CN1228075A - Process for preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity - Google Patents
Process for preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity Download PDFInfo
- Publication number
- CN1228075A CN1228075A CN97197382.2A CN97197382A CN1228075A CN 1228075 A CN1228075 A CN 1228075A CN 97197382 A CN97197382 A CN 97197382A CN 1228075 A CN1228075 A CN 1228075A
- Authority
- CN
- China
- Prior art keywords
- general formula
- compound
- alkyl
- halogen
- haloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 272
- 230000008569 process Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title description 36
- 230000002363 herbicidal effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 382
- -1 alkyl-substituted benzene compounds Chemical class 0.000 claims abstract description 124
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 77
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical class C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 claims abstract description 63
- 150000003217 pyrazoles Chemical class 0.000 claims abstract description 36
- 230000001590 oxidative effect Effects 0.000 claims abstract description 16
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 216
- 238000006243 chemical reaction Methods 0.000 claims description 178
- 239000011541 reaction mixture Substances 0.000 claims description 126
- 229910052736 halogen Inorganic materials 0.000 claims description 102
- 150000002367 halogens Chemical class 0.000 claims description 91
- 238000005804 alkylation reaction Methods 0.000 claims description 72
- 238000005886 esterification reaction Methods 0.000 claims description 72
- 230000032050 esterification Effects 0.000 claims description 71
- 230000029936 alkylation Effects 0.000 claims description 70
- 239000000758 substrate Substances 0.000 claims description 68
- 239000003795 chemical substances by application Substances 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 60
- 230000003647 oxidation Effects 0.000 claims description 57
- 238000007254 oxidation reaction Methods 0.000 claims description 57
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 53
- 230000026030 halogenation Effects 0.000 claims description 53
- 238000005658 halogenation reaction Methods 0.000 claims description 53
- 150000001266 acyl halides Chemical class 0.000 claims description 47
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 42
- 239000000460 chlorine Substances 0.000 claims description 41
- 239000002243 precursor Substances 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 125000002252 acyl group Chemical class 0.000 claims description 39
- 238000009833 condensation Methods 0.000 claims description 39
- 230000005494 condensation Effects 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 34
- 230000002378 acidificating effect Effects 0.000 claims description 34
- 238000005893 bromination reaction Methods 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 125000001188 haloalkyl group Chemical group 0.000 claims description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 239000002168 alkylating agent Substances 0.000 claims description 30
- 229940100198 alkylating agent Drugs 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 29
- 230000031709 bromination Effects 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- 125000004414 alkyl thio group Chemical group 0.000 claims description 27
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 27
- 125000005252 haloacyl group Chemical group 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 26
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 24
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 23
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 21
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 17
- 229910052751 metal Inorganic materials 0.000 claims description 17
- 239000002184 metal Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 235000002639 sodium chloride Nutrition 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 16
- 150000003842 bromide salts Chemical class 0.000 claims description 16
- 229910001882 dioxygen Inorganic materials 0.000 claims description 16
- 230000002140 halogenating effect Effects 0.000 claims description 16
- 150000002905 orthoesters Chemical class 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 15
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 15
- 238000001556 precipitation Methods 0.000 claims description 15
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 239000005864 Sulphur Substances 0.000 claims description 11
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 11
- 239000012346 acetyl chloride Substances 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 6
- 230000005595 deprotonation Effects 0.000 claims description 6
- 238000010537 deprotonation reaction Methods 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical group OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims description 5
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 101100246550 Caenorhabditis elegans pyr-1 gene Proteins 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 150000002429 hydrazines Chemical class 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000011 acetone peroxide Substances 0.000 claims description 2
- 235000019401 acetone peroxide Nutrition 0.000 claims description 2
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000622 liquid--liquid extraction Methods 0.000 claims description 2
- 125000005527 methyl sulfate group Chemical group 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 13
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 230000010933 acylation Effects 0.000 claims 3
- 239000002671 adjuvant Substances 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 229910014265 BrCl Inorganic materials 0.000 claims 1
- 150000008050 dialkyl sulfates Chemical group 0.000 claims 1
- 150000003333 secondary alcohols Chemical class 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 235000012976 tarts Nutrition 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 69
- 230000002152 alkylating effect Effects 0.000 abstract description 6
- 125000005907 alkyl ester group Chemical group 0.000 abstract description 3
- FKLQIONHGSFYJY-UHFFFAOYSA-N propan-2-yl 5-[4-bromo-1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-chloro-4-fluorobenzoate Chemical compound C1=C(Cl)C(C(=O)OC(C)C)=CC(C=2C(=C(N(C)N=2)C(F)(F)F)Br)=C1F FKLQIONHGSFYJY-UHFFFAOYSA-N 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 140
- 239000000047 product Substances 0.000 description 55
- 239000000243 solution Substances 0.000 description 47
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 38
- 239000002585 base Substances 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 229910052760 oxygen Inorganic materials 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 125000003226 pyrazolyl group Chemical group 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000006482 condensation reaction Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000003999 initiator Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 125000000160 oxazolidinyl group Chemical group 0.000 description 7
- 230000001737 promoting effect Effects 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 5
- 239000003849 aromatic solvent Substances 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 238000006386 neutralization reaction Methods 0.000 description 5
- 238000012805 post-processing Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 229910019093 NaOCl Inorganic materials 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 3
- 229930007927 cymene Natural products 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- 230000001035 methylating effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000009333 weeding Methods 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 2
- 241000345998 Calamus manan Species 0.000 description 2
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- YXPNHTIXNGHNOP-UHFFFAOYSA-N benzoic acid;1h-pyrazole Chemical class C=1C=NNC=1.OC(=O)C1=CC=CC=C1 YXPNHTIXNGHNOP-UHFFFAOYSA-N 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
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- 235000013339 cereals Nutrition 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
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- 125000005179 haloacetyl group Chemical group 0.000 description 1
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- CNFDGXZLMLFIJV-UHFFFAOYSA-L manganese(II) chloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Mn+2] CNFDGXZLMLFIJV-UHFFFAOYSA-L 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
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- 238000005191 phase separation Methods 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
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- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
Processes for preparing substituted 3-aryl-5-haloalkyl-pyrazoles and, specifically, for preparing C1-5 alkyl esters of 5- [1-(C1-5 alkyl) -4-halo-5-(C1-3 haloalkyl) -1H-pyrazole-3-yl]-2,4-dihalo-benzoic acids such as isopropyl 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-2-chloro-4-fluorobenzoate, are presented. The described processes include novel approaches for forming phenyl-diketones, forming and alkylating pyrazoles, brominating heterocyclic compounds, oxidizing alkyl-substituted benzene compounds, and esterifying carboxylic acids. These processes may be combined to prepare 3-aryl-5-haloalkyl pyrazoles, or alternatively, used in subcombinations or individually to prepare intermediates or other useful compounds.
