R3 represents a hydrogen atom, a phenyl or an alkyl group of 1-4 carbon atoms, which process comprises reacting an azetidine of the formula II: <CHEM> wherein R1 has the meanings defined above, and X represents a hydrogen atom, a carboxyl or a group, with an alkali metal base at a temperature of from 150 to 300 DEG C in the presence of a catalyst comprising a metal of the Group IIB of the Periodic System and/or a compound of said metal, and if desired converting the obtained azetidine-3-carboxylic acid salt into the corresponding acid; and to novel alkali, alkaline earth and quaternary ammonium salts of such acids.
    公开号:SU1516008A3
    申请号:SU864028238
    申请日:1986-09-29
    公开日:1989-10-15
    发明作者:Адриан Вербруге Питер；Де Вал Джаннетье；Де Линд Ван Вейнгарден Герхард；Виллем Ван Рейгендам Ян
    申请人:Шелл Интернэшнл Рисерч Маатсхаппий Б.В. (Фирма)；
    IPC主号:
    专利说明:

    SD
    about:
    The invention relates to a process for the preparation of azendine-3-carboxylic acid of the general formula
     Here, R, is hydrogen or benzyl, or its salts with a hybrondling property. The aim of the invention is to simplify the process by conducting it under conditions which allow to avoid the destruction of the azetidine ring in an alkaline medium.
    PRI me R 1. In a Teflon reactor (400 ml), washed with nitrogen and heated in a bath with silicone oil, equipped with a refrigerator, which is connected to a gas meter, and a magnetic stirrer, load 41.5 g H-benznp-3, 3-bis (gnzroksimetil) azevdin (2000 mmol), 39.5 g of potassium hydroxide (85 wt.%, 600 mmol), 3 g of zinc diacetate-21110 and 60 ml of ON-IIN (petroleum hydrocarbon oil).
    The mixture is heated for 24 hours at 200 ° C. to form 14.4 liters of hydrogen. Then
    00
     om
    The reactor is cooled and the resulting reaction mixture is mixed with 100 demineralized water. The precipitate is removed. Two layers are formed. The lower light yellow aqueous layer containing the reaction products is processed as follows. The aqueous layer was separated and transferred to a column (length 40 cm,
    Eluent
    I Fractions
     The product is contaminated with the corresponding mono-alcohol (), the Product is N-benzyl-azethidine-3-carboxylic acid ..
    Fractions are collected and discolored using charcoal. After evaporation of the water in yakum, 34.5 g of a white powder are obtained. Analysis: N-benzyl etidine-3-carboxylic acid, 96% pure. The output of 85.8%, 0.44 wt.% Na 0.1 wt.%.
    Example 2 A teflon reactor (400 ml), flushed with nitrogen and heated in silicone oil, equipped with a magnetic stirrer and a cooler, which is attached to a gas meter, are charged with 41.5 g N-benzyl-3,3-bis (hydroxymethyl) azetidine (300 mmol ), 30 g of potassium hydroxide (87%, 466 mmol), 3 g of zinc diacetate.
    The mixture is aggravated for 5 hours at 200 ° C with the formation of 1.4.3 liters of hydrogen. The reactor is cooled and the resulting reaction mixture is treated as follows.
    The reaction product is directly transferred to 100 ml of methanol and the insoluble particles (zinc oxide) are removed. To the light yellow methanol filtrate were added 26.9 g of CaCIj (96% purity, 233 mmol) dissolved in. 1 00 ml of methanol, with ne stirring the mixture and holding it for 1 hour at. After cooling the resulting suspension to 20 ° C, the precipitate
    diameter 8 cm) with ion exchange resin, activated 2 N.HC1. 1.8 l of Dialite C26TP (acid ion exchange resin) was loaded into the column.
    Collect 2 liters of fractions of 300 ml each, isp, use for water and ammonia, the table presents the collected fractions.
    T
    Colour

    Product
    0
    five
    0
    five
    0
    five
    consisting of KC1, Ca (OH) a. and calcium format, collected on a filter and washed with methanol.
    The resulting light yellow methanol filtrate contains the calcium salt of N-benzyl-ee-tidine-3-carboxylic acid. After evaporation of the methanol, 43.6 g of a white solid residue are obtained.
    Physical properties: obtained, calcium salt is soluble in methanol, warm isopropanol, tetrahydrofuran and n-butyl alcohol. Insoluble in water.
