CN1028360C - 制备普鲁卡因的方法 - Google Patents

制备普鲁卡因的方法 Download PDF

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CN1028360C
CN1028360C CN91111746.6A CN91111746A CN1028360C CN 1028360 C CN1028360 C CN 1028360C CN 91111746 A CN91111746 A CN 91111746A CN 1028360 C CN1028360 C CN 1028360C
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reaction
alcohol
carry out
transesterification reaction
out transesterification
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CN1062722A (zh
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E·A·尤根斯
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Steroid Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Compounds Of Unknown Constitution (AREA)
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Abstract

制备普鲁卡因的方法，其特征在于，按已知方式使对一硝基苯甲酸在丁醇中酯化，得到的硝基酯不经中间分离而催化加氢，在蒸去大部分所用醇后，在碱金属醇盐存在下、于80-150℃、最好80-130℃用二乙基氨基乙醇与加氢溶液反应，并在负压下不断去掉反应释放出来的醇。

Description

对-氨基苯甲酸二乙基氨基乙酯（普鲁卡因）通常是通过对-硝基苯甲酰氯与二乙基氨基乙醇反应并随后催化加氢而制得。同时，用硫酸作催化剂、用二乙基氨基乙醇使对-氨基苯甲酸酯化的方法也是已知的（USP812554）。在奥地利专利说明书213874中，叙述了在醇钠（钠溶于二乙基氨基乙醇中）存在下，通过对一氨基苯甲酸酯与二乙基氨基乙醇的反应而制备普鲁卡因的方法。在该反应中释放出来的醇要从反应混合物中连续地除去。为了避免副产物，反应温度不应超过100℃。同时，在蒸出过剩的烷基胺时也应保持在该温度限之内。通常只用易于反应的甲酯作为反应原料酯。
用于制得甲酯和乙酯的反应原料是对-氨基苯甲酸或对-硝基苯甲酸。为了获得好的产率，在酯化中必须添加一种带水剂如苯以除去水。令人惊异的是现已确知，对反应性较低的丁酯而言，不必遵守上述温度限，且可能连续除去反应中释放出来的醇。随后在工作温度高至165℃的范围内，可在一个显然较高的温度下蒸出过量的烷基胺而不降低产量。这意味着有可能显著地减小真空度，与奥地利专利所示的压力35到60毫巴相比，它的压力为150到200毫巴。大规模工业实施本方法具有显著的优点。还进一步发现，如通 过硝基苯甲酸的酯化并随后还原而得的质量较差的对一氨基苯甲酸丁酯也能够在醇钠存在下与二乙基氨基乙醇进行酯交换。按照本发明方法，取消了高损耗和很费钱的中间分离，而且易于沸腾的醇如甲醇以及讨厌的带水剂如苯也不需要了。丁醇是一种蒸汽压较低的溶剂，因而这种方法成为一种不需大量附加措施而对环境无害的方法。
在添加较少量硫酸的情况下，对一硝基苯甲酸在丁醇中酯化，并随后使该硝基酯催化加氢。除去过量的醇，并在添加二乙基氨基乙醇和少量醇钠之后，在80-150℃、优选80-130℃、特别优选的是80-110℃、尤其是在90-95℃下，实施酯交换反应。反应中释放出的丁醇在负压下连续排出。反应结束后，通过加入酸或水以破坏催化剂。升温至150℃在负压下蒸去过量的二乙基氨基乙醇，剩余物或在高真空下蒸馏，或溶解在乙酸丁酯中，用氯化氢沉淀得普鲁卡因的氢氯化物。以所用的对一硝基苯甲酸为基准，此法所得的普鲁卡因为理论值的94%，这相当于级收率高于98%理论值。
本方法的巨大优点在于，在酯化时不必为除水而采用助溶剂，因为其蒸汽显然较低，故从其逸散角度看，丁醇的处理更简单，回收率显然更高。此外，该方法不进行中间产物的分离
实施例1
把16.7g对-硝基苯甲酸置于具有0.02ml硫酸的40ml丁醇中加热至沸腾，形成的反应水在一个捕集器中分出。一旦不能再 分出水且转化完全后，冷却至60℃并加入0.1g苏打。加入0.5gPd/碳催化剂后，在10bar的氢压、50-100℃下加氢，在耗氢停止后，冷却至50℃，检查pH值，必要时用少许几滴氢氧化钠调节至pH为9。然后，把大部分丁醇在负压下蒸出直至110℃。加入40ml二乙基氨基乙醇后，为了达到无水态，再蒸出约3ml，然后再加入0.2g甲醇钠并在100-110℃从一个约150mbar的真空塔中连续地释放出来的丁醇。反应结束后，加入0.2ml冰醋酸。过量的二乙基氨基乙醇在负压下蒸馏出来直至内部温度为150℃。剩余物或是在高真空下蒸馏，以得到普鲁卡因碱，或是冷却到60℃后溶于100ml乙酸丁酯和50ml水中，加入氢氧化钠溶液以调节pH至11，作相分离，有机相再用50ml水萃取。把氯化氢通入乙酸丁酯溶液中直至pH为6，使普鲁卡因的氢氯化物沉淀下来。产量为26g，或为计算值的95%，再次沉淀后该化合物在154℃熔化。
实施例2
重复实施例1所述步骤，但酯交换反应的温度降到90-95℃。在4-5小时内将完全转化。
同样按实施例1所述步骤进行分离，获得的产量实际上相同。

