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    • 专利摘要:
    The invention relates to alkyl substituted nitriles or carboxylic acids, in particular, the general formula 1: R, RjR, C - g, where R, And or n R2, n-C, H, C, 2H25, Or benzyl Rg H, and 1-, or benzylJ Z nitrile or carboxyl, possessing biological, activity and finding application in medicine. Simplification of the process and expansion of the range is achieved by carrying out the synthesis in the presence of another base and introducing the initial reagents in a certain order. Synthesis of 1 is carried out from a carboxylic acid derivative of general formula II: R, CH2Z, where R and Z are indicated above, a halide compound of general formula 111: R 2 X, where X is halogen, R2 is higher, or general formula 1U:, where X and R, - as indicated above, in an anhydrous organic solvent (RR) at (-10) - (+ 72) s in the presence of a complex base of the general formula Y: R4R4NM, - RjOM, where R H or CjHyJ Ry-C, - Cy— straight or branched chain or M, and, Na or K, and molar ratio (,):: () is 2-5: 1. The starting reagents are introduced in the following order: a) suspension of compound U in PR is added to a solution of a mixture of compounds P and I in PR at 0-72 ° C; b) a solution of a mixture of compounds P and III in an OR is added to a suspension of compound Y in an OR at (-10) () ° C. Benzene, toluene, cyclohexane, isopropyl ether, tetrahydrofuran or their mixture are used as OR. In the case of compound 1, it is re-reacted with compound IV, where,, or benzyl. The method reduces the number of stages from three to one. 5 tab.
    公开号:SU1299497A3
    申请号:SU803213402
    申请日:1980-12-05
    公开日:1987-03-23
    发明作者:Буиссе Мишель；Шиняк Мишель；Грен Клод；Пижероль Шарль
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to an improved process for the preparation of alkyl-substituted compounds of formula 1
    H ng sg
    Jaz
    where R, is a hydrogen atom or n-propyl, is RJ-ethyl, n-propyl, isobutyl, dodecyl or benzyl, a hydrogen atom, i-propyl, isobutyl or benzyl, Z is nitrip or carboxyl with biologically active properties and used in medicine.
    The aim of the invention is to simplify the process and expand the range of target products.
    After that, the mixture in the flask is cooled to 12 + 1 Ci in portions. a mixture of complex base while maintaining the temperature at 9-18 s. The add procedure is completed in
    The goal is achieved in 20–60–90 min. Stirring is continued by the interaction of the carboxylic acid derivative with an alkyl halide in an anhydrous organic solvent in the presence of a complex base.
    25
    another 60 minutes at 10-15 ° C, then the mixture is cooled to 0-5 ° C.
    formulas
    MNC -R50M
    R4
    The dropping funnel containing the layered base is replaced with an identical dropping funnel containing 100-125 ml of water under a nitrogen atmosphere. The reaction medium is slowly hydrolyzed at a temperature below. The mixture is then transferred to a separatory funnel.
    with a molar ratio of base components of 2-5: 1 at (-10) - (+ 72) ° C.
    Example 1. Getting di-N-: prprilcetonitrile from valeronitrile.
    but. Obtaining a complex base of sodium amide / 1; -sodium butoxide in the ratio of 2: 1.
    In a flask with a volume of 0.5 l, equipped with a stirrer, thermometer, isobaric dropping funnel filled with nitrogen,
    and a fridge with calcium chloride lo-oio / o / go ",. ,
    “1SP C (24 mmHg nl 1.416. Vousa, place 150 ml of isopropyl alcohol” ”
    ,.,:,. G 40 Example2, Getting
    go ether and 100 ml of tetrahydrofuran
    The aqueous phase is decanted and the icic layer is washed twice with water, twice with 125 ml of 10% acid and twice with 125 ml of water, the dried phase is dried over 35 ri and the solvents are removed under spherical pressure. As a result
    are di-n-propyl acetonitr
    81.3% (101.8 g), bp. 170 ° .go
    Rime 1, Obtaining Pilacetonitrile from Valeronite
    The system is then filled with nitrogen and 81.9 g (2.1 mol) of sodium amide powder is added.
    Then in this medium is added at -. drop under a nitrogen atmosphere at room temperature, a solution of 51.8 g (0.7 mol) of tert-butanol in 50 ml of tetrahydrofuran. The temperature of the reaction medium is raised to 45-50 ° C and maintained at that temperature until the addition of tert-butanol is complete.
    Stir the medium for another 90 minutes at 40-50 s, then cool it to 20 ° C.
    b. Formation of carbanion valeronitrile and alkylation of n-propyl-bromide.
    In a 1 L flask equipped with a mechanical stirrer, a thermometer, a fridge with a calcium chloride trap and an isobaric dropping funnel, which in turn is equipped with a stirrer and filled with nitrogen, put 83, g (1 mol) valeronitrile, 123 g (1 mol) p propyl bromide and 350 ml of isopropyl ether.
    A mixture of the complex base is placed in an addition funnel and the flask is rinsed twice with 25 ml of tetrahydrofuran. The system is then filled with nitrogen and the mixture of the complex base is stirred.
    After this, the mixture in the flask is cooled to 12 + 1 Ci in portions. a mixture of complex base while maintaining the temperature at 9-18 s. The add procedure is completed in
    60-90 min. Stirring is continued.
    60-90 min. Stirring is continued.
    another 60 minutes at 10-15 ° C, then the mixture is cooled to 0-5 ° C.
    60-90 min. Stirring is continued.
    A dropping funnel containing a complex base is replaced with an identical dropping funnel containing 100-125 ml of water under a nitrogen atmosphere. The reaction medium is slowly hydrolyzed at a temperature below. The mixture is then transferred to a separatory funnel.
    The aqueous phase is decanted and the organic layer is washed twice with 125 ml of water, twice with 125 ml of 10% hydrochloric acid and twice with 125 ml of water. The organic phase is dried over sodium sulfate and the solvents are removed at atmospheric pressure. Resulting in semi
    oio / o / go ",. ,
     With (24 mm Hg. Nl 1,416. „„
    start di-n-propyl acetonitripsh1 with the output
    81.3% (101.8 g), bp. 170 ° C,
     With (24 mm Hg. Nl 1,416. „„
    Example2, Getting
    EXAMPLE 2, Preparation of diH-pro pilacetonitrile from valeronitrile.
    A. Preparation of complex base sodium amide / sodium isopropylate 2: 1.
    Reproduce the method described in Example 1a using 16.4 g (0.42 mol); 1mide of sodium, 8.4 g (0.14 mol) of isopropanol in 40 ml of isopropyl ether and 20 ml of tetrahydrofuran.
    B. Formation of carbanion valeronitrile and alkylation with n-propyl bromide.
    Reproduce the method described in Example 1B using a mixture of 16.6 g (0.2 mol) of valeronitrile and 24.6 g (0.2 mol) of propyl bromide in 60 ml of isopropyl ether.
    A mixture of the complex base is added to this medium and the addition funnel is washed with 10 ml of tetrapudrofuran. The addition procedure is completed in 1 hour at 10-15 ° C. After completion of this procedure, the mixture is kept at 15 ° C. The reaction product is treated and isolated.
    in the same way as described in example 1 b. After that, the solvent is evaporated.
    The result is a di-n-propyl acetate of nitrile (15.6 g) with an average of 62.5%. Boiling point 170 ° C.
    Example 3. Getting di- - propyl acetonitrile from valeronitrile.
    A. Preparation of complex base sodium amide / sodium p-propyl in a 2: 1 ratio.
    Reproduce the method of Example 2a using the same amounts except for using p-prop nol instead of isopropanol.
    b. Formation of carbanion valeronitrile and alkylation with i-propyl bromide.
    Reproduce the method of Example 2 b.
    As a result, di-n-propyl acetonitrile is obtained with a yield of 68.9% (17.2 g) of T. b.p. 170 ° C.
    Example 4. Getting di-n-propyl acetonitrile from valeronitrile.
    a. Preparation of a complex base of sodium amide / sodium ethoxyethylate.
    Reproduce the method of Example 2a, except for using 12.6 g (0.14 mol) of 2-ethoxyethanol instead of isopropanol.
    B. Formation of carbanion valeronitrile and alkylation of H-propyl-bromide.
    Reproduce the method of Example 2b by adding a complex base for 2 hours at 5-10 ° C. After the base is added, the mixture is kept at a temperature of 10-15 ° C for 1 hour. The result is di-n-propyl acetonitrile to yield 75.4% (18.9 g), b.p.
    170 ° C.
    Example 5. The preparation of di-n-propyl acetonitrile from valeronitrile,
    but. Preparation of complex base sodium amide / sodium tert-butoxide in the ratio of 3: 1.
    Reproduce the method of Example 2a, except for using 21.84 g (0.56 mol) of sodium amide and
    five
    0
    five
    five
    0

    12.3 g (0.14 mol) tert-amyl alcohol.
    b. Formation of carbanion valeronitrile and alkylation of n-propyl-bromide.
    Reproduce the method of Example 2b using the same amounts.
    The result is di-n-propyl acetonitrile with a yield of 59.1% (14.8 g). Bp 170 ° C.
    Example 6. The preparation of di-n-propyl acetonitrile from valeronitrile.
    a. Preparation of a complex base of sodium amide / sodium tert-amylate in a 5: 1 ratio.
    Reproduce the method of Example 2a, except for using 32.76 g (0.84 mol) of sodium amide and 12.3 g (0.14 mol) of tert-amyl alcohol.
    b. Formation of carbanion valeronitrile and alkylation with i-propyl bromide.