Description
Background of invention
The present invention relates generally to have the preparation method and more particularly of 3-aryl-5-halogen alkyl pyrazole of the replacement of weeding activity, relate to 5-[1-(C
1-5Alkyl)-4-halo-5-(C
1-3Haloalkyl)-and the 1H-pyrazole-3-yl]-2,4-dihalo-benzoic C
1-5Alkyl ester is 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl for example]-preparation method of 2-chloro-4-fluorobenzoic acid isopropyl ester.When the present invention preferably relates to the preparation method of this 3-aromatic base-5-haloalkyl pyrazoles, the benzene compound that the present invention also relates to form the benzene diketone, form alkylation pyrazoles, bromination pyrazoles and other heterogeneous ring compound, oxidation of alkyl replaces and the independent method steps of esterification carboxylic acid.
The aryl pyrazole compound of various replacements is known and is used as chemical intermediate, medicine and weedicide.For example United States Patent (USP) comprise 3326662 (Tomoyoshi etc.), 3948937 (Johnson etc.), 4008249 (
FischerDeng), 4072498 (Moon etc.), 4260775 (Plath etc.), 4468871 (Ebel etc.), 4752326 (Ohyama etc.), 5032165 (Miura etc.), 5045106 (Moedritzer etc.).Various 3-aryl-5-halogen alkyl pyrazoles are disclosed in the United States Patent (USP) 5281571 and 5489571 (Woodard etc.).
The method for preparing aryl pyrazole compound generally is known.United States Patent (USP) 5281571 (Woodard etc.) has been narrated a kind of method for preparing the 3-aryl-5-halogen alkyl pyrazole of replacement.In brief, in the presence of alkali, there is the reaction of the methyl phenyl ketone of methyl substituents and ester to form the benzene diketone on the phenyl moiety, then separated product and handle with hydrazine and to make its cyclisation.The arylpyrazole that obtains is further reacted, comprise the N-alkylation and the halogenation of pyrazoles part, the methyl oxidation on the phenyl moiety forms the formation of phenylformic acid and its benzoic acid derivative.
Some for example are fit to methods of the 3-aryl-5-halogen alkyl pyrazole that preparation replaces, consider that expense, selectivity that increases isomer that reduces reagent or the productive rate that increases product and output are not by preferably.Summary of the invention
Therefore the objective of the invention is to optimize the method steps of preparation 3-aryl-5-halogen alkyl pyrazole according to expense, reliability, selectivity, productive rate and output.It also is purpose of the present invention that benzene substrate that replaces for bromination heterogeneous ring compound, oxidation of alkyl and esterification replace or unsubstituted carboxylic acid provides improvement project.In brief, the present invention relates to the preparation method of general formula III b compound,
The methyl phenyl ketone of general formula III a
Carried out acidylate with alpha-carbon atom by the halo acyl halide of complete halogenated general formula A1.In this method: Ar is the phenyl of phenyl or replacement, R
2Be C
1-3Haloalkyl and Z are halogens.
The present invention also relates to prepare the method for the compound of general formula III d
The phenyl diketone of general formula III b
In reaction mixture, form alkyl pyrazole precursor intermediate with the hydrazine condensation.Hydrazine in reaction mixture is chemical relatively excessive concerning the phenyl diketone.Hydrazine is excessive be at least unreacted phenyl diketone and formation intermediate total mole number 15%.From reaction mixture, remove excessive hydrazine then and with this intermediate of alkylated.In this method: Ar is the phenyl of phenyl or replacement, R
1Be alkyl or the alkyl that replaced by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkyl sulfide; R
2Be derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide base or the alkylphosphines acyl group of alkyl, hydroxyl, alkoxyl group, acyl group, its carboxylic acid and aldehyde, acid amides and ester.
In another method of the compound for preparing general formula III d, the phenyl diketone of general formula III b forms alkyl pyrazole precursor intermediate with the hydrazine condensation in reaction mixture.The amount of hydrazine is excessive relatively concerning the phenyl diketone in this reaction mixture.This reaction mixture has organic phase and water, removes hydrazine in this reaction mixture by the method for removing water from reaction mixture.Use this intermediate of alkylated then.Ar, R in present method
1And R
2Definition the same.
The invention still further relates to a kind of method for preparing the alkylation pyrazole compound of general formula III e
This method comprises that the phenyl diketone of general formula III b and the hydrazine condensation in reaction mixture form alkyl pyrazole precursor intermediate.Under acidic conditions, intermediate and alkylated.Ar and R
1Definition the same.R
2Be derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide base or the alkylphosphines acyl group of alkyl, hydroxyl, alkoxyl group, acyl group, its carboxylic acid and aldehyde, acid amides and ester.R
2Preferably drive electron group and haloalkyl most preferably.
