• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:

    公开号:SU1217251A3
    申请号:SU823495517
    申请日:1982-09-30
    公开日:1986-03-07
    发明作者:Абехерли Клавдио
    申请人:Лонца Аг (Фирма)；
    IPC主号:
    专利说明:

    f-1
    The invention relates to a process for the preparation of alkyl esters of 4-C | --C d-alkoxyacetoacetic acid, which can be used as intermediates for the preparation of drugs.
    The purpose of the invention is to increase the productivity of the process.
    Example, 77.4 g (1.43 mol) of sodium methoxide (97% strength) are weighed into 100 g of acetonitrile at room temperature. This thoroughly stirred suspension is added dropwise through a single funnel with a drop counter for 5-6 min. m, in an atmosphere of N 101.9 (0.67 mol), 97.5% w / w 4-chloro-acetoacetic acid methyl ester (molar ratio ether: alcohol 1: 2.13) is added, the temperature rises, it is maintained by cooling in the range of 68-70 ° C. As soon as the heat production ceases, the cooling water supply is turned off and hot water of 70 ° C is supplied to preheat eva. This mustard-colored gruel is stirred further at 70 ° C for 24-25 minutes and then slowly added with stirring into an ice-cooled solution from, 6 g of glacial acetic acid and 215 g of water. At the same time, 37–4% N: / o hydrochloric acid is added dropwise with the help of a burette, while the pH is maintained with a glass electrode between 4.5-8. By the end of the neutralization process, the pH is set at 6.1 i 0.1 ". To neutralize, 56.4 ml of hydrochloric acid (37.4%) is required. During neutralization, the temperature is kept between 30-35 ° C, The mixture is placed in a separatory funnel, after a short time, the layers are separated. The aqueous layer is extracted once with 200 ml of acetonitrile and then twice with 100 ml of acetonitrile. The combined organic phases are evaporated in a rotary evaporator at 30–35 ° C and pressures of 20 Torr to constant weight. The evaporated solvent is regenerated and used for the next batch. The raw product is distilled at 0.5–1.5 Torr / 90 s to obtain methyl ether 4-halogenacetoacetic acid, Yield 89.8 g, which is equal to 91.7% based on the ester used. Content of the product is 98.8%. Capacity with a total reaction time of about 30 minutes - 1.83 mol / h
    12
    Example 2 103.6 g (1.52 mol) of sodium methoxide are weighed into 143 g of acetonitrile at room temperature. In this suspension in the atmosphere of Ng
    108.6 g (0.66 mol) of 4-chloroacetoacetic acid ethyl ester (molar ratio of ether and alcohol: 1: 2.3) are added dropwise over 6-7 minutes. Temperature slightly
    rises and is kept for 26-30 min at 66-7l c,
    When processing as in Example 1, 103.9 g (90.4%) of 4-ethoxyacetoacetic acid ester with the content of the basic substance of 98.5% is obtained. Performance with a total reaction time of about -35 minutes is 1.55 mol / h.
    And p and me R 3. 84,6 g (1.60 mol)
    Sodium methylate is weighed at 15 ° C. in 180 ml of acetonitrile. 101.9 g (0.67 mol) of 4-chloroacetoacetate methyl ester is added dropwise to this suspension in a nitrogen atmosphere of B for 5-6 minutes.
    acids (molar ratio of ether and alcoholate 1: 2.38). The temperature slightly rises and is maintained for 23-26 minutes at 60 ° C. When treated as in Example 1, 86.2 g (88.0%) of 4-methoxyacetoacetic acid ester is obtained with a basic substance content of 98.9%. Performance with a total reaction time of about 30 minutes 1, 76 mol / h.
    Example 4, 77.4 g (1.43 mol) of sodium methoxide are weighed at room temperature in 100 g of acetonitrile. 101.9 g (0.67 mol) of 4-chloroacetoacetic acid methyl ester (molar ratio of ether and alcoholate 1: 2.13) are added dropwise to this suspension in a nitrogen atmosphere for 5-6 minutes. Temperature
    slightly increases and is held for 24-25 minutes at 80 C. At
    82.15 g (83.9%) of 4-methoxyacetoacetic acid ester with the content of the basic substance of 98.9% is obtained in the treatment analogously to Example 1. Performance with total duration
    about 30 min. 1, 70 mol / h, Pr imper 5. 77.4 g (1.43 mol) of sodium methylate at room temperature are weighed in 117 g of propionitrile. Add to this suspension dropwise in a nitrogen atmosphere for 5-6 minutes, 101.9 g (0.67 mol) of 4-chloroacetoacetic acid methyl ester (molar ratio of ether and
    3
    alcohol 1: 2,13). The temperature rises slightly and is maintained for 24-25 minutes at 7 ° C. When processing as in Example 1, 88.4 g (90.3%) of 4-methoxyacetoacetic acid ester is obtained with a basic substance content of 99.1%. Performance with a total reaction time of about 30 minutes is 1.80 mol / h.