    Example 3: A. In a Teflon reactor (400 ml) | washed with nitrogen and heated) in silicone oil, equipped with a magnetic stirrer and a cooler that is attached to the gas meter, load 23.5 g of 3,3-bis (hydroxymethyl) azetidine (200 mmol), 30 g of potassium hydroxide (87%, 466 mmol ), 3 g of zinc diacetate i 2HiO and 60 ml of Oidin 15.
    The mixture is heated for 6 hours at 195 ° C. to form 14.5 liters of hydrogen. The reactor is cooled and 100 ml of demineralized water are added. After removing the precipitate (zinc oxide) and forming two layers, the lower aqueous layer is separated from the upper hydrocarbon layer. Water layer containing potassium515
    Azeti din-3-carboxylic acid salt and potassium formate are evaporated in vacuo to give 50 g of a white solid residue.
    B. The residue obtained is transferred to a column filled with activated 2N. HC1 Duolite C26TR and watered according to the procedure described in Example 1. Acid fractions contain formic acid, azetwedin-3-carboxylic acid (6 acid was isolated in the amount of 16 g as a white powder (purity 96% by H-NMR spectroscopy) . 76% yield,
    B. In the same way as in Section A, 50 g of a white solid residue is obtained, which is transferred to 150 ml of methanol. To the mixture was added 26.9 CaCla (96%, 253 mmol), dissolved in 150 ml of methanol. After stirring for 1 hour with and keeping for 1 day at room temperature, insoluble substances are filtered off and the filtrate is evaporated. The solid residue is stirred in isopropyl alcohol, filtered and dried. Received 21 g of white powder. IR spectrum, cm: 3300 wide wide band (OH, NH), 1570 wide wide band (C00), 38t), 1160, 775, 730.
    The obtained laundry powder is transferred at 60 ° C and the mixture is treated with phosphoric acid to pH 5.3 and then CaO to pH 6.5. After filtration, the resulting clear solution is evaporated to give 17.3 g of a white solid. The resulting azetidine-3-carboxylic acid is 90% pure.
    EXAMPLE 4 Conducted the same reaction as Example 2, but cadmium dinitrate was used as a catalyst instead of zinc diacetate. The reaction proceeds extremely bistro, after 1.5 hours, 14.5 liters of hydrogen are formed. (An orange-brown catalyst can be easily separated from water or methanol with 5 g of coal and reused twice before its activity is reduced).
    The reaction product is processed as follows. After cooling, 100 ml of demineralized water is added to the resulting reaction product to dissolve the potassium salts. Insoluble materials are removed. With vigorous stirring at 50 ° C
    008
    26.9 g of CaC (96%, 233 mmol) in water are added to the aqueous reaction product. A belby bulk precipitate is formed. After cooling to room temperature, the precipitate containing the calcium salt of N-benzipazetidine-3-carboxylic acid and calcium hydroxide mixture is collected and washed 3 times with water. The wet sediment is then suspended in 100 ml of demineralized water, heated to 50 ° C, and treated with phosphoric acid (85%) at a pH of 5.3 in order to obtain a new precipitate.
    having a different look. The pH is immediately adjusted to 7 by adding 0., 5 g CaO. After filtering the precipitate containing Caz (Ca (OH) 2 and cadmium phosphate), the clear light yellow filtrate is evaporated under vacuum to give N-benzyl azethidine-3-carboxylic acid as a white solid (yield 80%).
    Example5. To strongly alkaline
    An aqueous solution of MgSO4 (0.05 mol in 20 ml of water) was added to a solution of N-benzyl azethidine-3-carboxylic acid (0.05 mol) in 30 ml of water. The resulting mixture is extracted with 50 ml of n-butyl
    Q | Alcohol. After washing three times with water (20 ml each), the solution of butyl alcohol is evaporated to obtain 9.5 g of K-bé magnesium salt, nzilazethidine-3-carboxylic acid as a white solid.
    Similarly, using an aqueous solution of BaeT receive barium salt. Magnesium and barium salt N-benzyl azethidine-3-carboxylic acids do not immediately form a precipitate in water, but, as described above, can be easily extracted by extraction.
    The IR spectra of the salts of N-benzyl-azethidine-3-carboxylic acid were obtained.
    Magnesium salt, IR spectrum, 2000 wide wide band (OH), 1585 wide wide band (C00), 1375, 1365, 1315, 1285 ,, 1275, 1210, 1180, 1140, 1070, 1025, 1000, 965,
    Q 910, 880, 845, 820, 760, 740, 700 (all sharp).
