• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Process for the preparation of a compound of formula or a salt thereof wherein R, represents a hydrogen atom or a group of formula R2SO2 or phenyl-CH(R3)-wherein R2 represents a phenyl, tolyl or C1-4 alkyl group and R3 represents a hydrogen atom or a phenyl or C 1.4 alkyl group, which process comprises contacting nickel in an oxidation state of at least 3 with a 3-hydroxymethyl azetidine derivative of formula wherein R4 represents a group of formula R2SO2 or phenyl-CH(R3)-and R5 represents a hydrogen atom or a hydroxymethyl group or a group of formula COOH or a salt thereof, followed, where R5 is not a hydrogen atom, by the decarboxylation of the compound of the 3,3-dicarboxylic intermediate product or a salt thereof and. if desired to produce a compound in which R. represents a hydrogen atom, by deprotection of the N-atom. Also. novel N-substituted azetidine carboxylate derivatives of the formula wherein X represents a group CH2OH or COOY where Y represents a hydrogen or an alkali or alkaline earth metal atom.
    公开号:SU1586512A3
    申请号:SU864027253
    申请日:1986-04-14
    公开日:1990-08-15
    发明作者:Адриан Вербругг Питер；Де Вааль Жаннетье；Вилльям Софер Дэвид
    申请人:Шелл Интернэшнл Рисерч Маатсхаппий Б.В. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing azetidine-3-carboxylic acid or its N-benzyl derivative of the General formula
    RN <0> ^ COOH '(!)
    I where R. t is hydrogen or benzyl.
    Nickel (3+) is better in an electrochemical cell containing an electrode cylinder (it is formed by winding in a spiral a flexible package of alternating layers - electrode and intermediate insulating, through which an electric lithium flows), with an electric charge of 8 22 farads per 1 mole of oxidizable azetidine. When current is passed, un "and nickel (3+) are on the surface of the anode and simultaneously in contact with nickel ions (2+) and alkali metal hydrate. For oxidation, it is better to use nickel peroxide obtained in situ by the reaction of alkali metal hypogalite with a nickel salt (2+). The left product is isolated or decarboxylation of the resulting 3,3 - dicarboxylic acid is carried out, or, if necessary, the benzyl group is removed from nitrogen. These conditions simplify the process through the use of cheap and affordable starting materials that allow the use of smaller equipment. 5 cp f-ly '.
    The purpose of the invention is to simplify the process and increase the economic effect through the use of cheaper and more affordable source products, allowing the use of equipment on a smaller scale.
    Example 1. Electrochemical oxidation of N-benzyl-3, 3-bis (oxymethyl) azetidine.
    SU ,, „_ 1586512 AZ
    A 200 ml glass beaker is equipped with a cylindrical nickel anode (4.0 cm high, 4.50 cm diameter) and a steel mesh cathode · height 4.0 cm, diameter 4.40 cm, mesh characteristic: 0.16 holes mm, wire thickness 0.1 mm), located inside the cylindrical anode and separated from the anode by a polypropylene fiber mesh cylinder (height
    4.5 cm, diameter 4.45 cm, mesh characteristic: holes 0.18 mm, fiber thickness 0.15 mm). Thus obtained electrolytic cell is equipped with a polypropylene lid and a rod of a magnetic stirrer to ensure vigorous mixing of the contents of the cell. 150 ml of a 1.0 M aqueous solution of sodium hydroxide 20 are loaded into a cell, 15.5 g of N-benzyl-3 are added,
    3-bis (oxymethyl) azetidine and dissolved at! stirring, and then 0.5 g of Nickel (II) nitrate in 1 ml of water.
    The electrolysis is carried out at 25 C, 25 passing an electric current of 0.6 A · through the cell for 30 hours (9 F / mol N-benzyl-3, 3-bis (oxymethyl) azetidine). The potential difference on the cell is maintained at a level of 1.9-2.1 V until the last f / mol (approximately the last 3 hours), after which the potential difference is increased to 2, 5 V.
