CN1229337C - 制备肟醚的方法 - Google Patents
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- -1 oxime ethers Chemical class 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 150000002923 oximes Chemical class 0.000 claims abstract description 13
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 7
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical class OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 claims abstract description 5
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- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical group ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 6
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- 238000010934 O-alkylation reaction Methods 0.000 description 1
- NEEBJNJJGNYFRB-UHFFFAOYSA-N S1C(=NCC1)NC(=O)N.CC(=CC)C Chemical compound S1C(=NCC1)NC(=O)N.CC(=CC)C NEEBJNJJGNYFRB-UHFFFAOYSA-N 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
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- 229960001708 magnesium carbonate Drugs 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/14—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
一种制备式I肟醚的方法,其中取代基R1和R2可分别是氰基、C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、苯基和萘基,R3可以是C1-C4烷基,该方法是使用选自卤代烷、硫酸二烷基酯和碳酸二烷基酯的烷基化试剂烷基化式II肟,其中反应在5-25%(重量)的选自腈、N-烷基吡咯烷酮、环脲衍生物、二甲基甲酰胺和二甲基乙酰胺的极性非质子溶剂,55-95%(重量)的选自脂族烃、芳族烃、烷基羧酸烷基酯和醚的非极性溶剂,和0-25%(重量)水的溶剂混合物中进行。
Description
本发明涉及一种制备式I肟醚的方法
其中取代基R1和R2可以相同或不同,各自可以是氰基、C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、苯基和萘基,R3可以是C1-C4烷基,所述方法是使用选自卤代烷、硫酸二烷基酯和碳酸二烷基酯的烷基化试剂于碱性条件下烷基化式II的肟,
其中反应在下列组成的混合物中进行:
5-25%(重量)的选自腈、N-烷基吡咯烷酮、环脲衍生物、二甲基甲酰胺和二甲基乙酰胺的极性非质子溶剂,
55-95%(重量)的选自脂族烃、芳族烃、烷基羧酸烷基酯和醚的非极性溶剂,和
0-25%(重量)的水,含量总和为100%。
从现有技术可以了解烷基化活性肟的方法。
Bull.Acad.Sci.USSR,Div.Chem.Sci.(Engl.Transl.),EN,第28卷,第121-128页(1979)描述了使用偶氮烷、卤代烷和硫酸二烷基酯的肟烷基化反应;特别试验研究了氧烷基化和氮烷基化之间的竞争。描述了在丙酮、乙醇、水或二乙基醚中,以一般产率制备α,α’-双羰基肟的O-烷基醚。为了有利于O-烷基化,由于硝酮是热不稳定的,建议采用尽可能高的温度,或烷基化试剂尽可能量大。
Ind.J.Chem.,第30B卷,第749-753页(1991)描述了其中R1和R2为甲基或苯基的式II肟的甲基化反应。在无水K2CO3存在下,在丙酮中与甲基碘化物反应生成O-甲基醚,产率为65%或67%。
WO-A00/18726描述了在各种溶剂中式II肟的烷基化反应。反应也可以在这些溶剂的混合物中进行。
当所述合成以工业规模进行时,使用含水溶剂混合物具有技术优势。但是,含水一般确实会导致产率下降。
本发明的目的是提供一种经济且工业可用的制备式I的肟O-烷基醚的方法,即使使用含水溶剂混合物,其具有高选择性和高产率,并且简单易于实施。