    Barium salt, IR spectrum,: 3300 wide wide band (OH), 1570 wide band (C00), 1385, 1315, 1285, 1215, 1190, 1154 1084, 1035, 970, 920, 860, 748, 710, 705.
    Calcium salt, IR spectrum,: 3420 sharp wide band (OH), 2350 wide band, 1650 sharp
    five
    band, 1570 large acute band (COO-), 1375, 1360, 1320, 1305, 1280, 1240, 1190, 1142, 1080, 1050, 1020, 1000, 955, 940, 910, 890, 855, 760, 692, 635 (all sharp).
    Example A 400 ml N-benzyl-3,3-bis (hydroxymethyl) azetidine 41.5 N-benzyl-3,3-bis (hydroxymethyl) azetidine (200 imol) is placed in a Teflon reactor (400 ml), flushed with nitrogen and heated in silicone oil, equipped with a magnetic stirrer. ), 19.2 g sodium hydroxide (97%, 466 mmol), 3 g zinc diacetate. “
    The mixture is heated for 24 hours at 200 ° C. to form 14.4 liters of hydrogen. The reactor is cooled and the reaction product is then processed. The reaction product consists of sodium salt of N-benzene eclasetidine-3-carboxylic acid and sodium format. Both salts can be separated from each other using lix of different solubility in ethanol. Therefore, the reaction product is mixed with 250 ethanol, the mixture is boiled under stirring and cooled, at room temperature, while the sodium salt of N-benzylazetidine-3-carboxylic acid ni. recirculating, sodium formate along with zinc oxide is removed from the alcohol solution by filtration. The clear ethanolic filtrate is then evaporated to obtain the sodium salt of N-benzyl-3-carboxylic acid. 38 g of sodium salt of N-benzyl azetidsh-1-3-carboxylic acid were obtained.
    IR spectrum, main peaks,: 3400 large wide band (OH), 1650 sharp aromatic band, 1580 large wide band), 1405, 1285, 1241, 1215, 1190, 1175, 1155, 1180, 1035, 1010, 960, 860 , 780, 745, 700 (all sharp).
    PRI me R 7. In a Teflon reactor (400 ml), flushed with nitrogen and heated in silicone oil, loaded with a magnetic stirrer and chilled by NICOM, connected to a gas meter, load 41.5 g N-benzyl-3, 3 bis (hydroxymethyl) azetidine (200 mmol), 30 g of potassium hydroxide (87%, 466 mmol), 3 g of zinc diacetate 2HO.
    The mixture is heated for 5 hours at 200 ° C with the formation of 14.3 liters of hydrogen. The reaction is cooled and the resulting reaction

    0 5 0
    0 З

    five
    the mixture is treated as follows. The reaction mixture consists of the potassium salt of N-benzyl azethidine-3-carboxylic acid and the potassium format. Both salts can be separated from each other by using their different solubilities in isopropyl alcohol. Therefore, the reaction product is mixed with 250 ml of isopropyl alcohol, the mixture is boiled with stirring and then cooled to room temperature. While the potassium salt of N-benzylazideidine-3-carboxylic acid goes into solution, the potassium in admixture with zinc oxide is removed from the alcohol solution by filtration. By evaporation of the clear solution, 34 g of the potassium salt of N-benzpazetidine-3-carboxylic acid are obtained in the form of a hygroscopic white solid.
    IR spectrum, main peaks, cm: 3300 large wide band (OH), 1570 large wide band (C00), 1315, 1300, 1235, 1210, 1190, 1175, 1150, 1075, 1045, 1030, 1000, 964, 927 , 915, 905, 880, 855, 815, 780, 760, 740, 715, 695, 625.
    Take p8. A. The reaction mixture obtained in Example 6 is processed as follows. The reaction mixture was mixed with 250 ml of this: -, nola, and 266 mmol of formic acid was added to the resulting suspension. After precipitation of the entire sodium format, it is filtered out of solution. Thereafter, the solvent is evaporated. 32 g of N-benzyl azethidine-3-carboxylic acid were obtained as a white solid.
    B. The reaction mixture obtained in Example 7 is processed as follows. The reaction mixture is mixed with 250 ml of isopropyl alcohol and 266 mmol of formic acid is added to the resulting mixture. After precipitation of the entire potassium format, it is filtered out of solution. After evaporation of the solvent, 32 g of N-benzyl azethidine-3-carboxylic acid are obtained in the form of a white solid.
    Example 9. To a Teflon reactor (400 ml), 83 g of N-benzyl-3, 3-bis (hydroxymethyl) azetidine, 60 g of potassium hydroxide (87%), 17.1 g of sodium hydroxide (99%), 1 g cadmium nitrate.