    The electrolyte is filtered, resulting in a pale yellow solution, „. · 35 which is evaporated under reduced pressure to a third of its original volume. Concentrated hydrochloric acid is added until a pH of 2 is reached, then the mixture is kept at. for 16 hours. A white solid which precipitates is separated by filtration, washed with water and dried under vacuum, whereby 10.9 g of N-benzylazetidine-3, 3-dicarboxylic acid are obtained in the form of a white powder, pure (liquid chromatography) under high pressure) 92%, so pl. 170 ° C (with decomposition).
    The product decomposes upon heating (so it makes no sense to talk about the temperature of the melting point) and is characterized by the NMR spectrum of its sodium salt.
    IR spectrum, cm 1 1 : 1800-3000 (wide absorption peak, OH bonds); 1705 t $$ sharp peak (COOH); 1640 (high and wide peak, C00 ~) _; 685, 720, 775, 810, 825, 876 (high, sharp peaks).
    Adding sodium hydroxide hydrate to the free acid gives the disodium salt as a white water-soluble white powder (no melting point).
    NMR spectrum (P g 0), ppm: 7.35 5 N, s .; 3.75 2H, s. : 3.70 (4 N, s.).
    IR spectrum, cm ' 1 : 3620 (sharp peak); 1600 (high wide double peak, C00 '; 780, 755 and 705 (sharp peaks).
    In a similar manner, a two-calcium salt is obtained in the form of a water-soluble white powder (no melting point).
    IR, cm 1 : 3625 (sharp peak); 1600 (high wide peak, С00 *; 1205 (small), 1140 (small), 1080 (small), 1065 (small), 1033, 965, 945, 890, 870, 780, 752, 720 (sharp peaks).
    The addition of calcium or magnesium ions to a solution of the indicated sodium salt gives, respectively, dibasic calcium or magnesium salts, each of which has the form of a white powder, poorly soluble in water.
    IR spectrum (calcium salt), cm ' 1 : 1550 (high wide peak, С00'; 1200 (sharp double); 1080 (sharp); 1035 (sharp double); 950, 880 (high), 785, 750, 720 (double), 700 (sharp peaks).
    IR spectrum (magnesium salt) cm “ 1 : 1625 and 1565 (high broad peaks, LLC; 1300, 1250, 1230 (double), 1195, 1055, 1045, .965, 925, 900,
    840, 800, 765, 725, 705 (sharp peaks).
    PRI me R 2. Electrochemical oxidation of N-benzyl-3-hydroxymethyl azetidine.
    • The glass beaker with a capacity of 200 megapixels is equipped with a flat nickel electrode (6.8 * 4.7 cm) and. with a flat platinum electrode (4.8 x 4.8 cm), both were positioned vertically at a distance of approximately 3 cm from each other. Thus obtained cell for electrolysis is equipped with a polypropylene cover and a rod of a magnetic stirrer to ensure vigorous mixing of the contents of the cell.
    Before activating the Nickel electrode, both electrodes are washed with 2 AND an aqueous solution of hydrochloric acid, and then with water. The nickel electrode is activated. 150 ml of an aqueous solution containing
    1586512 6 sodium acetate (0.1 mol), nickel (II) nitrate (0.05 mol) and sodium hydroxide (0.005 mol). An electric current of 32 mA is passed through the cell (nickel as the anode and platinum as the cathode) for 10 s, and the solid thus obtained is mixed in boiling isopropyl alcohol and the sodium chloride is removed by filtration. Isopropyl alcohol was evaporated · ’···, resulting in the production of N-benzylazetidine 3-carboxylic acid, and the polarity of the electrodes was changed for 5 s. The polarity is again changed by repeating the procedure for 5 minutes, during which a dark deposit formed on the nickel electrode. The solution is removed, the electrodes and the cell are washed with water.
    150 ml of a 0.5 m aqueous solution of sodium hydroxide are poured into the cell and N-benzyl-3-hydroxymethylazetidine (2.0 g) is added. The electrolysis is carried out at 25 ° C, passing an electric current of 0.1 A through the cell (nickel as the 20 anode, and the plate as the cathode) for 24.3 hours (8F / mol N-benzyl-Z- (oxymethyl ) azetidine).
    The electrolyte was extracted with diethyl ether (50 mp, 2 times), and the aqueous 25 layer was acidified with concentrated hydrochloric acid until a pH of 5 was reached. The solution was then evaporated to dryness under reduced pressure and the residue was washed with methanol (150 ml). Evaporation of methanol gave a beige solid (2.4 g), which was purified using a Dowex 50 type ion-exchange resin, resulting in N-benzylazetidine-3-carboxylic acid (1.33 g, isolated yield 62 %), mp 152-154 ° C.