    Reproduce the method of Example 26 using the same amounts of valeronitrile and H-propyl bromide, except that during the addition of the complex base, the temperature is kept at 0-3 C. The result is di-p-propyloacetonitrile in 25.1% yield ( 6.3 g). Bp 170 ° C.
    Example 7. Getting di-and propylacetonitrile from valeronitrile.
    A. Getting a complicated foundation
    35 sodium amide / potassium t-butylate in a ratio of 2: 1.
    Reproduce the npiiMepy 2 a method except for using 10.92 g (0.23 mol) of sodium amide and 15.7 g (0.14 mol) of potassium t-butylate in 45 ml of tetrahydrofuran.
    b. Formation of carbanion valeronitrile and alkylation of n-propyl-bromide.
    0
    40
    Reproduce the method of Example 2b using the same amounts of valeronitrile and n-propyl bromide, but with 55 ml of tetrahydrofuran as the diluent.
    The result is di-H-propyl acetonitrile with a yield of 42.5% (10.6 g). Bp
    170 ° C.
    Example 8. Getting di-n-propylacetonitrile from valeronitrile.
    but. Preparation of a complex base of lithium amide / potassium tert-butylate in a 2: 1 ratio.
    0.97 g, (O, 14 mol) lithium at (-40) - (-45) ° C are added to 200 ml of liquid ammonia and the mixture is stirred for 8 h.
    Liquid ammonia is removed and 7.9 g (0.07 mol) of potassium t-butylate in 35 ml of tetragchrofrofuran are added. The mixture is stirred for 2 hours while heating to 55 ° C.
    b. The formation of carbanion raleonitrile and alkylation with n-propyl bromide.
    The mixture obtained in Example 8a was cooled to 15 ° C and a solution of S, 3 g (0.1 mol) of valeronitrile and 12.3 g (0.1 mol) of H-propyl bromide in 30 ml of tetrahydrofuran was added.
    The addition procedure lasts 1 hour at 15 ° C, after which the mixture is held at this temperature for another 1 hour.
    The reaction product is treated in the same manner as described in the previous examples.
    The result is di-n-propyl acetonitrile with a yield of 56.4% (7 g), b.p., 170 s.
    Example 9. The preparation of di-n-propyl acetonitrile from valeronitrile.
    A. Preparation of complex base lithium diethylamide / lithium amylate in a 2: 1 ratio.
    A solution of 6.15 g (0.07 mol) of tert-amyl alcohol in 30 ml of tetrahydrofuran is added to 160 ml of a suspension of 15% lithium diethylamide in hexane (0.21 mol). The mixture is heated for 2 hours at 55 ° C. After completion of the reaction, the complex base is in the form of a solution.
    b. Formation of carbaniol valeronitrile and alkylation of n-propyl bromide.
    Reproduce the method of Example 86 using the same amounts of I-propyl bromide and valeronitrile, i.e. 0.1 mol. The reaction product is treated in the manner described.
    The result is di-N-propyl acetonitrile with a yield of 35% (44 g).
    Boiling point 170 ° C.
    Example 10. Getting di-npropylacetonitrile from valeronitrile.
    but. Preparation of complex base sodium amide / sodium tert-butoxide in a 2: 1 ratio.
    Reproduce the method of Example 2a using the same amounts of reagents, but replacing isopropanol with 10.4 g (0.14 mol) with tert-butanol and
    five
    ABOUT

    ABOUT
    five
    0


    0
    five
    a mixture of 30 M.P. benzene and 30 ml of tetrahydrofuran. as solvents.
    b. Formation of carbanion valeronitrile and alkylation with n-propyl-bromide.
    Reproduce the method of Example 2b except for using 65 ml of benzene and 65 ml of tetrahydrofuran at 14-18 ° C. After the addition is complete, the mixture is kept at 15 ° C for another 60 minutes. The product is made according to the method used in the preceding examples.
    The result is di-n-propyl acetonitrile with a yield of 41.5% (10.4 g). Bp 170 ° C.
    Example 11. The preparation of di-H-propyl acetonitrile from valeronitrile.
    a. Preparation of complex base amide sodium / sodium tert-amylate in a ratio of 2 ;; one.
    Reproduce the method of Example 2a, except for using 12.3 g (0.14 mol) of tert-amyl alcohol in 30 ml of benzene instead of isopropanol and 16.4 g (0.42 mol) of sodium amide in 30 MP of benzene.
    b. Formation of carbanion valeronitrile and alkylation with -propyl-bromide.
    Reproduce the method of Example 26 using the same amounts of valeronitrile and n-propyl bromide in 160 ml of benzene. 34 ml of hexamethylphosphoric triamide is added to the complex base and the mixture thus obtained is placed on the reaction medium at b.p. 5-13 C.
    After the addition is complete, stirring is continued at this temperature for another 2 hours, and then the mixture is treated as indicated.
    The result is di-n-propyl acetonitrile with a yield of 36.6% (9.1 g). Bp 170 ° C.
    Example 12. Getting di-N - propylacetonitrile from valeronitrile.
    a. Preparation of a complex base of sodium amide / sodium t-amylate in a 2: 1 ratio.
    Reproduce the method of Example 2a, except for using 12.3 g (0.14 mol) of tert-amyl alcohol instead of isopropanol and 70 ml of tetragvdrofuran as solvent.
    b. Formation of carbanion valeronitrile and alkylation with p-propyl-bromide.
    Reproduce method m of Example 2b using the same amounts of p-propyl bromide and valeronitrile in 60 ml of tetrahydrofuran. The addition of the complex base to the reaction mixture is carried out at the reflux temperature of the mixture.
    After the procedure, add
    The temperature of the mixture is maintained at 72 ° C for another 2 hours.
    )five
    The reaction product is treated as indicated.
    The result is di-H-propyl-acetonitrile with a yield of 52% (13 g). Boiling point 170 ° C.
    Example 13. Obtaining di-n-propyl acetonitrile from valeronitrile.
    a. Preparation of complex base sodium amide / sodium tert-butylate in a 2: 1 ratio.
    Reproduce the method of Example 2a using 4.87 g (0.125 mol) of sodium amide and 3.14 g (0.0425 mol) of tert-butyl alcohol and 80 ml of tetrahydrofuran as a diluent. while the temperature does not exceed 25 C. The mixture of the complex base does not heat,
    b.Education of carbanion valero-. nitrile and alkylation
    bromide.
    8.3 g (0.1 mol) of valeronitrile and 12.3 g (0.1 mol) of AND-propyl bromide are dissolved in 70 ml of tetrahydrofuran. Wednesday prepared according to the example
    As a result, 2-lt-nponmi-tetradecananitrile is obtained with a yield of 24.6% (12.4 g), Pp 1.4425, bp. 140 ° C / 10.4 mm Hg
    Example 15. Preparation of o-H-propyl - “:, - cyclohexane 1 acetonitrile from valeronitrile.
    A. Preparation of a complex base sodium amide / sodium tert-amylate in a ratio of 2: 1.
    Reproduce the method of Example 14a using the same amounts of reagents and diluent.
    b. Formation of carbanion valeronitrile and alkylation with cyclohexyl chloride.
    Reproduce the method of Example 2b except for using 16.6 g (0.2 mol) of valeronitrile and
    H-propyl-30 23.7 g (0.2 mol) of cyclohexyl chloride d 60 ml of tetrahydrofuran. The result is oi -C-propyl-c-cyclohexylacetonitrile with a yield of 26.3% (8.7 g).
    35 Example 16. Preparation of and -n-propyl-about-benzylacetone.
    a. Preparation of a complex base of sodium amide / sodium t-amylate in a 2: 1 ratio.
    40 Reproduce the method of Example 14a using the same amounts of pea genes and solvent.
    b.Education of carbanion valeronitrile and alkylation of benzylchlorine45 house.
    Reproduce the method of Example 2b except for using .16.6 g (0.2 mol) of valeronitrile and 25.3 g (0.2 mol) in 60 ml of tetrahydropyltetradecanannitrile from valeronite -50 Furan.
    As a result, 2-H-propyl-c-benzyl acetonitrile is obtained with a yield of 52.8% (18.3 g).
    Example 17. The preparation of 4-methyl- 55 2-n-propyl-pentanitrile from valeronitrile.
    but. Preparation of complex base sodium amide / sodium tert-amylate in a 2: 1 ratio.
    13a, cooled to 1 ° C, after which a solution of valeronitrile and H-propyl bromide is added to the mixture of the complex base. The addition rate is chosen so that the temperature does not exceed 4 ° C. The addition procedure lasts 45 minutes. Increase the temperature C for 1 hour, after which the hydrolysis is carried out in the same manner as described in the previous paragraphs.
    The result is di-H-propyl acetonitrile with a yield of 51% (6.4 g). Bp 170 ° C.
    Example 14. Obtaining 2-nrila.
    but. Preparation of complex base sodium amide / sodium tert-amylate in a 2: 1 ratio.
    Reproduce the method of Example 2a, except for using 16.4 g (0.42 mol) of sodium amide and 12.3 g (0.14 mol) of tert-amyl
    alcohol, and 70 ml of tetrahydrofuran as a solvent.
    b. Formation of carbanion valeronitrile and alkylation with T-chlordodecane.
    Reproduce the method of Example 2b except for using 16.6 g (0.2 mol) of valeronitrile and 40.95 g (0.2 mol) of 1-chlordodecane in 60 ml of tetrahydrofuran.