The present invention relates to the method for regioselective alkylation 3 (5)-aryl-5 (3)-haloalkyl pyrazoles in addition.The compound of general formula III c
Under the not deprotonation situation of N-hydrogen atom of general formula III c compound with alkylated.Obtain the 3-aryl isomer of 1-alkyl-3 (5)-aryl-5 (3)-haloalkyl pyrazoles of general formula III e
This reaction simultaneously also obtains its corresponding 5-aryl isomer, the amount of 3-aryl isomer account at least formation 1-alkyl-3 (5)-aryl-5 (3)-haloalkyl pyrazoles total amount about 90%.In the method: Ar is the phenyl of phenyl or replacement; R
1Be C
1-5Alkyl; And R
2Be C
1-3Haloalkyl.
The invention still further relates to the method for bromination heterocycle substrate.Under oxidizing condition, make the reaction of heterocycle substrate and bromide salt.
The invention further relates to the method for the benzene substrate of direct oxidation alkyl replacement.In the presence of metal catalyst and benzoyl peroxide, make the reaction of this substrate and molecular oxygen.
The present invention relates to the method for esterification carboxylic acid substrate.In initial esterification scheme, carboxylic acid and halogenating agent react and the acyl halide esterification that obtains are formed the corresponding carboxylic acid ester.Esterifying agent used in present method is formed by pure and mild acyl halide mixing.Next, an independently esterification scheme is with the trialkyl ortho ester esterification carboxylic acid substrate formation carboxylicesters of general formula F1.In present method, R
10Be C
3-5Alkyl and R
11It is hydrogen or alkyl.
The present invention also relates to prepare the method for general formula I
The compound of general formula I f
Become acyl halide by halogenation, then with esterifying agent with this acyl halide esterification.This esterifying agent is by general formula R
10The pure and mild acyl halide of OH mixes formation.In this method: R
1Be C
1-5Alkyl; R
2Be C
1-3Haloalkyl; R
3, R
5And R
6It is halogen; And R
10Be C
3-5Alkyl.
In the other method of preparation compound of Formula I, the compound of general formula I f
By the trialkyl ortho ester esterification of general formula F1
R
1, R
2, R
3, R
5, R
6And R
10The same and R of definition
11It is hydrogen or alkyl.
In another method of preparation compound of Formula I, the compound of general formula I e
Under oxidizing condition, become the compound of general formula I f and with the compound esterification of general formula I f by the bromide salt bromination.In this method: R
1, R
2, R
5, R
6And R
10The same and R of definition
3It is bromine.
In another method of preparation compound of Formula I, the compound of general formula I d
In the presence of metal salt catalyst, catalyst promoting agent and benzoyl peroxide, become the compound of general formula I e by molecular oxygen oxidation
Then the compound halogenation of general formula I e is become the compound of general formula I f, then with its esterification.R
1, R
2, R
5, R
6And R
10Definition the same.R
3It is halogen.
In the other method of preparation general formula I, the compound of general formula I b
Be condensed into alkyl pyrazole precursor intermediate by the hydrazine in the reaction mixture.Under acidic conditions, this intermediate is alkylated into the compound of general formula I d then with alkylating agent,
Then the compound oxidation of general formula I d is become the compound of general formula I e, rehalogenization becomes the compound of general formula I f, again with its esterification.In this method, R
1, R
2, R
3, R
5, R
6And R
10Definition the same.
In the other method of preparation general formula I, the compound of general formula I a
Represented its structure and α carbon by abundant halogenated halo acyl halide acidylate with general formula A1.
Compound and the hydrazine of the general formula I b that obtains are condensed into alkyl pyrazole precursor intermediate.This intermediate is alkylated into the compound of general formula I d by alkylating agent, is oxidized to the compound of general formula I e, and halogenation becomes the compound of general formula I f, and resterification becomes the compound of general formula I.In this method, R
1, R
2, R
3, R
5, R
6And R
10Definition the same.In the other method of the compound for preparing general formula I, the compound of general formula I a is become the phenyl diketone of general formula I b by halo acetyl halide or alkyl halogen acetates acidylate.Hydrazine in phenyl diketone and the reaction mixture is condensed into alkyl pyrazole precursor intermediate.This reaction mixture has organic phase and water, and the hydrazine that is present in the back-pressure mixture is excessive relatively for the compound of general formula I b.The resolution of precipitate that reaction mixture heating is made formation in organic phase, and from organic phase water phase separated.From reaction mixture, remove excessive hydrazine by the method for from reaction mixture, removing water then.Under acidic conditions, form the compound of general formula I d then with this intermediate of alkylating agent alkylation, in the presence of metal salt catalyst, halide salts and acetone promotor and benzoyl peroxide, become the compound of general formula I e then by molecular oxygen oxidation, halogenation becomes the compound of general formula I f then, and esterification becomes the compound of general formula I then.In this method, R
1, R
2, R
3, R
5, R
6And R
10Definition the same.
The invention further relates to the method for the compound of preparation general formula I I.
In this method, the compound of general formula I Ia
Become the compound of general formula I Ib by trifluoroacetyl halogenide or Trifluoroacetic Acid Ethyl Ester acidylate,
Then the compound of general formula I Ib and the hydrazine in reaction mixture are condensed into alkyl pyrazole precursor intermediate.The hydrazine that is present in the reaction mixture is excessive relatively for the compound of general formula I b.This reaction mixture has organic phase and water, makes the resolution of precipitate of formation in organic phase the reaction mixture heating.Water phase separated from organic layer also is convenient in heating.By removing water, from reaction mixture, remove excessive hydrazine.Under acidic conditions, use this intermediate of methylating reagent alkylation then, form the compound of general formula I Id,
In the presence of metal salt catalyst, halide salts, acetone and Benzoyl Peroxide,, form the compound of general formula I Ie with the compound of molecular oxygen oxidation general formula I Id.
Under oxidizing condition, be the compound of general formula I If with the compound of bromide salt bromination general formula I Ie
Then its esterification is become the compound of general formula I I.