    The mixture is heated for 5 hours at 200 ° C to form 5 liters of hydrogen. Reactor
    15
    20
    25
    cooled and the reaction mixture is processed. 400 ml of ethanol containing 0.5 g of phosphoric acid (85%) is added, the mixture is heated with stirring and then cooled with stirring. The precipitate, the contents of sodium format and cadmium phosphate, is removed by filtration. The filtrate is processed to obtain 59.5 g of N-benzyl azethidine-3-o-carboxylic acid after recrystallization from isopropyl alcohol,
    Example Ip, 41.5 g of N-benzyl-3, 3-bis (hydroxymethyl) azetidine, 30 g of potassium hydroxide (87%), 0.25 g of cadmium dihyhrate are loaded into a teflon reactor (400 ml).
    The mixture is heated for 2 hours at IPO-ZOO C. After cooling the reaction product, 100 sludge water is added to dissolve the potassium salts. Insoluble materials (cadmium salts) are removed. 70 g of tartaric acid (467 mmol) in 70 ml of water are added. After 2 hours at room temperature, the solution is filtered. As a result, 86.6 g (460 mmol) of potassium nitart were removed. Water and formic acid are evaporated from the remaining solution. Tetrahydrofuran (250 ml) was added and after 2 h, the resulting suspension was filtered to obtain S-benzyl-azethidine-3-carbonic acid (34.2 g). Acetic acid (150 ml) was added to the resulting acid and 10% palladium on carbon (2 g) was used as a catalyst. Hydrogen is passed through the mixture at 50-55 ° C for 22 hours, the mixture is filtered and the solvent is evaporated. Isopropyl alcohol; (75 ml) is added and after 2 hours the suspension is filtered, then dried to obtain a residue of 17 g of azetidine-3-carboxylic acid.
    PRI me R 11. In the described teflon reactor (400 ml), 41.5 g of N-benzyl-3, 3-bis (hydroxymethyl) azetidine, 30 g of potassium hydroxide, 0.3 g of cadmium dinitrate are loaded. 4IgO.
    The mixture is heated for 1.5 hours at 190-50
    200 ° C. After cooling the reaction product, 100 ml of water is added to dissolve the potassium salts. Insoluble materials (cadmium salts) are removed. Then 58.7 g (467 mmol) of basal acid in 50 ml of water are added. After 2 hours of stirring at room temperature, the solution is filtered. As a result, 58.4 g are removed.
    d5
    thirty
    35
    40
    five
    0
    five
    about
    (456 mmol) potassium oxalate. Water and formic acid are evaporated from the remaining solution. Acetone is added and after 2 hours the suspension is filtered to obtain an N-benzyl azethidine-3-carboxylic acid (34.3 g). Acetic acid (100 ml) and 10% palladium on carbon (2 g) as a catalyst are added to the acid obtained. Hydrogen is passed through the mixture for 3.5 hours at 60-65 seconds, after which the mixture is filtered and the solvent is evaporated. Isopropyl alcohol is added and after 18 hours the slurry is filtered, then dried to give 17.1 g of azetidine-3-carbonic acid.
    EXAMPLE 12: 83.5 g of N-benzyl-3,3-bis (hydroxymethyl) azetidine, 60 g of potassium hydroxide (87%), 20 g of sodium hydroxide (99%), 20 are charged into a Teflon reactor. g of calcium, 6.5 g of zinc oxide.
    The mixture is heated for 6 hours at 200 ° C with the release of 27.5 liters of hydrogen. The reaction mixture is treated with stirring with 400 ethanol containing 6 g of phosphoric acid (85%). The solution is cooled with stirring to room temperature, filtered and processed to give N-benzyl azethidine-3-carboxylic acid (56.2 g).
    Example 13. I mol of N-benzyl-3, 3-bis (hydroxymetne) azevdine is loaded into a stainless steel glass-capped reactor connected through a gas cooler reflux condenser. The reactor is heated in an air bath with a gas flame to I-20 s and 2.3 mol of potassium hydroxide in the form of 85% tablets and 0.1 mol of zinc oxide are added. The mixture is continued to heat until the gas evolution rate reaches 5 min. After slowing down
    0
    five
    0
    gas evolution the temperature is slowly increased to 210-215 ° C. The mixture is processed by slowly adding 200 g of water, which is sufficient to dissolve all the reaction products with the exception of the catalyst. The time from the start of the addition of potassium hydroxide and zinc oxide to water is 8.7 hours.