    As a result, 2-lt-nponmi-tetradecananitrile is obtained with a yield of 24.6% (12.4 g), Pp 1.4425, bp. 140 ° C / 10.4 mm Hg
    Example 15. Preparation of o-H-propyl - “:, - cyclohexane 1 acetonitrile from valeronitrile.
    a. Preparation of a complex base of sodium amide / sodium t-amylate in a 2: 1 ratio.
    Reproduce the method of Example 14a using the same amounts of reagents and diluent.
    b. Formation of carbanion valeronitrile and alkylation with cyclohexyl chloride.
    Reproduce the method of Example 2b except for using 16.6 g (0.2 mol) of valeronitrile and
    9 .1299497
    Reproduce the method of example | using the same amounts of pea14
    genes and diluent.
    b. Formation of carbanion valeronitrile and alkylation with isobutyl bromide.
    Reproduce the method of Example 2b, except for using 16.6 g (0.2 mol) of valeronitrile and 27.4 g (0.2 mol) of isobutyl bromide.
    The result is 4 methyl-2-p-propylpentanitrile with a yield of 63% (17.5 g), bp, 190 ° C, p 1.4199, IR spectrum; at 2240 cm. Gas chromatography separation: valeronitrile 6.4%, 2-isobutylvaleronitrile 83.9%, 2,2-di-isobutylvaleronitrile 9.3%.
    Example 18. The preparation of di-n-propyl acetonitrile from acetonitrile.
    a. Preparation of complex base sodium amide / sodium tert-butylate in a 2: 1 ratio.
    Reproduce the method of Example 1a using 164 g (4.2 mol) of sodium amide in 500 ml of tetrahydrofuran and 103.6 g (1.4 mol) of t-butanol in 700 ml of tetrahydrofuran.
    b. Formation of acetonitrile carbanion and alkylation of H-propyl-bromide.
    Reproduce the method of Example 1 b. The reaction is carried out using a mixture of 41 g (1 mol) of acetonitrile and
    0
    -ten
    Reproduce the method of Example 2a using 8.2 g (0.21 mol) of sodium amide and 5.2 g (0.07 mol) of t-butanol in BO ml of tetrahydrofuran.
    b. Formation of acetonitrile carbanion and alkylation with N-propyl bromide.
    Reproduce the method of example.
    13b except for use
    4.1 g (0.1 mol) of acetonitrile and 246 g (0.2 mol) of N-propyl bromide dissolved in 70 ml of tetrahydrofuran. The complex base mixture is cooled to -10 ° C and then slowly treated with a mixture of acetonitrile and E-propyl bromide at this temperature for 40 minutes. Next, the medium is treated in the same way as described in the preceding examples.
    As a result, di-H-propyl acetonitrile is obtained with a yield of 62.8% (7.9 g) of bp. 170 ° C.
    Example 20. Obtaining dibenzylacetonitrile from acetonitrile.
    but. Preparation of complex base sodium amide / sodium t-amylate in a ratio of 2: 1.
    Reproduce the method of example.
    14a, using the same amounts of pea20
    25
     genes and diluent.
    b. Formation of acetonitrile carbanion and alkylation with benzyl chloride.
    Reproduce the method of Example 18b, except that a 246 g (2 mol) p-propylb romide reactive, 35 was diluted using 4.1 g (0.1 mol) dissolved in 600 ml of tetrahydrofuran, acetonitrile and 25 , 3 g (0.2 mol)
    when cooling the mixture to OC. The procedure for adding a suspension of a complex base lasts 90-120 minutes, the temperature of the mixture is maintained at
    0-5 ° C for the entire addition. The temperature is then adjusted and the mixture is kept at this temperature for 1 hour with stirring under a nitrogen atmosphere. The medium is hydrolyzed by pu-. By this, slowly pouring 400 ml of water and 400 ml of ethyl ether into the mixture with stirring. The aqueous phase is decanted and the organic layer is concentrated
    40
    50
    in a vacuum.
    As a result, di-n-propyl acetonitrile is obtained in a yield of 83.7% (104.8 g) of bp. 170 ° C.
    Example 19. The preparation of di-n-propyl acetonitrile from acetonitrile.
    but. Preparation of complex base sodium amide / sodium tert-butoxide in a ratio of 2: 1.
    -ten
    Reproduce the method of Example 2a using 8.2 g (0.21 mol) of sodium amide and 5.2 g (0.07 mol) of t-butanol in BO ml of tetrahydrofuran.
    b. Formation of acetonitrile carbanion and alkylation with N-propyl bromide.
    Reproduce the method of example.
    13b except for use
    4.1 g (0.1 mol) of acetonitrile and 246 g (0.2 mol) of N-propyl bromide dissolved in 70 ml of tetrahydrofuran. The complex base mixture is cooled to -10 ° C and then slowly treated with a mixture of acetonitrile and E-propyl bromide at this temperature for 40 minutes. Next, the medium is treated in the same way as described in the preceding examples.
    As a result, di-H-propyl acetonitrile is obtained with a yield of 62.8% (7.9 g) of bp. 170 ° C.
    Example 20. Obtaining dibenzylacetonitrile from acetonitrile.
    but. Preparation of complex base sodium amide / sodium t-amylate in a ratio of 2: 1.
    Reproduce the method of example.
    14a, using the same amounts of pe0
    five

    benzyl chloride, dissolved in 30 ml of tetrahydrofuran.
    The result is dibenzyl-40 acetonitrile with a yield of 75.3% (16.7 g). Separation by gas chromatography: monobenzyl acetonitrile 12.6%, dibenzyl acetonitrile 63.6%, tribenzyl acetonitrile 10.6%.
    Example 21. Obtaining diisobutylacetonitrile from acetonitrile.

    50
    but. Preparation of complex base sodium amide / sodium tert-amylate in a 2: 1 ratio.
    Reproduce the method of Example 14a using the same amounts of reagents and diluent.
    b. Formation of acetonitrile-carbanion and alkylation with isobutyl bromide.
    Reproduce the method of Example 18-6, except that the reaction is carried out using 4.1 g (0.1 mol) of acetonitrile and 27.4 g
    (0.2 mol) isobutyl bromide in 30 ml of tetrahydrofuran.
    As a result, diisobutyl acetonitrile is obtained with a yield of 45% (6.9 g) of bp. 90-91 ° G, / 15 mm.RZ-.st. 0.825. Gas chromatography: monoisobutyl acetonitrile 0%, diisobutyl acetonitrile 76.4%, triisobutyl acetonitrile 11.4%.
    Example 22. The preparation of tri-n-propyl acetonitrile from acetonitrile.
    a. Preparation of complex base sodium amide / sodium tert-butylate in a 2: 1 ratio.
    Reproduce the method of Example 2a using 17.55 g (0.45 mol) of sodium amide and 11.10 g (0.15 mol) of tert-butanol in 40 ml of tetrahydrofuran.
    b. Formation of acetonitrile carbanion and alkylation of n-propyl-bromide.
    To the mixture of the complex base obtained in Example 22a, a mixture of 4.1 g (0.1 mol) of acetonitrile and 40.59 g (0.33 mol) of H-propyl bromide was added. During the whole addition, which lasts 25 minutes, the temperature is kept between 8 and 26 ° C. After the addition is completed, the mixture is kept for another 60 minutes with stirring at room temperature. Subsequent operations are exactly the same as described in the previous examples.
    As a result, tri-n-propyl acetonitrile is obtained in a yield of 66% (11 g) of Ti. 68-70 ° C.
    Example 23. The preparation of tri-n-propyl acetonitrile from di-c-propyl-acetonitrile.
    but. Preparation of complex base sodium amide / sodium tert-butoxide in a 2: 1 ratio.
    Reproduce the method of Example 2a, except for using 8.2 g (0.21 mol) of sodium amide and 5.2 g (0.07 mol) of tert-butanol in
    100 ml of tetrahydrofuran. I
    b. Formation of di-I-propyl acetonitrile carbanion and alkylation with N-propyl bromide.
    To a mixture of the complex base obtained in Example 23a, which is at 20 + 2 ° C, is added a mixture of 12.5. g (0.1 mol) of di-n-propyl acetonitrile and 16 g (0.13 mol) of p-propyl bromide. This procedure lasts 5 min. The mixture is stirred at a temperature maintained between 20 and 30 ° C for 40 minutes. After that, let the temperature slowly return to 24 ° C. The hydrolysis is carried out as described in the previous examples.
    As a result, tri-n-propyl acetonitrile is obtained with a yield of 94.5% (15.8 g), bp 68-70 ° C.
    Example 24. Obtaining di-propylacetic acid from acetic acid.
    but. Preparation of complex base sodium amide / sodium tert-butoxide in a 2: 1 ratio.
    In a flask in which a nitrogen atmosphere is maintained, 23.4 g (0.6 mol) of sodium amide is suspended in 60 ml of tetrahydrofuran. Then a solution of 14.8 g (0.2 mol) is added to the medium.
    tert-butanol in 10 ml of tetrahydrofuran. The temperature is raised to 55 C.
    The medium is maintained at this temperature for 90 minutes and then returned to room temperature.
    b. Formation of acetic acid carbanion and alkylation with n-propyl bromide.