Further feature of the present invention and purpose are obvious for those of ordinary skill in the art and will further illustrate hereinafter.Detailed Description Of The Invention
The present invention includes the novel method step that forms benzene diketone, formation and alkylation pyrazoles, bromination pyrazoles and other heterogeneous ring compound, oxidation of alkyl substituted benzene compound and esterification carboxylic acid.These steps can be united to make and are used for preparing 3-aryl-5-halogen alkyl pyrazole, or use wherein several steps in addition or use wherein separately that a step prepares intermediate or other compound.Bromination used herein, oxidation and esterification process are particularly suitable for the substrate of wide scope, such as hereinafter detailed description.The method of this paper obviously is being better than prior art aspect expense, reliability, selectivity, productive rate and the turnout.The concrete advantage of preferable methods step is discussed hereinafter.
By the 3-aryl-5-halogen alkyl pyrazole of the inventive method preparation can be used for significantly prevent and treat wide leaf and grassy weed for example be grown in various farm crop for example corn, soybean, wheat, barley, paddy rice etc. draw rattan, Rush, pigweed, Siberian cocklebur, piemarker and sesbania etc. greatly really.But they are undesirable trees and climing rattan in the effectively preventing forest also.3-aryl-5-halogen alkyl pyrazole can have multiple application mode and can be used for herbicidal composition, for example is total to weedicide or unites use with safener, mycocide, sterilant, nematocides and/or other Remedies for diseases.By the herbicidal compound of preferred version of the present invention preparation, 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-2-chloro-4-fluorobenzoic acid isopropyl ester for bud before control and small grain for example relevant wide leaf and the grassy weed of wheat is effective especially.
Herein, no matter term " alkyl ", " alkenyl " or " alkynyl group " use separately or formation (for example haloalkyl, alkoxyl group, alkoxyalkyl etc.) in compound, all refer to a straight chain and/or a chain portion.Unrestriced alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkylalkyl, cycloalkenyl group and cycloalkenyl alkyl comprise following: methyl, ethyl, sec.-propyl, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl etc.; The butenyl of vinyl, allyl group, butenyl, methylallyl, isomery, pentenyl, hexenyl, heptenyl, octenyl; The proyl of ethynyl, isomery, butynyl, pentynyl, hexin base etc.; Have the alkoxyl group of abovementioned alkyl, many alkoxyl groups, alkoxyalkyl and multi-alkoxy alkyl, for example methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy and hexyloxy and corresponding many alkoxyl groups and alkoxyalkyl, for example methoxymethoxy, methoxy ethoxy, oxyethyl group methoxy base, ethoxy ethoxy, methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, propoxy-methyl, isopropoxy methyl, butoxymethyl, isobutoxy methyl, tert.-butoxy methyl, pentyloxy methyl, hexyloxy methyl etc.; Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl etc.; Isomerized cyclopentenyl, cyclohexenyl and cycloheptenyl that one or two unsaturated link(age) is arranged; Aryl, aralkyl and alkaryl comprise phenyl, isomerized tolyl and xylyl, benzyl, naphthyl etc.
Term " haloalkyl " is meant the alkyl that is replaced by one or more halogens (chlorine, fluorine, bromine or iodine) atom.Multi-haloalkyl has the halogen atom of identical or mixed type." whole haloalkyl " is meant that each hydrogen atom in the alkyl is all replaced by halogen atom.The haloalkyl of certain specific carbon atom " halo fully " is meant that the hydrogen atom that links to each other with this carbon is all replaced by halogen atom.Representational single, two and tri haloalkyl comprise: chloromethyl, chloroethyl, brooethyl, bromotrifluoromethane, iodomethyl, iodine ethyl, chloropropyl, bromopropyl, iodine propyl group, 1,1-dichloromethyl, 1,1-two brooethyls, 1,1-two chloropropyls, 1,2-dibromopropyl, 2,3-dibromopropyl, 1-chloro-2-bromotrifluoromethane, 2-chloro-3-bromopropyl, trifluoromethyl, trichloromethyl etc.
Term " heterocycle " is meant the closed-loop structure that one or more other atoms are arranged except that carbon atom in ring herein.Typical heterocycle comprises: alkyl thiadiazolyl group, piperidyl, piperidyl alkyl; Dioxolane alkyl, thiazolyl; The alkyl thiazolyl; Benzothiazolyl; The halogeno-benzene benzothiazolyl; Furyl; The furyl that alkyl replaces; Furyl alkyl; Pyridyl; Alkylpyridyl; Wan Ji oxazolyl; The tetrahydrofuran base alkyl; 3-cyano thiophene base; The thienyl alkyl; The thienyl that alkyl replaces; 4,5-polyalkenyl-thienyl; Piperidino-(1-position only); The Alkylpiperidine subbase; Pyridyl; Dihydro or tetrahydro pyridyl; The alkyl tetrahydro morpholinyl; The alkyl morpholine base; The azabicyclo nonyl; Diazabicyclo alkyl, benzo alkyl pyrrolidine base; Oxazolidinyl; Full Qing oxazolidinyl; Wan Ji oxazolidinyl; Fu Nan Ji oxazolidinyl; Sai fen Ji oxazolidinyl; Bi Ding Ji oxazolidinyl, Mi Ding Ji oxazolidinyl, benzoxazole alkyl, C
3-7Volution alkyl oxazolidinyl, alkylamino alkenyl; Alkylideneimino; Pyrrolidyl; Piperidone base; Perhydro azatropylidene base; Perhydro azocine base; Pyrazolyl; The pyrazoline base; Piperazinyl; Perhydro-1,4-diaza base; Quinolyl; Isoquinolyl; Dihydroquinoline base, tetrahydric quinoline group and perhydro quinolyl, dihydro-isoquinoline base, tetrahydro isoquinolyl or perhydro isoquinolyl; Indyl and indolinyl and perhydro indyl etc.