    Example Z. Electrochemical oxidation of N-benzyl-3, 3-bis (oxymethyl) 'azetidine at 60 ° C.
    In accordance with the activation step of the nickel anode and the electrolysis procedure of Example 2, N-benzyl-3, 3-bis (oxymethyl) azetidine (10.0 g) is subjected to oxidation in a 2.0 M aqueous solution of sodium hydroxide at ° C, using a current density of 14 mA / cm -2 to achieve 12.6 F / mol N-benzyl-3, 3-bis (oxymethyl) azetidine.
    The electrolyte is cooled, extracted with diethyl ether (50 mp, 2 times) and acidified with concentrated hydrochloric acid until pH 2 is reached. This solution is boiled under reflux for 2 hours, then it is neutralized to pH 7 with an aqueous solution of sodium hydroxide and evaporated to dryness condition. Half a pale yellow solid (8.13 g, purity 80%, isolated yield 70%);
    PRI me R 4. The electrochemical oxidation of N-benzyl-3, 3-bis (oxymethyl) azetidine in a cell type Swiss cylinder, followed by conversion into disodium salt of 1-benzylazetidine-3,3-dicarboxylic acid. This cell is used as part of a fluid circulation circuit, consisting respectively of a pump, flowmeter, Swiss cylinder cell type (having an anode area of 0.6 m 1 ), a heat exchanger and a mixing vessel (stirrer). This vessel is used to separate the gaseous hydrogen generated in the reactor from the liquid and, in addition, to add ingredients and to measure pH.
    The cell is pre-treated by circulating through it a 0.03 M solution of nitric acid in water, then a solution of 25.5 g of NaOH (0.64 mol) in 350 g of water, to which a solution of 5 mmol of Ni (NO 3 ) 2 is preliminarily added. During the circulation of an alkaline, nickel salt solution, an electric current of 2A is passed through the cell for 10 minutes. This leads to the deposition on the electrode surface of most of the colloidal 4Q nickel hydroxide, which is formed by mixing Ni (NOj) i with a solution of NaOH. To this solution is added a solution of 43.9 g (0.21 mol) of N-benzyl-3, 3-bis (oxymethyl) azetidine in 40 g of water.
    This solution is oxidized with a charge of 49 A / h (1.83 F, 8.7 F / mol) with a potential difference across the cell
    2-2.5 V. The time average current density is 33 A / m 2 . The fluid circulation velocity 5θ is l / h. The fluid temperature varies from 20 to 30 ° C. Various samples taken during the reaction make up to 10% of the initial 55 initial volume of the starting material. The resulting solution was extracted with ether to remove impurities (0.6 g), and then concentrated to 237 g by distillation of water under reduced pressure. 750 ml of 96% virgin ethanol are added to this solution. This precipitates in the form of white salt. After refluxing this mixture for 1 h at 85 ° C and subsequent cooling to room temperature, the salt is separated by filtration. The filtrate was again concentrated under reduced pressure to a mass of 69 g. 400 ml of 96% ethanol was added thereto | θ. After refluxing for 1 h and subsequent cooling to room temperature, the precipitate formed is separated by filtration. fifteen
    The combined precipitates after drying have a mass of 46.3 g and contain May 66. % disodium salt of N-benzylazetidine-Z,
    3-dicarboxylic acid according to HPLC (high pressure liquid chromatography). The output in terms of the starting material is 57 mol.%. According to NMR spectroscopy, the precipitate does not contain other organic materials, the remaining '34% is accounted for by sodium carbonate 25
    Example 5. Electrochemical oxidation of N-benzyl-Z, 3-bis (oxymethyl) azetidine in a cell of the Swiss cylinder type, followed by conversion of 1-benzylazetidine-Z to the disodium salt,
    3-dicarboxylic acid.