    4.8 g are placed in a flask in which the nitrogen atmosphere is maintained
    (0.1 mol) of 50% sodium hydride in mineral oil and 60 ml of tetrahydrofuran. After this, 6 g (0.1 mol) of acetic acid in 10 ml of tetrahydrofuran are added dropwise. Temperature
    raise to 55-60 ° C. The sodium acetic acid obtained in the form of a gel is kept under stirring for 2 hours. After this, the complex base prepared according to Example 24a is added at one time at 20 ° C. The mixture is heated to 50 ° C for 1 hour and then 24.6 g (0.2 mol) of i-propyl bromide is added to it while maintaining the temperature at 50-55 ° C. After
    the completion of the addition procedure, the temperature reaches 60 ° C. The temperature of the medium is then maintained at 55 ° C for 1 hour. After that, the mixture is incubated for 8 hours at 20 C.
    The mixture is hydrolyzed by adding water and the aqueous phase is decanted. This phase is acidified by adding an aqueous solution of concentrated hydrochloric acid and the mixture is then extracted several times with ethyl ether. The ether phase is washed with water, dried, after which
    the ether is evaporated.,
    The result is a mixture that contains 18.6% di-H-propylacetic acid and 45% valeric acid. Yield 2.7 g, t.kip. 219-222 ° C, p 1.4239.
    Example 25: Preparation of di-n-hophopylacetic acid from valeric acid.
    but. Preparation of complex base sodium amide / sodium tert-butoxide in a 2: 1 ratio.
    Reproduce the method of Example 21a using 11.7 g (0.3 mol) of sodium amide and 7.4 g (0.1 mol) of tert-butanol in 80 ml of tetrahydrofuran.
    Lithium valerate is obtained by adding a 33% (0.055 mol) 13% solution of bulium in hexane to a solution of 5.1 g (0.05 mol) of valeric acid and 30 ml of tetrahydrofuran in a nitrogen atmosphere. The mixture is heated at 60 ° C for 1 hour. At the same time, a complex base is added to the lithium valerate sludge, and then see
    about.
    b. The formation of carbanion valeri- "g. ,,and"
     - heated for 1 h at 60 C. nova acid and alkylation with-propyl bromide.
    After that, 9.25 g - (0.075 mol) of n-propyl bromide was added over 1 hour and the mixture was heated at 60 for 90 minutes. Then mix
    Sodium valerate is prepared according to Example 21 b, which is sodium acetate, but using 4.8 g (0.1 mol) of 50% sodium hydride in mineral oil. 60 ml of tetrahydrofuran and 10.2 g (0.1 mol) of valeric acid. After this, 18.45 g (0.15 mol) of I-pro-25 pilbromide is added and the medium is heated to 60 ° C under a nitrogen atmosphere. Then a complex base is slowly added to this mixture with stirring over 80 minutes.
    The addition funnel is washed with 20 ml of tetrahydrofuran. The medium is incubated for another 90 minutes at
    After that, 9.25 g - (0.075 mol) of n-propyl bromide is added over 1 hour and the mixture is heated at 60 ° C for 90 minutes. The mixture is then treated 20 as in Example 21 b.
    The result is a mixture with a yield of 72.5% (1.6 g), this mixture contains 21.5% of di-n-propylacetic acid and 51% valeric acid. B. boil .219-222 ° C. 1.4239.
    Example 27. Preparation of di-H-propylacetic acid from valeric acid.
    A. Preparation of complex base lithium diethylamide / lithium tert-butylate
    in the ratio of 2: 1 „
    To a mixture of 13.2 g (0.15 mol) of tert-butanol and 21.9 g (0.3 mol) of diethyl amide in 54 ml of benzene and 54 ml of hexa-35 methylphosphoric triamide was added 3.2 g (0.46%). mol) lithium "The reaction mixture is held under stirring for 5 hours at 25-30 C.
    b.The formation of carbanion valeria-0nova acid and alkylation with-propyl bromide,
    Lithium valerate is obtained in tetrahydrofuran, as described in Example 26b, except that the lithium vitarate obtained in this way is injected by evaporation of tetrahydrofuran. I
    In a mixture of 90 ml of hexane and 90 ml of lithium-to-amide, obtained by dissolving the Q of luol, 16.2 g (0.15 mol) are suspended
    60 ° C and left to stand for 8 hours at 20 ° C. After hydrolysis, successive operations are repeated as described in Example 21 b.
    The result is a mixture with a quantitative yield (2.4 g), this mixture contains 83.3% of valeric acid and 16.7% of di-H-propylacetic acid, b.p. 219-222 C.
    Front 1.4239.
    Example 26, Production of di-H-propylacetic acid from valeric acid.
    but. Preparation of a complex base of lithium amide / tert-amylate lithium in a 2: 1 ratio.
    at a temperature of from -40 to -45 With 1 g (0.15 mol) lithium in 200 ml of liquid ammonia in the presence of several crystals of iron nitrate as
    valerate lithium; To this medium is added a mixture of a complex base, obtained according to example 27a, and the temperature of the reaction medium is supported by the catalyst. After completion of the reaction, j c at 20 C. After completion
    adding a complex base the temperature of the mixture is set to 36 ° C for 1 hour.
    ammonia is removed and the complex base is prepared by adding 8.8 g (0.1 mol) of t-amyl alcohol in a nitrogen atmosphere in an environment
    30 ml of tetrahydrofurano. The mixture is heated for 2 hours at 55-60 C.
    b. The formation of carbanion valerianic acid and alkylation with-pro-propbromide,
    Lithium valerate is obtained by adding, under a nitrogen atmosphere, 33 ml (0.055 mol) of a 13% butyl lithium solution in hexane to a solution of 5.1 g (0.05 mol) of valeric acid in 30 ml of tetrahydrofuran. The mixture is heated at 60 ° C for 1 hour. Then a complex base is added to the lithium valerate suspension, after which the mixture
    about.
     . ,,and"
    heated for 1 h at 60 C.
    heated for 1 h at 60 C.
    After that, 9.25 g - (0.075 mol) of n-propyl bromide is added over 1 hour and the mixture is heated at 60 ° C for 90 minutes. Then the mixture is treated as in example 21 b.
    In a mixture of 90 ml of hexane and 90 ml of toluene, 16.2 g (0.15 mol) are suspended
    valerate lithium; To this medium is added a mixture of a complex base, prepared according to Example 27a, the temperature of the reaction medium being maintained at a level of 20 ° C. Upon completion
    adding a complex base the temperature of the mixture is set to 36 ° C for 1 hour.
    Then, 27.54 g (0.22 mol) of AND-propyl bromide is added. Medium temperature
    1512
    increase to 50 ° C. After that, the mixture is kept at 50-57 ° C for 8 hours. The medium is then cooled to -5 ° C and 100 ml of concentrated hydrochloric acid is added, maintaining the temperature below 0 ° C. The solvents are then removed at
    reduced pressure at a temperature not exceeding 40 ° C and the residue is diluted by adding 75 ml of water. The mixture is extracted 4 times with 250 ml of ethyl ether. The ether phases are combined and washed with water. The ether solution is then dried over sodium sulfate and the ether is removed under reduced pressure. The result is a di-propylacetic acid 2.6 g with a yield of 35.8% and 50.7% of valeric acid. Bp 219-222 ° C, n 1, 423
    Example 28. Preparation of t-butyl di-n-propyl acetate from t-butyl valerate.
    a. Preparation of a complex base of sodium amide / sodium t-amylate in a 2: 1 ratio.
    Reproduce the method of Example 2a, except for using 6 g (0.155 mol) of sodium amide in 25 ml of tetrahydrofuran and 3.1 g (0.035 mol of tert-amyl alcohol in 10 ml of tetrahydrofluran.
    b. Formation of carbanion tert-butylvalerate and alkylation of n-pro with pilbromide.
    The mixture obtained in Example 28a was cooled to -10 ° C and a solution of 7.9 g (0.05 mol) of tert-butyl valerate in 10 ml of tetrahydrofuran was slowly added. After the addition is complete, the mixture is stirred for another 60 minutes at -10 ° C.
    Then, at -10 ° C, 7.4 g (0.06 mol) of H-propyl bromide and 9 g (0.05 mol) of hexamethylphosphoric triamide are added. The mixture is kept for 1 hour with stirring at -10 ° C. After hydrolysis by adding water, the mixture. extracted with ether. The ether phase is dried and the ether is evaporated.
    The result is a tert-butyl-di-H-propyl acetate with a yield of 49.5%, (5 g).
    Example 29. Obtaining N, N-diethyl-di-n-propylacetamide from N, N-diethylvaleramide.
    but. Preparation of complex base sodium amide / sodium tert-amylate in a 2: 1 ratio.
    Reproduce the method of Example 2a, but using 8.2 g (0.21 mol)







    sixteen
    sodium amide and 6.16 g (0.07 mol) of t-amyl alcohol in 50 ml of tetrahydrofuran.
    b. Formation of the carbanion N, N-diethylvaleramide and alkylation with N-propyl bromide.
    A mixture of 15.7 g (0.1 mol) s, K-diethylvaleramide and 12.3 g (0.1 mol)
    npropyl bromide in 20 ml of tetrahydro.
    five
    0
    0
    the furan is cooled to 2 ° C. To this medium is added a mixture of complex precipitation with stirring, the trace being so that the temperature does not exceed 20 C.
    The stirring was continued for another 90 minutes at this temperature, after which the hydrolysis was carried out in the same manner as described in the previous examples.
    As a result, N, N-diethyl-di-and-propylacetamide (5.5 g) are obtained with a yield of 27.75% and 46.75% of unreacted H, H-diethylvaler amide is returned.