Method of the present invention preferably is used for preparing compound of Formula I 3-aryl-5-halogen alkyl pyrazole,
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
1-5Alkyl.Haloalkyl R
2Preferably nearest carbon quilt halogenation fully with the pyrazoles ring.In scheme most preferably, this method is used for preparing 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-2-chloro-4-fluorobenzoic acid isopropyl ester, its structure represents with the compound of general formula I I,
The general compound that is used for preparing general formula I as described below of the preparation of the arylpyrazole of general formula I I, and in embodiment 1, further illustrate.In following method steps, except as otherwise noted, various substituting groups (for example, R with symbol definition
1, R
2Deng) definition identical with the compound of general formula I arranged.
Preferably the substituted acetophenone with general formula I a is a starting point, carries out the compound that full step prepares general formula I,
It can change into the compound of general formula I by a series of step (A-E), and step of converting is as follows:
Steps A
Steps A relates to the methyl phenyl ketone acidylate and becomes the phenyl diketone.As described below, be used for the methyl phenyl ketone of acidylate step, preferred 2,4-dihalo--5-methyl-acetophenone, phenyl moiety is unsubstituted or other substituting group is arranged in the methyl phenyl ketone that the present invention uses.Generally speaking, by following reaction, the methyl phenyl ketone of general formula III a can be transformed into the phenyl diketone of general formula III b:
Wherein Ar is the phenyl and the R of phenyl or replacement
2Be C
1-3Haloalkyl, and the phenyl diketone that makes from the nearest carbon of carbonyl by halogenation fully.
Herein, term " phenyl of replacement " refers to the group of general formula Ar-1,
R wherein
4Be selected from following groups: C
1-8Alkyl; C
3-8Cycloalkyl, cycloalkenyl group, cycloalkylalkyl or cycloalkenyl alkyl; C
2-8Alkenyl or alkynyl group; Benzyl; Above-mentioned group can by halogen, amino, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio,
-YR
8Or-NR
8R
9Mercaptoalkyl; Alkoxyalkyl or multi-alkoxy alkyl; Carbamyl; Amino, nitro or cyano group; Halogen; Hydroxyl; Contain O, S (O)
mAnd/or NR
8Heteroatomic C
1-10Heterocyclic radical; C
6-12Aryl, aralkyl or alkaryl;
-YR
8Or-NR
8R
9Replace; With two or more above-mentioned R
4Group is by connecting the ring that base forms 9 yuan of rings of as many as, and it can be by a R arbitrarily
4Group replaces, connect base comprise saturated or undersaturated carbon ,-(C=X)-, heteroatoms O, S (O)
mAnd NR
8X is O, S (O)
m, NR
8Or CR
8R
9Y is O, S (O)
m, NR
8M is 0-2; N is 1-5; And R
8And R
9Be selected from following group: hydrogen; C
1-8Alkyl; C
3-8Cycloalkyl, cycloalkenyl group, cycloalkylalkyl or cycloalkenyl alkyl; C
2-8Alkenyl or alkynyl group; Benzyl; Above-mentioned group can be by halogen, amino, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio; The sulfane base; Alkoxyalkyl; Multi-alkoxy alkyl; Carbamyl; Halogen; Amino, nitro; Cyano group; Hydroxyl; Contain O, S (O)
mAnd/or the heteroatomic C of N
1-10Heterocycle; C
6-12Aryl, aralkyl or alkaryl replace; With two or more above-mentioned R
4Group is by connecting the ring that base forms 9 yuan of rings of as many as, and it can be replaced by a group arbitrarily, connect base comprise saturated or undersaturated carbon ,-(C=X)-, heteroatoms O, S (O)
mWith
N
The phenyl of replacement of the present invention preferably includes the compound of general formula Ar-2 especially,
Wherein: R
5Be hydrogen or halogen, R
6Be hydrogen, halogen, nitro, cyano group or YR
8, R
7Be hydrogen, low alkyl group, haloalkyl or
, wherein X is O, S (O)
m, NR
8Or CR
8R
9Y is O, S (O)
m, NR
8M is 0-2; And R
8And R
9Definition is with general formula Ar-1.In further particularly preferred scheme, R
5Be halogen, R
6Be halogen, R
7Be low alkyl group, haloalkyl or
Wherein W be hydrogen, hydroxyl, halogen or-OC
1-5Alkyl.
The methyl phenyl ketone of general formula III a is known.For example 2 of general formula I a, 4-dihalo--5-methyl-acetophenone can be obtainable 2 by commerce, and 4-dihalo toluene makes.In brief, in the presence of Lewis acid or protonic acid, temperature of reaction is about-50 ℃-200 ℃, and preferably about 0-100 ℃, can be with the acylating agent toluene that replaces of acyl halide, acid anhydrides or ketenes acidylate for example.The amount preferable range of acylating agent is that a molar equivalent is extremely excessive with respect to the toluene that replaces, preferred about 2 molar equivalents.Acylation reaction can be carried out in solvent-free or any inert solvent.Preferred solvent comprises oil of mirbane, dithiocarbonic anhydride, organic acid or halohydrocarbon.Reaction can be carried out under pressure, and pressure range is about 1 * 10
5Pa (about 1psig) is to 1.7 * 10
5Pa (about 10psig).Reaction times is according to condition changings such as reagent concentration, temperature.Preparing the phenyl diketone of general formula III b from methyl phenyl ketone can be substantially carry out according to the method for the compound of following preparation general formula I b and general formula I Ib.