Claims (4)

1、制备普鲁卡因的方法，其特征在于，在丁醇中用已知方法使对-硝基苯甲酸酯化，得到的硝基酯无需中间分离而催化加氢，在蒸掉大部分所用的醇后，得到的加氢溶液在碱金属醇盐存在下、在80-150℃与二乙基氨基乙醇反应，并在负压下不断地除去反应释放出来的醇。
2、按权利要求1的方法，其特征在于，在80-130℃进行酯交换反应。
3、按权利要求1的方法，其特征在于，在80-110℃进行酯交换反应。
4、按权利要求1的方法，其特征在于，在90-95℃进行酯交换反应。
CN91111746.6A 1990-12-21 1991-12-20 制备普鲁卡因的方法 Expired - Fee Related CN1028360C (zh)

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DEP4041179.6 1990-12-21
DE4041179A DE4041179A1 (de) 1990-12-21 1990-12-21 Verfahren zur herstellung von procain

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DE (3) DE4042433A1 (zh)
DK (1) DK0492494T3 (zh)
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US1396913A (en) * 1917-10-11 1921-11-15 Levinstein Ltd Production of aminoalkylesters and of alkylaminoalkylesters of para aminobenzoic acid
US1676470A (en) * 1921-09-27 1928-07-10 Abbott Lab Production of esters of aromatic acids
AT213874B (de) * 1958-08-22 1961-03-10 Leuna Werke Veb Verfahren zur Herstellung von p-Aminobenzoesäurealkaminestern
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EP0492494B1 (de) 1996-07-31
EP0492494A1 (de) 1992-07-01
DE4042433A1 (de) 1992-09-03
CS392291A3 (en) 1992-07-15
HU914076D0 (en) 1992-03-30
DE4041179A1 (de) 1992-07-02
ES2091855T3 (es) 1996-11-16
JPH04295452A (ja) 1992-10-20
GR3020704T3 (en) 1996-11-30
MX9102747A (es) 1992-06-01
CN1062722A (zh) 1992-07-15
ATE140915T1 (de) 1996-08-15
DK0492494T3 (da) 1996-12-02
HUT59657A (en) 1992-06-29
CZ282438B6 (cs) 1997-07-16
HU208303B (en) 1993-09-28
DE59108052D1 (de) 1996-09-05

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