    Example 30. Preparation of N, N-5 diethyl di-n-propylacetamide from N, N-diethyl aleramide.
    a. Preparation of a complex base of sodium amide / sodium t-amylate in a 2: 1 ratio.
    Reproduce the method of Example 28a, but using 5 ml of tetrahydrofuran.
    b. Formation of carbanion K% K-diethylvaleramide and alkylation with AND-propyl bromide.
    To a solution of N, N-diethylvaleramide in 15 ml of isopropyl ether at 20 ° C, a mixture of a complex base is added dropwise under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, after which 12.3 g (0.1 mol) of H-propyl bromide dissolved in 15 ml of isopropyl ether was added.
    Stirring is continued for 45 minutes and then the medium is hydrolyzed. The method described in the previous examples is used to isolate the desired product.
    As a result, H, K-diethyl-di-n-propylacetamide (7 g) is obtained in a yield of 34.9% and 55% of the unreacted N, N-diethylvaleramide is returned.
    Example 31. Preparation of valeronitrile from acetonitrile.
    but. Preparation of complex base sodium amide / sodium ethoxyethyl.
    In a pre-dried flask with a volume of 500 ml is placed 62.5 g of amide,
    five
    0
    five
    0
    five
    sodium and 145 g (200 ml) of diisopropyl ether.
    At room temperature with stirring under a nitrogen atmosphere, dropwise a flo6aBj; iHroT solution of 48.02 g of 2-ethoxyethanol and 72.5 g (100 ml) of diisopropyl ether while maintaining the temperature of the reaction medium 45-50 C,
    The medium is kept under stirring in an inert atmosphere for another 8 hours at 60 ° C and then 8 hours at room temperature.
    b. Formation of acetonitrile carbanion and alkylation with N-propyl bromide.
    In a pre-dried flask with a volume of 1 l, 53.3 g of acetonitrile, 123.0 g of i-propyl bromide and 280.5 g (400 ml) of diisopropyl ether are placed. The medium is stirred at room temperature under a nitrogen atmosphere. The complex base slurry is transferred to a 500 ml addition funnel and held while stirring. The flask containing the complex base was washed with 72.5 g (100 ml) of diisopropyl alcohol and this ether was added to the contents of the dropping funnel. Then to the reaction mixture portions are added to a suspension of complex
    40
    base while maintaining the internal temperature of the ZP-35 ° C. This procedure lasts 30 minutes.
    The medium is then allowed to settle for 30 minutes, then cooled to 0-5 ° C. After hydrolysis at this temperature by gradually adding 160 g of distilled water, the aqueous phase is allowed to settle for 15 minutes. The organic phase is successively washed with 65 g of distilled water, 47 g of 36% hydrochloric acid and three portions of 125 g of distilled water. The organic phase is dried over sodium sulfate and the solvent is evaporated at atmospheric pressure to reach 73 + 1 ° C in a Ha4ajie column.
    The result is 63.5 g of crude oil, titrating 88.2% and the same 50 petroleum product.
    Yield of vaperonitrile: 67.5% (73 g), bp.141 ° C, dl 0.804, p 1.39913.
    The result is 59.75 g of crude oil, titrating 76.4% of the desired product.
    The output of diiso & utilacetonitrile: 35 to 60% (46 g), BP. 90-91 s / 15mmrt.s, 825.
    The separation by gas chromatography monoisobutyl acetonitrile 0%, diisobutyl acetonitrile 76.4%, triisobutyl acetonitrile 11.4%.
    Using the described method, diallylacetonitrile from allylbromide is obtained. The resulting crude product is titrated to 39.9%.
    The output of diallyl acetonitrile: 30.7%.
    Example 33. Preparation of dibenzylacetonitrile from acetonitrile.
    but. Preparation of complex base sodium amide / sodium t-amylate.
    In a pre-dried flask with a volume of 500 ml, 81.9 g (2.1 mol) of sodium amide powder and 88.8 g (LLP ml) of dry tetrahydrofuran are placed. Use: hydrochloric method, half: na. At room temperature, the compounds are followed by stirring under nitrogen at the following products: hydrocinnamon mono-drops are added a solution of 61.6 g of benzyl bromide ryte (the resulting crude product is titrated to 62.1% in cerium (0.7 mol) tert-amyl alcohol and 44.4 g (50 ml) of dry tetrahydrofu5
    O
    0
    0
    0
    five
    0
    left product, yield 64.8%, 110.5 g, bp. , d 1.0014), isocapro-nitrile from isobutyl bromide, (the resulting crude product is titrated to. 81.3% in the target product, yield: 35.5%, 44.9 g, bp 15b, d 0.806,
     1,406); Allyl 4-pentenonitrile .70
    bromide (the resulting crude product is titrated to 58% in the desired product, yield 53.7%).
    Example 32. Getting diisobu tilacetonitrile from acetonitrile.
    a. Preparation of a complex base of sodium amide / sodium ethoxyethylate.
    Reproduce the method of Example 30a, but using 66.3 g of sodium amide in 181 g (250 ml) of diisopropyl ether and 51 g of 2-ethoxyethanol in 54.5 g (75 ml) of diisopropyl ether.
    b.Education of acetonitrile carbanion and alkylation with isobutyl bromide.
    20.5 g of acetonitrile, 137 g of isobutyl bromide and 325.5 g (450 ml) of diisopropyl ether are placed in a flask. The reaction is carried out at 30 + 2 ° C and the addition of a complex base is completed in 40 minutes. The operating conditions, as well as the procedure, were the same as described in example 30 b.
    The result is 59.75 g of crude oil, titrating 76.4% of the desired product.
    The output of diiso & utilacetonitrile: 5 60% (46 g), BP. 90-91 s / 15mmrt.st, 825.
    Separation by gas chromatography: monoisobutyl acetonitrile 0%, diisobutyl acetonitrile 76.4%, triisobutyl acetonitrile 11.4%.
    Using the described method, diallylacetonitrile from allylbromide is obtained. The resulting crude product is titrated to 39.9%.
    The output of diallyl acetonitrile: 30.7%.
    Example 33. Preparation of dibenzylacetonitrile from acetonitrile.
    but. Preparation of complex base sodium amide / sodium t-amylate.
    81.9 g (2.1 mol) of sodium amide powder and 88.8 g (TOO ml) of dry tetrahydrofur: are placed in a pre-dried flask with a volume of 500 ml. At room temperature, while stirring under a nitrogen atmosphere, a solution of 61.6 g is added dropwise.
    (0.7 mol) tert-amyl alcohol and 44.4 g (50 ml) of dry tetrahydrofu19
    wound while maintaining the temperature in the range of 45-50 ° C. The medium is maintained at 60 ° C. for 90 minutes and then 1 hour at room temperature.
    b. Formation of carbanion acetonitol and alkylation with benzyl chloride.
    In a pre-dried one liter flask, 25.5 g (0.5 mol) of dry acetonitrile, 126.5 g (1 mol) of benzyl chloride, and 266.4 g (300 ml) of dry tetrahydrofuran are placed.
    The medium is stirred under a nitrogen atmosphere while maintaining the internal temperature at 10-15 ° C during the entire procedure for adding a slurry of a complex base.
    This procedure lasts 90 minutes. Wednesday maintained at 15 ° C for 1 h
    129
    after addition and then hydrolyzing at a temperature below 15 ° C by adding a mixture of 400 g of distilled water and 285.6 g (.00 ml) of ethyl ether. The aqueous phase is decanted and the organic phase is successively washed with a solution of 70 g of water and 50. g of 36% hydrochloric acid and then with three portions of 125 g of water. Wednesday su2-benzylvaleronitrile (duration
    The boil over sodium sulfate and the solvent are removed at atmospheric pressure. 30 Add a complex base for 45 minutes, and up to 80 ° C at the beginning of the column. As a result, the alkylation temperature is 30-35 ° C, and tate gives 115 g of crude oil, the resulting crude oil is tit1, and is equivalent to 63.6% titrated to the desired product. , 9% in the target product, yield 62.5%,
    The output of dibenzylacetone: 66,2%,. "68.6 g. Separation of gas chromatograph 35 IR spectrum; when GRANIUM: monobenzyl acetonitrile 12.6% dibenzyl acetonitrile 63.6%, tribesyl acetonitrile 10.6%.
    -2245);
    , 2-dodecylvaleronitrile (the duration of addition of the complex base is 20 minutes, the alkylation temperature is 45-50 ° C, the resulting crude oil is titrated to 99.5% B the target product, the yield is 52.4%, bp at 0.4 mm Hg or 127 ° C at 0.15 mm Hg, p 1.4425, IR spectrum: at “2245 and
    Example 34. Preparation of 2-ethylvaleronitrile from valeronitrile.
    a. Preparation of a complex base of sodium amide / sodium ethoxyethylate.
    Reproduce the method of Example 31a.
    b. Formation of carbanion valeronitrile and alkylation with ethyl bromide.
    Reproduce the method of Example 31b, except that the alkylation is carried out at 28-30 ° C and the reaction medium is kept for 1 hour at room temperature before hydrolysis. 114 g of crude oil, 77.7% titrated into the desired product, are obtained.
    I
    The output of 2-ethylvaleron nitrosha: 80%,
    115.6 g, k.p. 1b4-1b5 ° C. Separation by gas chromatography: valeronitrile

    ) 0
    9949720
    12.4%, 2-ethylvaleronitrile 77.7%, 2,2-diethylvaleronitrile 2.3%.