In preferred step, by compound, prepare the phenyl diketone of general formula I b from the methyl phenyl ketone of general formula I a by following reaction with acylating agent acidylate general formula I a,
R wherein
2Be C
1-3Haloalkyl and R
5And R
6It is halogen.Suitable acylating agent is the halo acyl halide with its structure of compounds represented of general formula A1
Wherein Z is halogen and R
2Be C
1-3Haloalkyl.Preferred halo acyl halide has complete halogenated alpha-carbon, like this after the acidylate and after forming the pyrazoles ring later on, from the nearest R of pyrazoles ring
2Carbon is by halogenation fully.This carbon atom of halogenation can be brought into play the weeding activity of the compound of general formula I better fully.In addition, R
2The complete halogenation of carbon also helps synthetic required regional isomer, as following illustrated (step B).The preferred halo acetyl halide of halo acyl halide, preferred especially three halo acetyl halide, preferred more especially three halo Acetyl Chloride 98Min.s and trifluoroacetyl chloride most preferably.(embodiment 1, steps A).Another suitable acylating agent is an alkyl halogen acetates, preferred three alkyl halogen acetates and most preferably trifluoro-acetate or Trifluoroacetic Acid Ethyl Ester.Halo acyl halide and alkyl halogen acetates as acylating agent in reactive and yield aspects equally by preferably, but use the halo acyl halide lower at present than use three alkyl halogen acetates expenses.
The compound of general formula I b can prepare in any anhydrous solvent or mixed solvent, comprises ether, alcohol, methyl-sulphoxide, toluene, benzene etc., and preferred alcohols is as solvent.Reaction is preferably carried out in the presence of highly basic, for example alkali metal alcoholates, alkali amide or alkalimetal hydride, and the preferred as alkali alkoxide is sodium methylate for example.The solvent mixture of use alcohol/alkali metal alcoholates generally can obtain the substrate useful load of better productive rate and Geng Gao.
Preferred excessive a little acylating agent (methyl phenyl ketone with respect to reaction is the 1.2-1.5 molar equivalent) and excessive 75% methyl alcohol/25% sodium methoxide solution pre-mixing (amount with respect to the amount sodium methylate of methyl phenyl ketone is about 1.5 molar equivalents) form mix reagent.Therefore the mixing step heat release, before mixing, the initial temperature of methyl alcohol/sodium methoxide solution is about-20 ℃ to about 60 ℃, especially preferably about-10 ℃ extremely about 20 ℃ and most preferably from about-5 ℃.Controlled temperature is lower than about 60 ℃ and also preferably is lower than about 40 ℃ before the mixing step neutralization adds methyl phenyl ketone.Then the methyl phenyl ketone that replaces is added in the mix reagent, then add methyl alcohol/sodium methylate solvent (with respect to other 1.5 molar equivalents of the amount of methyl phenyl ketone) again.This be reflected at carry out under the normal pressure with temperature of reaction be about 25 ℃ to about 75 ℃, preferred especially about 50 ℃ to about 70 ℃ and most preferably from about 60 ℃.Reaction times mainly changes between a couple of days at several minutes according to the concentration and the temperature of reaction of reagent.60 ℃ of reaction times is that about 45 minutes typical yields can be greater than about 90%.
Before adding the methyl phenyl ketone substrate, preferably with halo acyl halide and alkoxide/alcoholic solution pre-mixing, the order of mixing acylating agent, substrate and solvent or solvent mixture is not crucial.For example, reaction also can add acylating reagent then by pre-mixing methyl phenyl ketone and basic solvent and finishes, or by adding acylating agent simultaneously and methyl phenyl ketone is finished.How the foundation of decision order controls reagent, substrate and solvent in conjunction with the heat release that causes if relating to.
After finishing reaction, if desired, the compound of general formula I b can separated and/or purification.By reaction mixture to about 50 ℃ with inorganic acid solution 10% hydrochloric acid soln neutralization reaction for example, the gained compound is precipitated out from solution, and further is cooled to about 10 ℃.Can purify by known method such as recrystallization by filtering separation precipitated product and if desired then.
When the phenyl diketone of general formula I b continues on for step B, can for example be used in solvent systems (for example aromatic solvent) among the step B with some suitable processing modes and replace the solvent systems (for example alcohol/alkali metal alcoholates) that uses in the steps A.For example, the compound of general formula I b can and separate by aforesaid method precipitation, and isolated phenyl diketone precipitation can be without further dry or direct slurries that form again in the solvent of step B of purifying.Special preferred reaction mixture is without the aftertreatment that separates phenyl diketone product.When replacing alcohol/alkali metal alcohol salt solvent with aromatic solvent, aftertreatment preferably include with mineral acid (for example 10% hydrochloric acid soln) neutralization reaction mixture and vacuumize a little down and about 45 ℃ to about 50 ℃ of following stripping alcohol.Alcohol at least about 50% is removed, and preferably is removed at least about 80% and most preferably is removed at least about 90% alcohol.Add aromatic solvent then and remove water layer.The change of present method comprises and begins stripping alcohol under reduced pressure, and reaction mixture is cooled to about room temperature, adds aromatic solvent, with the inorganic acid aqueous solution washing, further with deionized water wash with remove the water that obtains.In the superincumbent last two step post processing modes, organic phase contains required phenyl diketone product, and the step B that is used for as described below.
