CN106414417A - 制备二氢异噁唑衍生物的方法 - Google Patents
制备二氢异噁唑衍生物的方法 Download PDFInfo
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- CN106414417A CN106414417A CN201580027637.2A CN201580027637A CN106414417A CN 106414417 A CN106414417 A CN 106414417A CN 201580027637 A CN201580027637 A CN 201580027637A CN 106414417 A CN106414417 A CN 106414417A
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- 125000005048 dihydroisoxazolyl group Chemical class O1N(CC=C1)* 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- -1 Phenyl Chemical group 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- JHJQEZBIBPURIF-UHFFFAOYSA-N n,n-dichlorohydroxylamine Chemical compound ON(Cl)Cl JHJQEZBIBPURIF-UHFFFAOYSA-N 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 230000008030 elimination Effects 0.000 claims description 3
- 238000003379 elimination reaction Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
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- 239000000203 mixture Substances 0.000 description 15
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- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
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- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
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- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- LZJHACNNMBYMSO-UHFFFAOYSA-N 1,1-dimethyl-3-propylurea Chemical compound CCCNC(=O)N(C)C LZJHACNNMBYMSO-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- ZKZZLGBUKOYGKT-UHFFFAOYSA-N 1-chloro-3-hydroxyiminopropan-2-one Chemical compound ON=CC(=O)CCl ZKZZLGBUKOYGKT-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- ITIROJLQLPHMEQ-UHFFFAOYSA-N 3-chloro-2-ethenylphenol Chemical compound OC1=CC=CC(Cl)=C1C=C ITIROJLQLPHMEQ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 241000791201 Placobdella ali Species 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
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- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
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- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- UXOLDCOJRAMLTQ-UTCJRWHESA-N ethyl (2z)-2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(\Cl)=N\O UXOLDCOJRAMLTQ-UTCJRWHESA-N 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
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- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Plant Pathology (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种制备二氢异噁唑衍生物的新方法。
Description
本发明涉及一种制备二氢异噁唑衍生物的新方法。