    Using the same procedure, the following compounds were prepared by taking the indicated changes into account: 2-allyl-valero-nitrile (the addition time of the complex base is 40 minutes, the alkylation temperature is 30-35 ° C, the crude oil is titrated to 60.8% in the desired product, yield 61 3%, 98.1 g, bp 95 ° C / 22 mm Hg, 4318. Separation by gas chromatography: valeronitrile 12.4%, 2-allylvaleronitrile 60.8%, 2,2-diallylvaleronitrile
    J5 14.3%)
    2-isobutylvaleronitrile (duration of addition of a complex base is 27 minutes, alkylation temperature is 35-38 ° C, the crude oil obtained is titrated to 97.7% of the desired product, yield 72.7%, 131.6 g. Bp 190 ° C at 20 mm Hg, 1.4199, IR spectrum: at - 2245 cm, separation by gas chromatography: valero 5 nitrile 6.4%, 2-isobutylvaleronitrile 83.9%, 2.2-diisobutylvaleronitrile 5.2% );
    2-benzylvaleronitrile (duration
    complex base of 45 minutes, alkylation temperature 30-35 ° C, scientific crude oil tit1, is 9% in the desired product, yield 62.5%,
    .
    -2245);
     . “35 IR spectrum; at
    40
    , 2-dodecylvaleronitrile (the duration of the addition of a complex base is 20 minutes, the alkylation temperature is 45-50 ° C, the crude oil obtained is quenched at 99.5% B, the desired product, the yield is 52.4%, bp at 0.4 mm Hg or 127 ° C at 0.15 mm Hg, p 1.4425, IR spectrum: at “2245 and
    2195) i
    2-propargylvaleron nitrile1 (the duration of addition is difficult about base Q 30 minutes, alkylation temperature 30-33 minutes, the resulting crude oil is titrated to 35.5% in the target product, 31.2%, 49.1 g, IR spectrum
    ka):
    -I
    CH at 3280 cm, at 55 2240, at 2120 cm 1.4152, separation by gas chromatography: valeronitrile 48.7%, 2-propargylvaleronitrile 34.5%, 2,2-dipropargilvaleronitrile (0%).
    Example 35 Preparation of oL-benzyl-di-n-propyl acetonitrile from di-y-propyl acetonitrile. a "Preparation of a complex base of sodium amide / sodium ethoxyethylate,
    In a pre-dried flask with a volume of 250 ml, 8.2 g of sodium amide and 66.6 g (75 ml) of tetrahydrofuran are placed. At room temperature
    Using the described method, the following compounds are obtained:
    oi-ethyl-di-n-propyl acetonitrile (crude oil is titrated to 99.3%. 51.5%, 7.9 g, t, kip, 5b, C 11, 1.7 mm Hg, Art., or 49 in the target product ° C at 0.8 mm Hg, article ,, p 1.4288, IR spectrum: -CrN at 2240 cm); al-di-di-n-propyl acetonitrile (crude May
    Pro, kip, 74 С
    titrated at 98.1 / 5 in the target product, yield 62.5%, 11.3 g, t, kip, 74- at 1.6 mm Hg, st, pp 1.4378,
    75 ° C
    IR: CsN at 2240 cm 1
    Example 36, Getting di-ch20
    while stirring in a nitrogen atmosphere, titrated with 100% in a target solution, 6.3 g duct was added dropwise, yield 61.5%, 10.2 g, 2-ethoxyethanol in 22.2 g (25 ml) - at 1.6 mmHg, st ,, p, 1.4419, IR rafidrofuran, maintaining the temperature spectrum: at 2240 cm), about -isobenzoi between 40 and 45 ° C, then Wednesday-then di-di- n-propylacetonitrile (the crude is heated to 53-60 ° C and kept at this temperature for 2 hours. After that, the mixture is cooled to room temperature,
    b. Preparation of carbanion di-y-propylacetonitrile and alkylation with benzyl chloride,
    A mixture of 16.5 g of benzyl chloride and 12.5 g of di-p-propyl acetonitrile is added to the suspension of the complex base prepared in Example 35a over 5 minutes.
    The reaction is exothermic and the evolution of heat continues for 45 minutes after completion of the addition procedure of the complex base. Then the mixture is cooled to room temperature and this temperature is maintained.
    propyl acetonitrile from nitrile vallene novol acid (complex base is added to the nitrile / halide mixture, total amount of solvent: 6.4 volumes),
    a. Preparation of a complex base of sodium amide / sodium ethoxyethylate,
    In a 100 ml flask equipped with a condenser, magnetic stirrer, thermometer and isobarum funnel, 12.9 g (0.3307 mol) of sodium amide and then 40 ml of toluene are placed in the inlet to introduce nitrogen — the mixture is stirred under nitrogen atmosphere . It is then left out for 1 hour. After that, the mixture is cooled to 0-5 ° C and hydrolyzed by adding 50 g of distilled water, ensuring that the temperature does not exceed 20 ° C. After decanting, the solvent is removed at. reduced pressure. The concentrate is then taken in 107 g (150 ml) of ethyl ether. The ether phase is successively washed with two portions of 25 g each of a 10% aqueous solution of hydrochloric acid and three portions of 25 g each of distilled water. After drying with sodium sulfate, the ether is removed at atmospheric pressure and then under reduced ti (residual pressure: 55 mmHg, st,)
    As a result, 24.6 g of raw oil is obtained, titryush; it is 95.8% effective in the desired product. This oil is then rectified under reduced pressure.
    Output ot-benzyl-di-p-propyl acetonitrile: 75.9% (24.6 g), t, kip, 108 ° C at 0.5 mm of mercury, PC, 1.5071, IR spectrum: at 2240.
    Using the described method, the following compounds are obtained:
    oi-ethyl-di-n-propyl acetonitrile (crude oil is titrated to 99.3%. 51.5%, 7.9 g, t, kip, 5b, C 11, 1.7 mm Hg, Art., or 49 in the target product ° C at 0.8 mm Hg, article ,, p 1.4288, IR spectrum: -CrN at 2240 cm); al-di-di-n-propyl acetonitrile (crude May
    Pro, kip, 74 С
    Evoy 419, infrared about isobuic (crude oil
    titrated at 98.1 / 5 in the target product, yield 62.5%, 11.3 g, t, kip, 74- at 1.6 mm Hg, st, pp 1.4378,
    75 ° C
    IR: CsN at 2240 cm 1
    Example 36, Preparation of di-chloe, titrated to 100% in the target product, yield 61.5%, 10.2 g, at 1.6 mm Hg, article ,, p 1.4419, IR spectrum: at 2240 cm) , about -isobutyl di-n-propyl acetonitrile (crude oil
    20
    25
    propyl acetonitrile from nitrile vallene novol acid (complex base is added to the nitrile / halide mixture, total amount of solvent: 6.4 volumes),
    a. Preparation of a complex base of sodium amide / sodium ethoxyethylate,
    In a 100 ml flask equipped with a condenser, magnetic stirrer, thermometer and isobarum funnel, 12.9 g (0.3307 mol) of sodium amide and then 40 ml of toluene are placed in the inlet to introduce nitrogen — the mixture is stirred under nitrogen atmosphere . Then, a mixture of 9.9 (0.110 mol) of 2-ethoxyethanol and 10 ml of toluene is added from a single funnel. The mixture is heated to 60-65 ° C for 90 minutes and then stirred for 4-5 hours under a nitrogen atmosphere.
    b. Preparation of nitrile carbanion valerie of new acid and alkylation with i-propyl bromide,
    40
    In a 250 ml flask equipped with a magnetic stirrer, a thermometer, a cooler and an isobaric addition funnel, 16.6 g or 20.8 g (0.2 mol) of nitrile valerie of a new acid are placed in the inlet to introduce nitrogen. , 6 g or 18.2 ml (0.2 mol) of N-propyl bromide and 90 ml of toluene. The complex base is then transferred to an isobaric addition funnel and flushed with a 100 ml flask in a portion of 10 ml of toluene. The whole apparatus is then filled with nitrogen and the complex base is stirred to obtain a homogeneous medium. The reaction medium is also stirred, heated to and added for an hour.
    23
    m suspension of a complex base. The temperature is gradually increased until 45 C is maintained on. A5 ± 3 ° С with the help of a water bath. The duration of addition is approximately 5 ° C at 25 ° C for another 30 minutes and 1 hour. Stirring is continued for another 30 minutes in the atmosphere, then the medium is allowed to cool to room temperature. Reaction medium
    still under nitrogen, cool to 5-10 ° C and then slowly hydrolyzed by adding 40-50 ml of water. The organic layer is decanted and washed successively with a portion of 60 ml of a 20% (by volume) 5 solution of hydrochloric acid, then with four portions of water, 60 ml each. The organic layer is dried over sodium sulfate and filtered. In this way, di-n-propyl acetonitrile is obtained in a yield of 83.82% along with 5.95% valeronitrile and 2.4% tri-H-propyl acetonitrile.
    According to the described method receive di-And-propylacetonitrile with the following results (see tab.1).
    20
    under nitrogen, then cooled to 5 ° C. After slow hydrolysis with 50 ml of water, the mixture is decanted and washed successively with a portion of 60 ml of 2P% (by volume) hydrochloric acid and then in four portions (each 60 ml) of distilled water. After drying, the organic phase is concentrated at atmospheric pressure.