    High pressure liquid chromatography showed that the yield of the potassium salt of N-benzyl azethidine-3-carboxylic acid was 87%.
    1115
    The reaction mixture is filtered and the filtrate is extracted with methyl isobutyl ketone, after which the solution is treated with a 50% solution of tartaric acid in water (5 mol.% Excess relative to potassium hydroxide) and cooled to potassium bitartre is removed by filtration. The resulting crystals are rinsed twice with an equal volume of water. The filtrate has a potassium content of less than 30 pga.
    The filtrate is concentrated in vacuo at a temperature of about to co-centridine M-baieyl-azethidine-3-carboxylic acid npic-tepuo 50 wt.%. When cooled to room temperature, a small amount of acid crystals are formed, which are filtered. The remaining solution is transferred to acetic acid and subjected to hydrogenolysis at 30 ° C using 1 mol,% palladium on carbon and hydrogen gas as a catalyst, to obtain azetidine-3-carboxylic acid.
    EXAMPLE 14. A sour cream product of the oxidation reaction described above, with the suspension, a water solution (320 g) of K-salt of N-benzyl-esetids-3-caraH: .j ... i acid (250 mmol) and 640; whole potassium ions are purified in the following way.
    Aliquat 336 (331 g) is dissolved in 331 g of SEP 80/110 (petroleum solvent). A solution of sodium hydroxide (300 g) and formic acid (350 g) in water (3000 g) was added in 5 portions to remove the aqueous phase. The aqueous solution containing the azetidine derivative is added, stirred and the aqueous phase is discarded. The organics phase is washed with water in portions of 300 g each. The combined three aqueous extracts contain 11.7 mol of N-5eH3Hn-azetid-III-3-1sarboxylic acid. The organic layer is successively washed with four solutions, each of which contains 11.5 g of formic acid in 100 g of water. The combined aqueous extracts contain 223 mmol of N-benzyl azethidine-3-carboxylic acid JI, 0.64 mmol of potassium ions.
    Excess formic acid can be removed from the remaining organic phase containing Aliquat 336 by treating this phase with a base.
    600812
    The formic acid in the aqueous phase can be removed by evaporation or left as a source of hydrogen in the subsequent hydrogenation reaction of L — benzyl-isidin-3-carboxylic acid.
    ten
    权利要求:
    Claims (3)
    [1]
    Invention Formula
    G. The method of obtaining azetids-Z-carboxylic acid of general formula I
    KgkOsoon
    where R is hydrogen or benzyl, or its salts, characterized in that, in order to simplify the process, azevdine of general formula II
    five
    five
    0
    five
    0
    five
    CHgOH
     CHgOH
    where R is a benzyl group, is reacted. With sodium and / or potassium hydroxide at 150-225 C in the presence of zinc acetate, 1 OR of zinc oxide, npn of cadmium dinitrate as a catalyst, the resulting alkali metal salt of N-benzyl-yttidine-3-karyonic acid is separated or treated salts of Ca, Mg or Ba form the corresponding salt of N-benzyl azethidine-3-carboxylic acid, or N-benzyl azetidine-3-carboxylic acid in the form of Nay K, Ca, Mg or Ba translates. t mineral acid organic acid in the base, followed, if necessary, by hydrogenation with ednego to obtain soedgmeni I, wherein R, - hydrogen.
    [2]
    2. The method according to claim 1, of which the process is carried out in the presence of calcium oxide.
    [3]
    3. The method according to claim 1, about tl and h and Yu and shch and the fact that the process is carried out at 175-2254.
    4, Method, characterized by and with I, that Ca chloride is used as Ca salt.
    5, the method according to claim 1, about tl and h and u and with the fact that as the mineral acid is used phosphoric acid.
     i, The method according to d, 1, o. t l and h and y and with the fact that as Orpanic acid use B1shnuyu oxalic acid.
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    同族专利:
    公开号 | 公开日
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    NO863874D0|1986-09-29|
    BR8604686A|1987-06-23|
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    GR862465B|1987-02-02|
    NZ217725A|1989-09-27|
    IL80181D0|1986-12-31|
    HUT44010A|1988-01-28|
    IL80181A|1991-06-10|
    PH22845A|1989-01-19|
    DK464886D0|1986-09-29|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB8300860D0|1983-01-13|1983-02-16|Shell Int Research|Azetidine compounds|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858524024A|GB8524024D0|1985-09-30|1985-09-30|Preparation of azetidine-3-carboxylic acid|
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