In most preferred concrete scheme, prepare the phenyl diketone of general formula I Ib from the methyl phenyl ketone of general formula I Ia by following reaction:
Basic by prepared in reaction general formula I b compound mentioned above, be acylating agent with trifluoroacetyl chloride, trifluoro-acetate or Trifluoroacetic Acid Ethyl Ester.Trifluoroacetyl chloride is more cheap than trifluoro-acetate or Trifluoroacetic Acid Ethyl Ester, thus its aspect expense by preferred, but others they equally by preferably.The preparation of general formula I Ib compound will further illustrate in embodiment 1 (steps A).Step B
Step B relate to the cyclisation of phenyl diketone and then alkylation form alkylating 3 (5)-aryl-5 (3)-haloalkyl pyrazoles.Generally speaking, can the arylpyrazole of general formula III b be transformed into alkylating 3-aryl-pyrazoles of general formula III d by following reaction
Wherein: Ar is as the phenyl of steps A definition or the phenyl of replacement; R
1Be alkyl or the phenyl that replaced by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide base or alkylphosphines acyl group.R
1Preferred C
1-5Alkyl and R
2Preferred C
1-3Haloalkyl.By compound and the hydrazine condensation of general formula III b, preferred excessive hydrazine is removed any excessive hydrazine and carried out this reaction, and is as described below, and alkylation is with the compound of preparation general formula I d and IId.If desired, the midbody compound of general formula III c,
Wherein Ar and R
2Definition identical with the definition of the compound of top general formula III b and IIId, also can after the phenyl diketone of condensation general formula III b under the acidic conditions or condensation, in reaction mixture, add acid and obtain.Under acidic conditions, alkylated reaction can carry out to regioselectivity, and forms the 3-aryl isomer of general formula III e without the N-hydrogen deprotonation of general formula III c compound,
Wherein Ar and R
1Definition and wherein R identical with the definition of the compound of top general formula III b and IIId
2Be the derivative of alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide base or alkylphosphines acyl group.
The regioselectivity that step B is particularly related to following total overall reaction process prepares the 3-aryl-5-halogen alkyl pyrazole of general formula I d:
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl and R
5And R
6It is halogen.The phenyl diketone of general formula I b and the hydrazine condensation in the reaction mixture form one or more intermediates, will go through and be called together alkyl pyrazole precursor intermediate hereinafter.In reaction mixture, add then alkylating agent and with the reaction of alkyl pyrazole precursor intermediate, generalized case forms two mixture of isomers, one reinstates general formula I c representative,
Under acidic conditions and/or R
2Group is when driving the electronics base section, the primary product that this alkylated reaction forms is 1-alkyl-3-aryl-5-halogen alkyl pyrazole (general formula I d), rather than 1-alkyl-5-aryl-3-haloalkyl pyrazoles, the 3-aryl isomer that vide infra separately and 5-aryl isomer.
The preferred unsubstituted hydrazine of hydrazine.The present invention can use hydrazine that alkyl replaces for example methyl hydrazine get alkyl pyrazole through single step reaction, the regional isomer that obtains is mainly 5-aryl isomer, rather than 3-aryl isomer.Hydrazine can be in any suitable solvent or solvent mixture and phenyl two reactive ketones, and solvent comprises organic and water solvent.Consider commercial availability and expense, the preferred aqueous solution that uses hydrazine in the reaction.Consider to make things convenient for post-processing step the organic solution of preferred phenyl diketone.Aromatic solvent preferably has high relatively boiling point for example toluene, dimethylbenzene, cymene, cumene and ethylbenzene, and the most preferred solvent of phenyl diketone is a toluene.
This reaction most preferably adds the hydrazine aqueous solution in the toluene solution that contains the phenyl diketone, form two-phase reaction mixture, wherein the phenyl diketone in organic phase and hydrazine at aqueous phase.Preferably under about room temperature, add hydrazine solution to toluene solution.The hydrazine solution that adds capacity makes the hydrazine in the reaction mixture excessive with respect to phenyl diketone stoichiometric calculation.The purpose that adds the excessive hydrazine of stoichiometric calculation herein be for whole phenyl two reactive ketones after also have the hydrazine of residual content.The excessive hydrazine of any stoichiometric calculation preset time in reaction mixture or in reaction zone, the molar weight of the molar weight of hydrazine and phenyl diketone is all different at that time.The amount of the excessive hydrazine of stoichiometric calculation preferably is at least about 1% mole of normal content in reaction mixture, and normal content is the alkyl pyrazole precursor intermediate molar weight summation of unreacted phenyl diketone and formation.The amount of excessive hydrazine especially preferably is at least about 15% mole of normal content and is most preferably 20% mole of normal content.But not harsh for upper limit requirement, preferred about 5% mole to about 50% mole and preferred about 10% mole to about 25% mole especially of the amount of excessive hydrazine.Use excessive hydrazine can make the phenyl diketone be transformed into alkyl pyrazole precursor intermediate to greatest extent, therefore improved productive rate.After adding hydrazine solution, stir that this reaction mixture is convenient to hydrazine and the phenyl diketone carries out surface reaction.Also can contain some in the reaction mixture from the unreacted methyl phenyl ketone of former step (steps A).This reaction preferably carries out being about 0-60 ℃ with temperature of reaction under normal pressure, and especially preferably about 30-50 ℃ and most preferred temperature of reaction are about 40 ℃.Reaction times according to the concentration of reagent different with temperature of reaction from several minutes to several days.Under 40 ℃, finish at about 30 minutes internal reactions by gas Chromatographic Determination.
Bound by theory not, phenyl diketone (general formula I b) obtains one or more midbody compounds with the hydrazine condensation reaction.For example, depend on different reaction conditionss, form the 3-aryl-5-hydroxypyrazoles quinoline of Formula B 1 or 3 (5)-arylpyrazoles of Formula B 2 probably.
The main intermediate of carrying out condensation reaction under neutrallty condition is the compound of Formula B 1, and the main intermediate of carrying out condensation reaction under acidic conditions is the compound of Formula B 2.Therefore, with regard to purpose of the present invention, need not separate and/or characterize alkyl pyrazole precursor midbody compound, carry out condensation reaction or after condensation reaction is finished, in reaction mixture, add acid (for example in embodiment 2, using acetate solvate) under the acidic conditions by method mentioned above, can obtain the arylpyrazole intermediate of Formula B 2.Do not consider the definite structure of the intermediate that condensation reaction forms, phenyl diketone reagent and the intermediate that obtains preferably remain in the organic phase of reaction mixture, and hydrazine is preferably stayed the aqueous phase of reaction mixture.Yet some intermediates that obtain may be settled out from solution.