二氢异噁唑是杀真菌或除草剂活性成分的有价值的前体(US 2011/0223257 A1、WO 1995/007897 A1)或像抗癌HDAC-抑制剂那样的有价值的药物(WO 2008/006561 A1)。
已知的二氢异噁唑衍生物通过用异羟肟酸衍生物处理不饱和酮并随后进行闭环而制备(方案1)。实例可见于下述文献中：A.A.R.Mohamed和M.H.A.Eman,Monatsh.Chem.,140,229(2009)；T.Shah和V.Desai,J.Serb.Chem.Soc.,72,443(2007)；S.B.Lohiya和B.J.Ghiya,Indian J.Chem.,25B,279(1996)；S.R.Mohane,V.G.Thakare和B.N.Berad,Asian J.Chem.,21,7422(2009)；V.Tiwari,P.Ali和J.Meshram,Ultrasonics Sonochem.,18,911(2011)；或M.Kidwai,S.Kukreja和R.Thakur,Lett.Org.Chem.,3,135(2006)。
方案1：
该方法的缺点在于会出现结构异构体，而且需要多步才能得到最终产品。
或者，二氢异噁唑衍生物可通过1,3-偶极体(1,3-dipole)加成制备(Tetrahedron2000,56,1057–1064；Chemical&Pharmaceutical Bulletin 1976,24,1757或WO2011/085170)(方案2)：：
该方法的缺点在于必须使用碱，其——根据起始物料中是否存在不稳定的官能团——可引起副反应。如果发生任何副反应，通常导致收率降低。
鉴于上述现有技术，本发明的目的是提供一种没有上述缺点的方法，并由此提供一种制备高收率二氢异噁唑衍生物的路径。
上述目的通过一种制备式(I)的二氢异噁唑的方法实现，
其中，
R1为酮(a)
R2为任选地被通常互相独立的卤素和C1-C4烷基磺酰基氧基取代一次或多次的苯基；
R3选自氯或溴；
其特征在于，在碱、酸和酸性pH的溶剂的存在下，，式(II)的羟基亚氨基氯化物通过消除反应得到式(III)的化合物，
其中，
R3如上所定义，
式(III)的化合物在加入(IV)后原位转化为式(I)的化合物，
其中R2如上所定义。
出人意料地，式(I)的吡唑可在本发明的条件下以良好的收率和高纯度制备，这意味着本发明的方法克服了现有技术在之前所述的制备方法的上述缺点。
认为该反应出人意料的是，在pH小于7(酸性)的条件下，预料不到地由式(II)的化合物消除HCl。正相反，这些条件通常用于制备羟基亚氨基氯化物，例如在J.Org.Chem.45,3916(1980)或US 5,064,844中所记载的。因此，极其出人意料地发现，在明显低于7的pH值下，优选在pH 3和pH 5之间，可有效地生成1,3-偶极体(式III)并随后由烯烃衍生物捕获而形成式(I)的化合物。
优选地，在本发明方法中式(I)、(II)、(III)和(IV)的化合物的残基定义如下：
R1为酮(a)
R2为被氯和甲基磺酰基氧基取代的苯基；
R3为氯。
一般定义
任选取代的基团可为单取代或多取代的，其中在多取代的情况下，这些取代基可相同或不同。
在上式给出的符号的定义中，使用的统称术语通常代表以下取代基：
卤素：氟、氯、溴和碘，优选氟、氯、溴，且更优选氯。
烷基：具有1至4个碳原子的饱和的直链或支链烃基，例如(但不限于)C1-C4烷基，如甲基、乙基、丙基、1-甲基乙基、丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基。该定义也适用于作为复合取代基(例如烷基磺酰基、烷氧基)一部分的烷基。
本发明的化合物可以以可能的任何不同的异构形式的混合物存在，尤其是以立体异构体(例如E和Z异构体、苏型和赤型异构体)和光学异构体的混合物存在，但是如果有的话，也可以互变异构体的形式存在。公开并请求保护E和Z异构体，同样，也公开并请求保护苏型和赤型异构体、光学异构体及这些异构体的混合物，以及可能的互变异构形式。
方法说明
该方法如方案3所示：
方案3
在碱、酸和酸性pH的溶剂的存在下，式(II)的羟基亚氨基氯化物通过消除反应得到式(III)的化合物，式(III)的化合物在加入(IV)后原位转化为式(I)的化合物。
对于本发明的反应，必须控制pH值。该反应通过下述过程进行：在酸性条件下，加入缓冲体系或加入弱碱以捕获自发消除的HCl，从而确保式(IV)、(III)或(I)的化合物不再发生去质子化。优选地，，pH值在pH 3和pH 5之间，更优选在pH 3.5和pH 4.5之间。
弱碱可例如选自：碳酸氢盐，如碳酸氢钠或碳酸氢钾；或磷酸氢盐，如磷酸(二)氢(二)钠或磷酸(二)氢(二)钾；或有机酸的碱性盐，如乙酸钠或苯甲酸钠。优选碳酸氢钠。
缓冲体系由弱酸和弱酸的盐组成，例如可选自：乙酸/乙酸钠或乙酸/乙酸铵或甲酸/甲酸钠或二氢磷酸盐/一氢磷酸盐。优选乙酸/乙酸钠。
该反应可在选自下述的溶剂中进行：卤代烷，例如二氯甲烷或1,2-二氯乙烷；或芳香族化合物，例如苯、甲苯、二甲苯、氯苯、二氯苯；极性非质子溶剂，例如N,N-二烷基甲酰胺、N,N-二烷基乙酰胺、N-甲基吡咯烷酮、二甲基丙烯基脲、四甲基脲；或腈，例如乙腈、丙腈或丁腈；或醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇或异丁醇；醚，例如二乙醚、叔丁基甲基醚、二异丙基醚；酮，例如丙酮、甲基异丁基酮；羧酸酯，例如乙酸乙酯、乙酸丁酯。该反应可在这些溶剂的混合物中进行。优选该反应在乙腈、乙酸乙酯或其混合物中进行。有利地，该反应可在水的存在下进行。
该反应可在-10℃至所用溶剂的沸点、优选0℃至50℃、更优选5℃至40℃的温度范围内进行。
式(II)的化合物是已知的，且可如J.Org.Chem.45,3916(1980)或US5,064,844中所记载的过程制备。