    Each electrode is made of nickel fine mesh. The diameter of the filament of this mesh is 0.32 mm, and the spacing between the filaments is 0.8 mm. The macroscopic surface area of each electrode (i.e., the total area of its two surfaces) is 0.5 m 2 . The electrodes are separated at a distance of 0.8 mm using a woven polypropylene mesh. This cell is used as part of a circulating fluid circuit containing a pump, a flowmeter, an electrochemical cell, a sump to remove 45 gas generated in the cell, and a mixing vessel. The cooling of the liquid is carried out at. using a shirt with circulating water around the sump and the mixing vessel.
    5.0 g of nickel nitrate hexahydrate is dissolved in 10 ml of water. 342 g of N-benzyl-3, 3-bis (oxymethyl) azetidine are dissolved in 700 ml of water. 232 g of sodium hydroxide are dissolved in 500 ml of water. These solutions are poured into the mixer when water is added to the total volume.
    1.5 liters The solution is mixed and then the potential difference is connected in
    2.3 V. Current density 300 A / m 1 . Cko-i circulation gain 60 l / h. Temperature! the solution entering the cell, 35 ° C, and leaving the cell - 50 ° C. Electrolysis is continued for 1.5 hours to 9.0 F / mol of diol. Then the current density is reduced to 40 a / m 2 for. implementation of the transformation of a small remaining-. the amount of starting material without producing undesirable decomposition of water. The time-average current density used during this process is approximately 250 a / m 2. The system is drained and washed with water. Water is evaporated under reduced pressure until crystallization begins. Methanol is added in a volume exceeding approximately two times the volume of the remaining solution for 0.5 h at 60 ° C. The resulting solution was cooled to ambient temperature for more than 2 hours. Coarse precipitated crystals were removed by filtration, washed in methanol and dried. Methanol and water are evaporated from the filtrate before crystallization begins. Then methanol is added in a volume that is approximately two times the volume of the remaining solution, for 0.5 h at 60 ° C. The resulting solution was cooled to ambient temperature for more than 2 hours, and the resulting crystals were added to the first batch of crystals.
    The combined precipitates after drying contain approximately 65% of the disodium salt of N-benzylazetidine-3, 3-dicarboxylic acid, the rest is sodium carbonate. The yield, calculated on the starting material, is approximately 70 mol%.
    PRI me R 6. The oxidation of N-benzyl-3,3-bis (oxymethyl) azetidine obtained in advance of Nickel peroxide.
    A 10% aqueous solution of hypochlorite (150 ml) containing 32.3 g of sodium hydroxide is added with stirring to nickel sulfate, 6.0 N g 0 (100 g) in 230 ml of water for 0.5 h at room temperature. After another 1 h, the resulting black precipitate was separated by filtration, washed several times with water, and then dried in a desiccator over calcium chloride. The resulting nickel peroxide contains 0.0037 g of active oxygen atom per 1 g of product.
    N-benzyl-3, 3-bis (oxymethyl) azetidine (2.1 g, 10 mmol), sodium hydroxide (1.6 g, 40 mmol) and water / (30 ml) were stirred at 20 ° C, while stirring with the addition of nickel peroxide (22 g) for 24 hours. Nickel oxide hydrate was separated in jg as a green precipitate by filtration, after which a yellow aqueous solution remained, which was evaporated to dryness under reduced pressure. As was established 15 by high sensitivity liquid chromatography, the solid residue contains more than 8-0 May.% Disodium salt of N-benzylazetidine-3, 3-dicarboxylic acid. 20
    Example 7. Oxidation of N-benzyl-3, 3-bis (oxymethyl) azetidine with nickel peroxide.
    • t 1 '
    Bromine (10.6 g) was slowly added 25 at 20 ° C over 8 hours to a mixture of N-benzyl-3,3-bis (oxymethyl) azetidine (2.1 g) in water (50 ml) containing sodium hydroxide (9.3 g) and nickel chloride, 6H 2 O (1.5 g). After stirring overnight, the green precipitate of nickel oxide hydrate was separated by filtration, and the filtrate was evaporated to dryness. The residue is boiled in ethanol and the insoluble material (target product in the form of a sodium salt and sodium bromide) is separated and treated, whereby N-benzylazetidine-3, 3-dicarboxylic acid is obtained.
    Example 8. Oxidation of N-benzyl-3- (oxymethyl) azetidine with nickel peroxide.