我们发现通过一种制备式I肟醚的方法可以达到上述目的
其中取代基R1和R2可以相同或不同,各自可以是氰基、C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、苯基和萘基,R3可以是C1-C4烷基,所述方法是使用选自卤代烷、硫酸二烷基酯和碳酸二烷基酯的烷基化试剂于碱性条件下烷基化式II肟,
其中反应在下列组成的混合物中进行:
5-25%(重量)的选自腈、N-烷基吡咯烷酮、环脲衍生物、二甲基甲酰胺和二甲基乙酰胺的极性非质子溶剂,
55-95%(重量)的选自脂族烃、芳族烃、烷基羧酸烷基酯和醚的非极性溶剂,和
适当时最高为25%(重量)的水。
与现有技术不同,本发明方法中令人惊奇地在中温没有观察到硝酮的形成,并且尽管使用了空间要求不高的烷基化试剂和基材,O-烷基醚仍以良好以至非常好的产率获得。
合适的碱一般是盐性化合物,例如碱金属和碱土金属的碳酸盐如碳酸钠、碳酸钾和碳酸镁等,和例如碱金属碳酸氢盐如碳酸氢钠,以及例如碱金属的乙酸盐如乙酸钠。碳酸钾为特别优选。
碱一般以等摩尔量或过量使用;已经证实过量10-30%在多种情况下是有利的。碱可以固体或溶液形式使用,特别是水溶液的形式。出于实际应用原因,优选使用至少10%(重量)至饱和的水溶液。
合适的溶剂是脂族烃例如戊烷、己烷、环己烷和石油醚,芳族烃例如甲苯、邻-、间-和对-二甲苯,卤代烃例如二氯甲烷、氯仿和氯苯,醚例如二乙醚、二异丙基醚、叔丁基甲基醚、二噁烷、苯甲醚和四氢呋喃,N-甲基吡咯烷酮,N-辛基吡咯烷酮,和环脲衍生物例如二甲基丙烯基脲,二甲基亚砜,二甲基甲酰胺和二甲基乙酰胺,特别优选二甲基甲酰胺和二甲基乙酰胺,芳族烃例如甲苯和醚例如叔丁基甲基醚。
反应在下列组成的溶剂混合物中进行:5-25%(重量)、优选10-20%(重量)的上述极性非质子溶剂,最高25%(重量)的水和至少5%(重量)、优选55-95%(重量)、特别优选60-90%(重量)、更优选60-80%(重量)的上述非极性溶剂。
因为技术的原因,本方法优选在含水溶剂混合物中进行。
合适的烷基化试剂是卤代烷、硫酸二烷基酯和碳酸二烷基酯。从经济的角度,硫酸二烷基酯为优选。
烷基化试剂一般以等摩尔量或过量使用;已经证实过量5-15%(重量)在许多情况下都比较有利。
为了安全,当使用卤代烷和硫酸二烷基酯时,一般在反应后使用氨或胺,例如经常使用二乙胺破坏剩余的烷基化试剂。
在本方法的一个优选实施方案中,使用甲基化试剂。
反应一般在0-100℃、优选0-50℃、更优选10-25℃温度下进行。反应温度一般设定为与肟的热稳定性相适应的温度。
反应物的添加顺序不是很严格。在本方法的一个优选实施方案中,将固体或水溶液形式的碱引入溶剂中,肟和烷基化试剂同时以等摩尔量加入溶剂混合物中,合适时溶剂混合物含有水。在另外一个优选实施方案中,将肟加入到部分或全部烷基化试剂中。
本发明方法不局限于具有特定取代的化合物,只要取代在反应条件下是惰性的就可以。脂族基可以是直链或支链。取代基的链长对本发明不是实质性因素,但出于技术的原因,一般选择碳原子不多于4个的基团。
本发明特别优选用于制备戊烷-2,3,4-三酮3-O-甲基肟。
烷基一般为C1-C10烷基,特别是C1-C4烷基,卤代烷亦如此;环烷基含有3-6个环原子。
取代基R1和R2可以携带在反应条件下为惰性的其它基团,作为实例可以提到的有:卤素、氰基、SO3H、COOH、COOR4、C1-C10烷基、C2-C8链烯基、C2-C8炔基、苯基或杂芳基;R4为C1-C10烷基。
杂芳基是,例如呋喃基、噻吩基、吡咯基、异噁唑基、异噻吩基、吡唑基、噁唑基、咪唑基、吡啶基、哒嗪基、嘧啶基或三嗪基。
卤素为氯、氟、溴或碘。
链烯基和炔基有2-8个、优选3-6个碳原子。
通过本发明方法获得的肟O-烷基醚适合用作制备染料的中间体或用作药物或用于作物保护的活性成分。
下面的对比实施例示出了本发明主要特征的作用;实施例的目的是对本发明作进一步说明:
对比实施例:
1.在丙酮中甲基化[Ind.J.Chem.,第30B卷,第749-753页(1991)]
在约20℃、冷却条件下,将12.9g戊烷-2,3,4三酮3-肟溶于38.5ml丙酮的溶液和15.6g甲基碘滴入16.6g碳酸钾于40ml丙酮中的悬浮液中。在约20℃搅拌2小时后,蒸馏除去溶剂。残留物溶于水中并用叔丁基甲基醚萃取。由合并有机相获得12g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为97%),相当于理论产率的81.5%。
2.在二甲基甲酰胺中(DMF)甲基化
在约20℃、冷却条件下,将12.9g戊烷-2,3,4三酮3-肟溶于38.5gDMF的溶液和13.9g的硫酸二甲酯(DMS)滴入16.6g碳酸钾于40g DMF的悬浮液中。在约20℃搅拌2小时后,加入2.2g二乙胺以破坏剩余的DMS,接着在约20℃再搅拌1小时,加入130ml水。溶液用叔丁基甲基醚萃取。用1N H2SO4清洗后,由合并有机相获得12.8g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为90%),相当于理论产率的80.5%。