式(IV)的化合物是公知的。其为市售可得的，或可按照下述标准文献中记载的步骤制备：例如“有机合成(Organic Synthesis)”，如有机合成1928,8,84；有机合成1948,28,31；有机合成1953,33,62；有机合成1966,46,89；有机合成2006,83,45。
实施例
3-氯-2-乙烯基苯基甲磺酸酯的制备
将6g(0.038mol)溶解在50ml甲苯中的3-氯-2-乙烯基苯酚冷却至0-5℃。在0-5℃下在15分钟内，加入4.4g(0.043mol)三乙胺，然后加入4.9g(0.043mol)甲磺酸氯化物于5ml甲苯中的溶液。搅拌1小时后，将该反应混合物倒在冰上。相得到分离，将水相用25ml甲苯萃取。将合并的有机相用25ml水洗涤。在30℃下真空蒸出溶剂，，然后将残留物在庚烷/叔丁基甲基醚中结晶。
得到5g纯度为95％的3-氯-2-乙烯基苯基甲磺酸酯(收率：56％)。
3-氯-2-[3-(氯乙酰基)-4,5-二氢-1,2-噁唑-5-基]苯基甲磺酸酯的制备
将92g(0.55mol)4-氯乙酰乙酸乙酯和542g 37％的盐酸的混合物在25℃下搅拌24小时。在40℃下将该混合物真空浓缩至320g，然后冷却至5℃。加入215g 20％的氢氧化钠，以使内部温度不超过10℃。将该混合物冷却至0℃，再在15分钟内加入159g 20％的亚硝酸钠溶液。观察到气体放出，并最终使1-氯-3-(羟基亚氨基)丙酮沉淀。在0℃下搅拌30分钟后，将该混合物用360ml乙酸乙酯萃取一次，再用每次120ml乙酸乙酯萃取两次。向合并的有机相中加入51g碳酸氢钠和29g水。在0-5℃的温度下在30分钟内引入37.6g氯气。在0-5℃下搅拌30分钟后，分离出一半混合物，向其中加入46.4g 3-氯-2-乙烯基苯基甲磺酸酯(0.199mol)。将该混合物加热至35℃并搅拌，同时通过加入25％的碳酸氢钾水溶液将该混合物的pH调节到4.3至4.5。1小时后，加入另一半的氯肟溶液。在35℃下继续再搅拌4小时，同时用总量129g 25％的碳酸氢钾将pH保持在4.3至4.5。将混合物冷却至20℃，并使相分离。有机相在30℃下真空浓缩至106g。将160ml乙醇加入残油中，并将该混合物加热至70℃。然后，将该混合物通过中间晶种缓慢地冷却至20℃。有产物沉淀出，并在0℃下继续搅拌1小时。将产物滤出，用冷的乙醇洗涤，然后在30℃下真空干燥。
得到55.6g纯度为97％的3-氯-2-[3-(氯乙酰基)-4,5-二氢-1,2-噁唑-5-基]苯基甲磺酸酯(收率：77％)。
Claims (5)
1.制备式(I)的二氢异噁唑的方法，
其中，
R1为酮(a)
R2为任选地被通常互相独立的卤素和C1-C4烷基磺酰基氧基取代一次或多次的苯基；
R3选自氯或溴；
其特征在于，在碱、酸和酸性pH的溶剂的存在下，，式(II)的羟基亚氨基氯化物通过消除反应得到式(III)的化合物，
其中，
R3如上所定义，
式(III)的化合物在加入(IV)后原位转化为式(I)的化合物，
其中R2如上所定义。
2.根据权利要求1所述的方法，其特征在于，
R1为酮(a)
R2为被氯和甲基磺酰基氧基取代的苯基；
R3为氯。
3.根据权利要求1和2所述的方法，其中pH为3..5至4.5。
4.根据权利要求1-3中任一项所述的方法，其中使用包含乙酸和乙酸钠的缓冲液。
5.权利要求1-4的式(I)的化合物用于制备杀真菌剂的用途。
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| CN102791133A (zh) * | 2010-01-07 | 2012-11-21 | 纳幕尔杜邦公司 | 杀真菌杂环化合物 |
| WO2013098229A2 (de) * | 2011-12-27 | 2013-07-04 | Bayer Intellectual Property Gmbh | Heteroarylpiperidin und -piperazinderivate als fungizide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| OA09122A (en) | 1988-07-08 | 1991-10-31 | Schering Agrochemicals Ltd | Triazole insecticides. |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101970432A (zh) * | 2008-01-25 | 2011-02-09 | 杜邦公司 | 杀真菌杂环化合物 |
| CN102791133A (zh) * | 2010-01-07 | 2012-11-21 | 纳幕尔杜邦公司 | 杀真菌杂环化合物 |
| WO2013098229A2 (de) * | 2011-12-27 | 2013-07-04 | Bayer Intellectual Property Gmbh | Heteroarylpiperidin und -piperazinderivate als fungizide |
Non-Patent Citations (1)
| Title |
|---|
| HIDEMITSU UNO ET AL.: "Stepwise Intramolecular Cycloaddition of Nitrile Oxide Equivalents Derived from the Lewis Acid-promoted Reaction of 1 -Nitroalkadienes and Allylic Stannanes", 《J.CHEM.SOC.PERKIN TRANS I》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI844692B (zh) * | 2019-06-14 | 2024-06-11 | 日商組合化學工業股份有限公司 | 二氫異噁唑的製造方法 |
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