    Thus, 23.9 g of crude di-n-propyl acetonitrile are obtained. The yield is 78.2% together with 8.8% valeronitrile and 5.7% tri-n-propyl acetonitrile.
    According to the described method get di-N-propylacetonitrile with the following results (see tab.2).
    B. Nitrile in 3 volumes dissolve 25 liters, and a complex base in 3.6 volumes of solvent.
    but. Preparation of complex base sodium amide / sodium ethoxyethyl.
    Example 37. Preparation of di-H-propyl acetonitrile from nitrile valerie of a new acid (a mixture of nitrile / halide is added to a complex base
    A. The complex base is suspended in the total amount of solvent. Tov. in 6.4 volumes.
    but. Preparation of complex base sodium amide / sodium ethoxyethyl.
    In a 250 ml flask equipped with a broom, a refrigerator, a thermometer, and an isobaric dropping raven
    With an inlet to inject Q up to 60 ° C for 90 minutes and 12.9 g (0.3307 mol) of sodium amide and 100 ml of dry diisopropyl ether are placed under nitrogen. The medium is stirred under a nitrogen atmosphere and then 9.9 g (0.110 mol) of 2-ethoxyethanol in 60 ml of diisopropyl ether are added. The medium is heated to 90 minutes and stirred for 4-5 hours at room temperature.
    b. Preparation of nitrile carbanion valerie of new acid and alkylation with N-propyl bromide.
    To a suspension of the complex base thus obtained, a mixture of 16.6 g or 20.8 ml of CO, 2 mol) of valeronitrile and 24.6 g or 18.2 ml (0.2 mol) of n-propyl bromide is added dropwise in order to don't lift45
    50
    55
    It is stirred for 5 hours at room temperature. 15 ml of diisopropyl are then added. the ether.
    b. Preparation of nitrile carbanion valerie of new acid and alkylation with I-propyl bromide.
    At 25 ° C, a mixture of 16.6 g (0.2 mol) of valeronitrile and 24.6 g (0.2 mol) of h-propyl bromide in 75 ml of diisopropyl ether is added to the complex base thus obtained. The addition is continued for 25 minutes at 30 + 2 C, and the temperature indicated is maintained using water bath. The medium is then stirred at 30 ° C for 30 minutes, cooled to 5 seconds, and slowly hydrolyzed with 50 ml of water. After decanting, wash the medium
    With l129949724
    ranged from 20 to 25 ° C, a water bath (temperature of approximately 10 ° C) is used for this, the addition lasts 25 minutes. The medium is stirred at 25 ° C. for another 30 minutes.

    under nitrogen, then cooled to 5 ° C. After slow hydrolysis with 50 ml of water, the mixture is decanted and washed successively with a portion of 60 ml of 2P% (by volume) hydrochloric acid, then with four portions (each 60 ml) of distilled water. After drying, the organic phase is concentrated at atmospheric pressure.
    Thus, 23.9 g of crude di-n-propyl acetonitrile are obtained. The yield is 78.2% together with 8.8% valeronitrile and 5.7% tri-n-propyl-acetonitrile.
    According to the described method get di-N-propylacetonitrile with the following results (see tab.2).
    B. Nitrile in 3 volumes of solvent, and a complex base in 3.6 volumes of solvent.
    but. Preparation of complex base sodium amide / sodium ethoxyethyl.
    In a 250 ml flask equipped with a stirrer, a condenser, a thermometer and an isobaric addition funnel, 12.9 g (0.3307 mol) of sodium amide and then 60 ml of diisopropyl ether are placed with an inlet to introduce nitrogen. The mixture is stirred under a nitrogen atmosphere and 9.9 g (0.110 mol) of 2-ethoxyethanol, diluted with 15 ml of diisopropyl ether, are added dropwise. Wednesday heated
    wate up to 60 ° C for 90 minutes and
    It is stirred for 5 hours at room temperature. 15 ml of diisopropyl are then added. the ether.
    b. Preparation of nitrile carbanion valerie of new acid and alkylation with I-propyl bromide.
    At 25 ° C, a mixture of 16.6 g (0.2 mol) of valeronitrile and 24.6 g (0.2 mol) of h-propyl bromide in 75 ml of diisopropyl ether is added to the complex base thus obtained. The addition is continued for 25 minutes at 30 + 2 ° C, and the temperature indicated is maintained using a water bath. The medium is then stirred at 30 ° C for 30 minutes, cooled to 5 seconds, and slowly hydrolyzed with 50 ml of water. After decanting the medium is washed
    /:but
    20% hydrochloric acid and then four fractions of water, 60 ml each. The organic phase is dried and then concentrated at atmospheric pressure.
    According to the described method receive di-And-propylacetonitrile with the following results (see tab.3).
    Example 38. Preparation of di-n-propyl acetonitrile from addetonitrile.
    A. Addition of complex base to acetonitrile / n-propyl bromide mixture, total amount of solvent 10.8 volumes.
    a. Preparation of a complex base of sodium amide / 2 ethoxyethanol sodium.
    In a flask with a capacity of 100 ml, equipped with a refrigerator, magnetic stirrer, thermometer, and isobaric addition funnel, 12.9 g (0.3307 mol) of sodium amide and 40 ml of tbluol are placed in the inlet to introduce nitrogen. The mixture is stirred under a nitrogen atmosphere and a solution of 9.9 g (0.110 mol) of 2-ethoxyethano in 20 ml of toluene is added. Then the medium is heated to 60-65 ° C for 30 minutes and maintained with stirring under nitrogen for 4-5 hours. B. Preparation of acetonitral carbanion and alkylation with n-propyl bromide
    In a flask with a capacity of 250 ml, supplied 30 is then heated to 60 ° C for 90 minutes and kept under stirring under nitrogen atmosphere for another 4-5 hours.
    b.Poluchenie.karbanion acetonitrile cooler, stirrer, thermometer and isobaric dropping funnel, and alkylation n-propyl bromide. with inlet for injection. The nitrogen compound thus obtained is placed 4.1 g (0.1 mol) of dry matter is cooled to 15 seconds and through acetonitrile. 24.6 g (0.2 mol) of the addition funnel are quickly added with H-propyl bromide and 85 ml of toluene. a solution of 4.1 g (0.1 mol) of acetonitrile. The resulting composite base is 24.6 g (0.2 mol) of n-propyl bromide. Transfer to the isobaric addition funnel. The addition is continued for 10 minutes at. and a 100 ml flask is rinsed with 15 ml of toluene - 15-26 ° C. this temperature is maintained with a water bath. The addition funnel is rinsed with 10 ml diisopropy to obtain a homogeneous medium. 45 liters of ether and the reaction medium is stirred for 20 minutes at 25 ° C. After cooling to 5 ° C, the medium is slowly hydrolyzed by the addition of 50 ml of fresh base, and the temperature is decanted with sweat. The organic layer is kept at a level of 40-45 ° C with successively washed with 60 ml of 20% liquid. hydro ice bath. Adding Pro-. olic acid (by volume) for 22 minutes, then the temperature in four portions of 60 ml is maintained at 45 ° C. Then distilled water. After drying, the reaction medium is allowed to cool the organic sodium sulfate to room temperature, and the continuous phase is concentrated under atmospheric stirring for further pressure. 30 min. After cooling to 5 ° C in a nitrogen atmosphere, the medium is slowly hydro- As a result, 11.75% is obtained and 40-50 ml of water is sulphated. A mixture of decanting di-H-propyl acetonitrile. Output
    la The whole device is placed in a nitrogen atmosphere and the composite base is alternately stirred, and the reaction mixture is stirred and heated to 35 ° C. Then the complex suspension 129949726 is added in portions
    and the organic phase is washed with 60 ml of 20% (by volume) hydrochloric
    acids, then four fractions of water with 60 ml. The organic layer is dried over sodium sulfate and filtered.
    Thus, di-C-propylacetonitrile was obtained With a yield of 65.5%, together with 25.9% valeronitrile and 3% tri-h-propyl acetonitrile.
    According to the described method, diH-propyl acetonitrile is obtained with the following results (see table 4).
    C. Adding acetonitrile / H propyl bromide mixture to the composite base, total amount of solvent 18.6 volumes.
    A. Preparation of the complex base of sodium amide / sodium 2-ethoxyethyl.
    In a 230 ml flask equipped with a condenser, magnetic stirrer, thermometer and isobaric addition funnel, 12.9 g are placed with an inlet to introduce nitrogen.
    sodium amide and 100 ml of di-o-propyl ether. The mixture is stirred under a nitrogen atmosphere and a solution of 9.9 g (0.110 ml) of 2 ethoxyethanol in 600 ml of diisopropyl ether is added. Wednesday
    then heated to 60 ° C for 90 minutes and kept under stirring in a nitrogen atmosphere for another 4-5 hours.
    b. Preparation of acetonitrile carbanion and alkylation with n-propyl bromide. The complex base thus obtained is cooled to 15 seconds and a solution of 4.1 g (0.1 mol) of acetonitrile 24.6 g (0.2 mol) of n-propyl bromide is quickly added via an addition funnel. The addition lasts 10 minutes at 15-26 ° C. this temperature is maintained 271299А9728
    is 65.2% plus 16% valeronite-M and M are the same or different for ryl and 7.3% for tri-N-propyl acetonitrile. This means lithium atom, sodium
    According to the described procedure, di or potassium is obtained, and the molar ratio is
    N-propylacetonitrile with the following
    five
    results (see tab.5).