3.在叔丁基甲基醚(MTBE)中甲基化
在约20℃、冷却条件下,将12.9g戊烷-2,3,4三酮3-肟溶于38.5gMTBE的溶液和13.9g的硫酸二甲酯(DMS)滴入16.6g碳酸钾于40gMTBE的悬浮液中。在约20℃搅拌2小时后,加入2.2g二乙胺以破坏剩余的DMS,接着在约20℃再搅拌1小时,加入80ml水。溶液用叔丁基甲基醚萃取。用1N H2SO4清洗后,由合并有机相获得9.9g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为76.7%),相当于理论产率的53%。
4.在叔丁基甲基醚/丙酮中甲基化(87∶13)
在约20℃、冷却条件下,将12.9g戊烷-2,3,4三酮3-肟溶于38.5gMTBE的溶液和13.9g的硫酸二甲酯(DMS)滴入16.6g碳酸钾于30g叔丁基甲基醚(MTBE)和10g丙酮混合物中的悬浮液中。在约20℃搅拌2小时后,加入2.2g二乙胺以破坏剩余的DMS,接着在约20℃再搅拌1小时,加入80ml水。溶液用叔丁基甲基醚萃取。用1N H2SO4清洗后,由合并有机相获得11g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为85.8%),相当于理论产率的70.0%。
5.在DMF/MTBE中甲基化(89∶11)
在约20℃、冷却条件下,将12.9g戊烷-2,3,4三酮3-肟溶于38.5gDMF的溶液和13.9g的硫酸二甲酯(DMS)滴入16.6g碳酸钾于32g二甲基甲酰胺(DMF)和8g叔丁基甲基醚(MTBE)混合物中的悬浮液中。在约20℃搅拌2小时后,加入2.2g二乙胺以破坏剩余的DMS,接着在约20℃再搅拌1小时,加入130ml水。溶液用叔丁基甲基醚萃取。用1N H2SO4清洗后,由合并有机相获得13.5g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为91.9%),相当于理论产率的86.7%。
6.在DMF/MTBE中甲基化(48∶52)[WO-A00/18726]
在一个20升的容器内,将4.5g(32.6mol)碳酸钾悬浮于3.2升甲基叔丁基醚和1升DMF中。在搅拌下将混合物冷却到0-10℃。在内部温度<25℃下,用时2小时计量加入含有4128g(32mol)戊烷-2,3,4三酮3-肟、2升DMF和4032g(32mol)硫酸二甲酯的溶液。室温下搅拌混合物3.5小时。接着计量加入约20升水,分离上层的有机相,用2升甲基叔丁基醚洗涤水相,用1升5%浓度的盐酸洗涤合并的有机相,然后蒸馏除去溶剂。得到4214g、纯度为96.9%的标题化合物(GC百分面积),相当于理论产率的89%。
7.在DMF/MTBE中甲基化(13∶87)
在约20℃、冷却条件下,将129.0g戊烷-2,3,4三酮3-肟溶于385gMTBE的溶液和138.7g的硫酸二甲酯(DMS)滴入165g碳酸钾于100g二甲基甲酰胺(DMF)和300g叔丁基甲基醚(MTBE)混合物中的悬浮液中。在约20℃搅拌2小时后,加入21.9g二乙胺以破坏剩余的DMS,接着在约20℃再搅拌1小时,加入800ml水。溶液用叔丁基甲基醚萃取。用1N H2SO4清洗后,由合并有机相获得144.6g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为96.5%),相当于理论产率的97.6%。
8.在DMF/MTBE/水中甲基化(13∶66∶20)
在约17-19℃、冷却条件下,将129g戊烷-2,3,4三酮3-肟溶于246gMTBE的溶液和132g硫酸二甲酯(DMS)滴入含有332g浓度为50%重量碳酸钾水溶液、110g二甲基甲酰(DMF)、300g叔丁基甲基醚(MTBE)和7g硫酸二甲酯混合物中。在约20℃搅拌2小时后,加入36.5g二乙胺以破坏剩余的DMS,并且在约20℃再搅拌1小时后加入600ml水。溶液用叔丁基甲基醚萃取。用1N H2SO4清洗后,由合并的有机相获得136.9g戊烷-2,3,4三酮3-O-甲基肟(GC分析纯度为96.3%),相当于理论产率的92.1%。
Claims (11)
2.如权利要求1所述的方法,其中醚被用作非极性溶剂。
3.如权利要求2所述的方法,其中使用叔丁基甲基醚。
4.如权利要求1所述的方法,其中反应在水存在的条件下进行。
5.如权利要求1-4中任意一项所述的方法,其中二甲基甲酰胺或二甲基乙酰胺用作极性溶剂。
6.如权利要求1-4中任意一项所述的方法,其中硫酸二烷基酯用作烷基化试剂。
7.如权利要求1-4中任意一项所述的方法,其中极性溶剂的含量为10-20重量%。
8.如权利要求1-4中任意一项所述的方法,其中使用的碱选自碳酸氢盐、碳酸盐和乙酸盐。
9.如权利要求8所述的方法,其中使用碱金属或碱土金属的碳酸盐、碱金属的碳酸氢盐或碱金属的乙酸盐。
10.如权利要求8所述的方法,其中使用碳酸钾。
11.如权利要求1-4中任意一项所述的方法,其中式I取代基R1、R2和R3各自是C1-C4烷基。
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