    Example 6 77.4 (1.43 mol) sodium methoxide is weighed at room temperature with 116 g of isobutyronitrile. 101.9 g (0.67 mol) of 4-chloroacetoacetic acid methyl ester (molar ratio of ether and alcoholate 1: 2.13) are added dropwise to this suspension under nitrogen at room temperature for 5-6 minutes. . The temperature slightly rises and is kept for 24-25 minutes at. When treated as in Example 1, 77.0 g (78.7%) of 4-methoxyacetoacetic acid ester with a basic substance content of 97.6% is obtained. Performance with a total reaction time of about 30 minutes 1.57 mol / h.
    Example 7. 86.4 (1.60 mol) of sodium methoxide are weighed into 150 ml of tetrahydrofuran at room temperature. 101.9 g (0.67 mol) of 4-chloroacetoacetic acid methyl ester (molar ratio of ether and alcoholate 1: 2.31) are added dropwise to this slurry under nitrogen atmosphere for 5-6 minutes. The temperature rises slightly and is held for 26-29 minutes at 62-65 ° C. When processing as in Example 1, 81.2 g (83%) of 4-methoxyacetoacetic acid ester with a content of the main substance of 99% is obtained. Performance with a total reaction time of about 35 minutes 1.51 mol / h.
    Example 8.147.4 g (1.53 mol of sodium butylate) is weighed at room temperature in 150 g of acetonitrile. 130.0 (0.67 mol) butyl is added dropwise to this slurry under nitrogen atmosphere for 5-6 minutes 4-chloradetoacetic acid ester (molar ratio of ether and alcoholate 1: 2.28). The temperature slightly rises and holds it for 30 minutes at 69-71 C. During processing as in Example 1, get 137.1 (88.9% a) 4-butoxyacetoacetic acid ester with a basic substance content of 97.8%. Performance
    s 0 5
    about
    five
    five
    51
    with a total reaction time of about
    35 min 1.52 mol / h
    Example 9. Analogously to Example 1, 148.7 g (0.66 mol) of 2-ethyl-4-bromoacetoacetic acid methyl ester is reacted with 163.4 g (2.33 mol) of potassium methylate (molar ratio of ether and alkali l that 1: 3.5) in 250 ml of propionitrile for 1.5 hours at 50 ° C. 2-ethyl-4-methoxyacetoacetic acid methyl ester is obtained in a yield of 80.4 g, which corresponds to 69.3% based on 2-ethyl-4-bromoacetoacetic acid methyl ester used. Content of the main substance is 94.6%. Performance with a total reaction time of about 90 min. 0.46 mol / h.
    Example 10 1.761 g (14 mmol) of sodium hexylate with a content of the main substance of 94.1% are weighed in 15 ml of isobutyronitrile at 10 ° C. To this thoroughly stirred suspension for 2 minutes, add 1.4646 g. g (6.98 mmol) of tert-butyl butyl 4-chloroacetoacetic acid ester (molar ratio of ester and alcoholate 1: 2). The temperature rises slightly and is maintained at 78 ° C by appropriate heating. The brown reaction mixture is kept at this temperature for 34 minutes and then, by introducing a solution of such a calculated amount of potassium dihydrogen phosphate in 50 ml of water, is neutralized and processed in a similar way. 1.275 g of tert-butyl 4-hexyloxy-acetic-acetic acid is obtained, corresponding to a yield of 68.7% based on the 4-chloroacetoacetic acid tert-butyl ester used. The product content is 92.8%. Performance with a total reaction time of about 35 minutes 1.18 mol / h.
    Example 11. Analogously to Example 1, 134.6 mg (0.698 mmol) of tert-butyl 4-chloroacetoacetic acid are reacted with 399.7 mg (1.3 mmol) of potassium salt of stearyl alcohol (molar ratio of ether and alcoholate 1: 1 , 86) in 12 ml of isobutyronitrile at 100 C for 26 minutes. 0.19 g (34.1%) of 4-octadecyloxyacetoacetic acid tert-butyl ester is obtained with a basic substance content of 93.6%. Performance
    with a total reaction time of about 26 minutes, 0.80 mol / h.