    Sodium hydrate (1.7 g) and nickel chloride (0.35 g) are dissolved in 45 water (20 ml). N-benzyl-3- (oxymethyl) azetidine (1.06 g) was dissolved in dioxane (10 ml) and the two solutions were mixed, resulting in a milky emulsion. Bromine (2 g) was added dropwise over 4 hours at 20 ° C and, after stirring for another 3 hours, the excess nickel peroxide was destroyed with sodium sulfite, and the precipitate was separated by filtration. ,
    The clear filtrate is first acidified to pH 7 by adding sodium hydroxide and the solution is boiled until dry. N-benzylazetidine-3-carboxylic acid is removed from the residual salts.
    And PRI me R 9. Obtaining N-benzylazetidine-3, 3-dicarboxylic acid from the crude disodium salt.
    A portion of 49.3 g of the crude disodium salt of N-benzylazetidine-3, 3-dicarboxylic acid obtained in Example 4 with a purity of 72.6%, corresponding to 128 mmol, was dissolved in 150 mp water. This solution was acidified at room temperature by slowly (1 h) adding concentrated hydrochloric acid (36%) until a pH of 1.5 was reached. The obtained L precipitate was separated by filtration, washed with water and dried, whereby 27.3 g of N-benzylazetidine-3, 3-dicarboxylic acid with a purity of 100% <established by HPLC were obtained. The molar yield was 91% in terms of disodium salt.
    Example 10. Obtaining N-benzyl-3- (hydroxymethyl) a zetidine-3-carboxylic acid using electrolytic oxidation.
    A 800 ml glass beaker is equipped with a cylindrical nickel mesh anode (height 13.5 cm, diameter 8 cm, mesh type: hole 0.16 mm, wire thickness 0.1 mm), and a stainless steel cathode rod is inserted in its center (2 cm in diameter), The electrolysis cell thus obtained is provided with a Teflon lid and a magnetic stir bar to ensure vigorous mixing of the contents of the cell.
    After the activation step of the nickel anode of Example 2, 100 ml of a 1.0 M aqueous solution of sodium hydroxide is poured into the cell and N-benzyl-3, 3-bis (oxymethyl) azetidine (20.7 g) is added. The electrolysis is carried out at 25 ° C, passing an electric current of 0.62 A through the cell (nickel as an anode, steel as a cathode) for 6.0 hours, and then passing an electric current of 3.5 A (the same polarity of the electrodes ) for 5.0 hours (8 F / mol N-beneyl-3, 3-bis (approx. 1 simethyl) azetidine)
    The electrolysis product is recovered by rapidly evaporating most of the water, resulting in approximately 60 g of a semi-solid residue, which is boiled in 200 ml of ethanol. After cooling, the solid is separated by filtration, and as a result, disodium salt of N-benzylazetidine-3 is obtained,
    3-dicarboxylic acid. The ethanol filtrate is evaporated and the residual concentrated alkali solution is mixed with tetrahydrofuran (200 ml), whereby a white solid is obtained at the phase boundary between the yellow upper layer and a colorless aqueous layer. This solid was isolated on a glass filter and washed with tetrahydrofuran, whereby the sodium salt of | No.-beneyl-3- (oxymethyl) azetidine-3-car-15 (bonic acid) was obtained.
    This salt is dissolved in water, insoluble impurities are separated by filtration, (acidified to pH 2 with hydrochloric acid and extracted with ether. Then the product is neutralized. (PH 7) with sodium bicarbonate and (aminooxy acid is separated from inorganic materials in a known manner, resulting in 5 g of a white solid N-benzyl-3- (oxymethyl) azetidine-3-carboxylic acid.
    NMR spectrum, ppm: 7.50 (5H, s.); 4.35 (2H, s.); 4.20 (2H, s.); 4.12 (2H, s.); thirty
    3.72 (2H, s.).
    IR (peaks), cm ' 1 : 3250 (high wide); 1800-2800 (wide, OH bond); 1620 (high wide, С00 ~); 1060 (high sharp); 880, 760, 705.