    base component sewing
    In this way. The proposed method makes it possible to simplify the technology for producing alkyl-substituted compounds by reducing the number of stages, as well as to extend the range of target products. Formula inventions
    The method of obtaining alkyl-substituted compounds of General formula 1
    "TO
    R2-C-Z
    All
    where R, is a hydrogen atom or n-propyl, RJ is ethyl, n-propyl, isobutyl, dodecyl or benzene;
    where K has the indicated values,
    X is a halogen atom,
    in an organic solvent at R = a hydrogen atom, n-propyl, from-25 to 0 - (+ 72) ° С, or a solution of
    butyl or benzyl; . of the general formula W and the halide Z is nitrile or carboxyl, the compounds of the general formula PG in the form of the interaction of the derived solvent are introduced into the suspension of the carboxylic acid with the alkyl halide of the complex base in a general form of anhydrous organic growth II in an organic solvent in the presence of a base, at a temperature (-lO-C + ZO C, in particular, as a solvent, benzene is used to simplify the process and to expand toluene, cyclohexane, isopropyl the ester products, ether, tetrahydrofuran or their mixture and complex base suspension; the reaction process is carried out using formula (11) at a temperature of (-10) - (+ 72), the resultant compound of general formula 1,
    v / i M T-J QM r de R, and RJ have the indicated values,
     D) 5a Rg is a hydrogen atom, reintroduced
    t: 40 in the process of interaction with the halide
    where a hydrogen atom or ethyl, a compound of the general formula Y, Rg is alkyl containing 3-5 carbon atoms with a straight or branched chain, or a radical where X has the indicated values, CjHyOCHjCH; . 45 Rj-propyl, isobutyl or benzyl.
    Table 1
    Nitrile Valerie new acid, Di - «- prop taetonitrile. Three-and-propyl acetonitrile,
    base component sewing
    MK rRsOn "t
    equals 2-5: 1.
    in an organic solvent is introduced into
    solution of compound of general formula III
    R, CH2Z
    where RjK Z have the indicated meanings, and the halide compound of the general formula IV
    20
    V;
    general decree opil,

    Valeronitrile
    Di-N-propyl acetonitrile. Three-I-progosha acetonitrile,
    Toluene

    30-35

    #
    Valeronitrile
    Di-H-ace is nitrile.
    Three-n-propylacetonitrile "
    Diisopropyl ether

    Valeronitrile,
    Di-and-propyl acetonitrile, Tri-n-gopylopylacetonitrile.
    table 2
    Table 3
    thirty
    12.2 70.6 1.82
    Table 4.
    Toluene (8 volumes)
    ,
    "
    "
    10-30
    Valeronitrile.
    t Di-n-propyl acetonitrile.
    Three-n-propylacetonitrile.
    Editor S. Pekar
    Compiled by N. Kapitanova
    Tehred L. Serdyukova Proofreader G. Reshetnik
    Order 9P5 / 63 Circulation 372 Subscription to the State Committee of the USSR
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    Table 5
    sixteen
    22
    70.7 A, 9
    权利要求:
    Claims (1)
    [1]
    Claim
    M and M'- are identical or different and mean an atom of lithium, sodium or potassium, and the molar ratio of the components of the base is / LC 1
    MN: At 5 ohms, r 4 is 2-5: 1.
    in an organic solvent, a compound of the general formula III is introduced into the solution
    The method of obtaining alkyl substituted compounds of General formula 1
    R1-C-Z
    From where R, is a hydrogen atom or n-propyl ',
    R 4 is ethyl, and -propyl, isobutyl, dodecyl or benzene;
    R ^ is a hydrogen atom, n-propyl, iso-25 butyl or benzyl;
    Z is nitrile or carboxyl, comprising reacting a carboxylic acid derivative with an alkyl halide in an anhydrous organic solvent in the presence of a base, characterized in that, in order to simplify the process and expand the range of target products, a suspension of a complex base of the general formula 11
    I where R 4 is a hydrogen atom or ethyl,
    R g is alkyl containing 3-5 straight or branched chain carbon atoms, or the radical C g H 5 OCH 2 CH g ;
    r, ch 2 z, where R h Z have the indicated meanings, and a halide compound of the general formula IV where R 2 has the indicated meanings, X is a halogen atom in an organic solvent at a temperature of 0 - (+ 72) ° С, or a solution of a compound of the general formula Ш and a halide compound of the general formula GI in an organic solvent is introduced into a suspension of a complex base of the general formula P in an organic solvent at a temperature of (-10) - (+ 20) C, benzene, toluene, cyclohexane, isopropyl ether, tetrahydrofuran or a mixture thereof are used as a solvent and the reaction process is carried out at a temperature of (-10) - (+ 72) ° С, the obtained compound of the general formula 1, where R (and R 2 have the indicated values, and Rg is the hydrogen atom, are reintroduced into the process of interaction with the halide compound of the general formula Y
    R 3 X, where X has the indicated meanings,
    R 3 is n-propyl, isobutyl or benzyl.
    Table 1
    Solvent (6.4 volumes) Working conditions  VExit, Z Reaction temperature, ° C Duration of adding a COMPLEX base, min "1 eleven** 111 Benzene 45 ± 3 thirty 8.22 82,45 2,4 Cyclohexane 45 + 3 *5 1.66 86.14 2.68 Cncopropyl ether 40-45 60 4.6 87.1 3
    Valerianoic acid nitrile. * * Di - "- propylacetonitrile. ··· Tri-n-propylacetonitrile.
    table 2
    Solvent Working conditions Exit,% Reaction temperature° C The duration of the addition of a complex base, min 1* eleven** 111 ** ’ Toluene (6.4 volumes) 30-35 20 6.6 79.65 3.75 Benzene (5.6 volumes) 30-35 20 thirteen 71.8 4.8 Cyclohexane (6.4 volumes) 28-30 10 13.3 76 2,8 Benzene (4.8 Vol.) 30-35 32 7.6 78.8 6
    Valeronitrile ** Di-n-propylacetonitrile. *** Tri-n-propylacetonitrile.
    Table 3
    Solvent (6.6 volume)
    Working conditions
    Exit,% ,
    --------- Reaction temperature, C.
    The duration of adding a composite base, min
    1*
    eleven**
    111 ***
    Toluene 30-35 30 * Valeronitrile
    Di-N-ace is nitrile.
    Ktri-n-propylacetonitrile.
    12.2 70.6 1.82
    Table 4
    Solvent
    Working conditions Exit,% Reaction temperature, ° C The duration of adding a composite base, min 1* eleven** ***111
    Diisopropyl ether (10.8 volumes) 35
    60 21.5 56.8 2.1
    Cyclohexane (12.8 vol)
    40 + 2
    55 - 50.5 10 * Valeronitrile,
    Di-n-propylacetonitrile, * Tri-n-propylacetonitrile
    Table 5
    Solvent
    Working conditions Exit,% Temperatureabout_ Continue ... * "* reaction, C the stiffness of adding a composite base, min 1 eleven 111
    10-30
    70.7 4.9
    Toluene (8 volumes) * Valeronitrile.
    JL M, 4 ..
    Di-n-propylacetonitrile.
    Tri-n-propylacetonitrile.
    Compiled by N. Kapitanova Editor C, , Baker Tehred L. Serdyukova Proofreader G. Reshetnik
    Order 905/63 Circulation 372 Subscription
    VNIIIPI of the USSR State Committee for Inventions and Discoveries 113035, Moscow, Zh-35, Raushskaya nab., 4/5
    Production and printing company, Uzhhorod, st. Project, 4
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    同族专利:
    公开号 | 公开日
    IE51211B1|1986-11-12|
    NZ195753A|1983-07-15|
    PL228294A1|1981-08-07|
    AU534464B2|1984-02-02|
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    NO162380B|1989-09-11|
    JPS56127323A|1981-10-06|
    ZA807377B|1982-01-27|
    BR8008001A|1981-06-23|
    FI72508B|1987-02-27|
    CS221281B2|1983-04-29|
    IE802560L|1981-06-07|
    DK522080A|1981-06-08|
    BG47196A3|1990-05-15|
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    JPH0135809B2|1989-07-27|
    YU42230B|1988-06-30|
    EP0030528A1|1981-06-17|
    RO81453A|1983-04-29|
    DD155061A5|1982-05-12|
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    GB2066242A|1981-07-08|
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    ES8200068A1|1981-10-16|
    GB2066242B|1984-09-26|
    FI72508C|1987-06-08|
    AT3845T|1983-07-15|
    DK155045C|1989-06-26|
    DE3063918D1|1983-07-28|
    FI803793L|1981-06-08|
    引用文献:
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    US3301754A|1962-10-17|1967-01-31|Chemetron Corp|Methods and compositions for potentiating central nervous system depressants|
    US3936490A|1965-06-01|1976-02-03|Exxon Research And Engineering Company|Process for conducting organonitrile addition reactions|
    ES437790A1|1974-05-20|1977-05-16|Labaz|Therapeutic compositions containing methylamine derivatives or their salts|
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    JP2533651B2|1988-09-13|1996-09-11|財団法人相模中央化学研究所|Method for producing 2-oxo-3-aromatic carboxylic acid derivative|
    US4985402A|1990-04-25|1991-01-15|International Flavors & Fragrances Inc.|2-Methyl-1-nitrilo-2-methyl -1-hydroxylamino-3- propane, organoleptic uses thereof and processes for preparing same|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7930039A|FR2470758B1|1979-12-07|1979-12-07|
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