    Example 12. Analogously to example 1, 181.3 g (0.68 mol) of isopropyl 2-isopropyl-4-bromoacetoacetic acid are reacted in 180 g of adetonitrile with 157.9 (1.92 mol) sodium isopropylate (molar the ratio of ether and alcohol is 1: 2.82) at 91 ° C (reaction time is 12 minutes). 133.0 g of 2-eE-propyl-4-isopropyloxy-acetoacetic acid isopropyl ester is obtained, which corresponds to a yield of 81.7% based on the ester used. The content of the product is 94%. Performance with a total reaction time of about 12 minutes 4.10 mol / h.
    Example 13. Analogously to Example 1, 1.570 g (7.2 mmol) of 2 (3-methyl-but-3-en-1-yl) -4-chloroacetoacetic acid ethyl ester is reacted with 3.9226 g (72.6 mmol) sodium ethylate Resin, the ratio of ether and alcoholate 1:10) in 445 g of acetonitrile at 80 ° C for 27 minutes. 1.279 g of 2- (3-methyl-but-3-en-1-yl) -4-ethoxyacetoacetic acid ethyl ester are obtained, which corresponds to a yield of 78.8%. The content of the product is 97.6%. Performance with a total reaction time of about 27 minutes 1.75 mol / h.
    Example 14. Analogously to Example 10, 229.0 mg (0.965 mmol) of 4-bromoacetoacetic acid butyl ester is treated with 351.6 mg (1.566 mmol) of the potassium salt of lauryl alcohol (the molar ratio of ether and alcohol is 1: 1, 6 ) in propionitrile at 97 ° C for 37 minutes, the yield is 195.3 mg, which corresponds to 59.1% based on the ester used. Product Content 97.9%. Performance with a total reaction time of about 37 minutes 1.00 mol / h.
    Example 15. Analogously to Example 1, 21.53 g (0.067 mol) of 2-dodecyl-4-chloroacetoacetic acid methyl ester is reacted with 35.661 g (0.66 mol) of sodium methylate (molar ratio of ether and alcoholate 1 : 9.85) in 85 ml of acetonitrile at 50 ° C for 80 minutes. 15.8 g are obtained, which corresponds to 74.7% based on the ester of 2-dodecyl-4-methoxyacetoacetic acid methyl ester used. The product content is 98.1%. Performance with a total reaction time of about
    80 min 0.56 mol / h.
    For example 16. 77.4 g (1.43 mol) of sodium methoxide are weighed into 100 g of acetonitrile at room temperature. Gur this suspension is added dropwise under nitrogen atmosphere for 5-6 minutes 107.65 g (0.715 mol ) 4-chloroacetoacetic acid methyl ester (molar ratio of alcoholate and ester: 2.0: 1). The temperature slightly rises and is kept at 70 ° C for 26-28 minutes. When processing as in Example 1, 78.8 g (75.4%) of 4-methoxyacetoacetic ester with a basic substance content of 97.6% is obtained. Performance with a total reaction time of about 32 minutes 1.41 mol / h.
    Example 17. 54.03 (1.0 mol)
    Sodium methylate is weighed into 80 g of acetonitrile at room temperature. To this slurry is added dropwise under nitrogen atmosphere over
    5-6 min 15.06 g (0.1 mol) of methyl 4-chloroacetoacetic acid ester (molar ratio of alcoholate and ester 10: 1). The temperature slightly rises and is kept at 70 ° C for 20-24 minutes. When treated in the same way as in Example 1, 9.4 g (64.3%) of 4-methoxyacetoacetic ester with a content of the main product of 96.7% is obtained. Performance with a total reaction time of about 27 minutes 1.43 mol / h.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 4- C, -C, 8- ALKOXYACETACY ACETIC ACID FROM “- ^ - ALKYL ETHERS by reacting 4-chloro-or 4-bromoacetoacetic acid esters with an alkali metal alcoholate in an aprotic solvent at a molar ratio of 4-chloro ether of bromoacetoacetic acid and an alkali metal alcoholate 1: 1.6-10, with the aim of increasing the productivity of the process, the latter is carried out at 50-100 C using aprotic a solvent of a substance selected from the group: acetonitrile, propionit- * ril, tetrahydride rofuran, isobutyronitrile.
    t -121
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH632081|1981-10-01|
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