    Example 11. The conversion of N-benzylazetidine-3, 3-dicarboxylic acid 'into N-benzylazetidine-3-carboxylic acid.
    this immediately gas begins to be released from sodium carbonate, carbon dioxide. The mixture is heated and stirred, and then refluxed on a Dean-Stark water separator. After the evolution of carbon dioxide for 0.5 h, this evolution ceases, and 1.5 ml of the mixture of acetic acid and water are separated. The slightly cloudy solution was cooled to room temperature. A white fluffy solid containing sodium acetate (3.6 g) was isolated by filtration. By distillation of the clear filtrate, 4.5 g of N-benzyl-3-carboxyazetidine are obtained.
    Example 13. The conversion of N-benzylazetidine-3-carboxylic acid to azetidine-3-carboxylic acid.
    A solution of N-benzylazetidine-3-carboxylic acid was cooled to 50 ° C, and 0.6 g of palladium on charcoal was added as a catalyst (containing 10 wt.% Palladium). Then, at atmospheric pressure, hydrogen is bubbled through the solution for 3 hours. Using NMR spectroscopy, it was found that hydrolysis was complete at this point. The catalyst was separated by filtration and the filtrate was concentrated under reduced pressure until crystals formed. By adding isopropanol (50 ml) the product precipitated. Filtration and drying yield 2.39 g of azetidine-3-carboxylic acid with a purity of 97.4% (HPLC), which corresponds to a 93% yield of N-benzylazetidine-3-decarboxylic acid.
    A mixture of N-benzylazetidine-3, 3-dicarboxylic acid (6.0 g, 25 mmol) and acetic acid (60 g) was heated to 95 ° C with stirring. This leads to the release of CO g and dissolution of the solid. After 1 h at 95 ° C, gas evolution ceases. As a result of NMR analysis, it was found that the dicarboxylation to N-benzylazetidine-3-carboxylic acid was completed.
    Example 12. The conversion of the disodium salt of N-benzylazetidine-3, 3-dicarboxylic acid into N-benzyl-3-carboxyazetidine.
    A mixture of disodium salt of N-benzylazetidine-3, 3-dicarboxylic acid and sodium carbonate (approximately 2: 1 by weight, total weight
    7.5 g) is dissolved in 100 ml of a mixture of toluene - acetic acid (2) 1. 0 (0). At
    权利要求:
    Claims (7)
    [1]
    Claim
    1. A method of producing azetidine-3-carboxylic acid or its N-benzylpro45 derivative of general formula (I)
    50 where R 1 is hydrogen or benzyl, characterized in that, in order to simplify the process and increase the economic effect, the 3-hydroxymethylazetidine derivative of the general formula
    55 (I) * 2 sn 2 he
    15865 where benzyl;
    To g ~ hydrogen or hydroxymethyl, is oxidized with nickel (III) and, when R 2 is hydrogen, the target product is isolated, and when K 2 is hydroxymethyl, the resulting 3,3 / -dicarboxylic acid is decarboxylated and, if necessary, to obtain compound (I ), where K is hydrogen, remove the nitrogen-jq protecting benzyl group.
    [2]
    2. The method according to p. ^ Characterized in that the process is carried out with nickel peroxide.
    [3]
    3. The method according to p. 1, the effect is that the process is carried out with nickel peroxide obtained in situ by the interaction of alkali metal hypogalite with a nickel (II) salt,
    [4]
    4. 'Way to pop. 1, characterized in that the process is carried out by nickel (III) contained on the surface of the anode, passing an electric current, and at the same time in contact with nickel (II) ions and alkali metal hydrate.
    [5]
    5. The method of pop. 1, characterized in that the process is carried out in an electrochemical cell, containing. ”-; an electrode cylinder formed by spiral winding of a flexible stack of alternating layers; electrode layers and intermediate layers with electrical insulation properties through which electrolyte flows.
    [6]
    6. The method according to PP. 4 and 5, characterized in that the process is carried out by passing an electric charge from 8 to
    [7]
    11 f / mol of compound (II).
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    引用文献:
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    JP5211318B2|2007-03-28|2013-06-12|国立大学法人長崎大学|Method for producing α, α-disubstituted cyclic nitrogen-containing compound|
    EA200901381A1|2007-05-10|2010-06-30|Пфайзер Лимитед|AZETIDINE DERIVATIVES AND THEIR APPLICATION AS ANTAGONISTS OF PROSTAGLANDIN E2|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858509746A|GB8509746D0|1985-04-16|1985-04-16|Preparing azetidine derivatives|
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