After condensation reaction is finished, preferably before the alkylation intermediate forms the alkylation pyrazole compound of general formula I c or Id, the hydrazine of excessive separation and the alkyl pyrazole precursor intermediate that obtains.This lock out operation makes the explosion hazard of alkylation gained intermediate in the presence of hydrazine reduce to minimum.Can separate by any known technology, but preferably by being separated (in two-phase reaction mixture) or separating by the method (in the homogeneous reaction mixture) of liquid-liquid solvent extraction.Excessive hydrazine does not preferably separate the intermediate of gained and removes from reaction mixture.The preferred above-mentioned biphasic system of reaction mixture is removed excessive hydrazine by this reaction mixture of heating earlier with the method that the precipitation of any amount that may form in the reaction process is dissolved in the organic phase again.Heating helps the aqueous phase separation in the organic phase is become water layer and organic layer equally.If desired, also can add other solvent or increase partition ratio or reinforcement in biphasic system is separated.From reaction mixture, remove the aqueous phase layer that contains hydrazine then.Can further wash remaining organic phase with the aqueous solution (for example salt solution).This washing soln separates from organic solution equally and removes.In another biphasic system, the intermediate of gained and excessive hydrazine can be separated from each other by remove the organic phase that contains the gained intermediate from reaction mixture.In addition, this reaction can be carried out in single-phase organic system, wherein phenyl two reactive ketones of anhydrous hydrazine and general formula I b and remove excessive hydrazine by water extraction.If being reflected in the single-phase water solution, this carries out, can be by fetch separating obtained intermediate with organic solvent extracting.Described herein being separated separated than other with the liquid-liquid extraction post-processing step or purification techniques (for example precipitation and/or crystallization) is easy and than distillating method safety.
Phenyl diketone (general formula I b) and hydrazine condensation and remove any excessive hydrazine after, in reaction mixture, add this alkyl pyrazole precursor intermediate of alkylating agent alkylation.The alkyl pyrazole that obtains is generally with general formula I c representative.Suitable alkylating agent comprises alkylogen, alkyl sulfonic ester and sulfuric acid mono alkyl ester or sulfuric acid dialkyl, preferably sulfuric acid dialkyl.Work as R
1When being methyl, alkylating agent is preferably methyl-sulfate, methyl-iodide and monobromomethane.The amount of use methyl-sulfate is at least equimolar amount with respect to the amount of the phenyl diketone of general formula I b, because second methyl is not enough to this intermediate of alkylation.The alkylating agent that adds in reaction mixture preferably with respect to the amount molar excess of the phenyl diketone of participating in reaction, is crossed the about 1.01-1.3 molar equivalent of weight range, more preferably from about 1.0 5-1.25 molar equivalents and most preferably from about 1.1-1.2 molar equivalent.Generally in reaction mixture, add alkylating agent lentamente to avoid very exothermic.
Alkylated reaction can carry out under neutral, alkalescence or acidic conditions, and the preferred acidic condition is so that the 3-aryl isomer (embodiment 3) of the required general formula I d of the preparation of regioselectivity to greatest extent.The percentage of the 3-aryl isomer that obtains under acidic conditions is about 90% greater than arylpyrazole product total amount all the time, and usually greater than about 95%, but under non-sour condition, the percentage of the 3-aryl isomer of acquisition only is about 55%-80%.Bound by theory not, make based on such fact to it is believed that selectivity has improved, this fact is exactly that for example Formula B 2 compound advantages ground (greater than about 90%) exist with the form (Formula B 3) of 5-aryl tautomer intermediate and the 3-aryl form (Formula B 4) of a small amount of (less than about 10%) only:
Under alkaline condition, nitrogen-atoms is stayed very active electron pair so that alkylation by deprotonation.Because the deprotonation nitrogen-atoms mainly is from the nearest nitrogen-atoms of aryl, therefore main 5-aryl isomer under alkaline condition.On the contrary, when carrying out alkylated reaction under acidic conditions, deprotonation and the relative activity that has more of other nitrogen-atoms (promptly lacking the hydrogen nitrogen-atoms) do not take place.Therefore, the alkylated reaction selectivity forms 3-aryl isomer under acidic conditions.Consider concrete R
2Form, for example CF
2The reaction stability of Cl (embodiment 4), acidic conditions is also preferred than alkaline condition.
R
2The electronic capability of driving of group also has promoter action for the selectively producing of 3-aryl isomer.That improves selective alkylation drives electronics R
2Group comprises the derivative of substituted alkyl, acyl group, carboxylic acid and its aldehyde, acid amides and ester, halogen, haloalkyl (embodiment 3), nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide base or alkylphosphines acyl group.R
2Group be preferably haloalkyl and most preferably from the nearest carbon atom of pyrazoles ring by complete halogenated haloalkyl.Aromatic yl group plays a part relatively little for regioselectivity.
The preferred solvent of alkylated reaction comprises toluene, dimethylbenzene, cymene, acetone, dimethyl sulfoxide (DMSO), dimethyl formamide, diox etc., most preferably toluene.Alkylated reaction is most preferably under refluxad undertaken by intermediate and the sulfuric acid dialkyl reaction in dry toluene.For toluene solvant, can be neutral before the reaction; But in the alkylation process under refluxing, acidic conditions takes place immediately.For example, when methyl-sulfate was used as alkylating agent, intermediate methylated at the beginning, produces methylsulfonic acid immediately.In addition, for guaranteeing the preceding acidic conditions of reaction beginning, can add for example tosic acid of a spot of acid.This reaction preferably under normal pressure and temperature of reaction be about 60-120 ℃, most preferably from about carry out under 105 ℃.In alkylation process, the water that is present in the reaction mixture will be removed with toluene azeotropic mixture form.Preferred this azeotropic mixture of condensation also separates this phlegma, and toluene is turned back in the reaction mixture.This reaction process can be monitored by gas-chromatography, if necessary, can add other alkylating agent to promote finishing of alkylation pyrazoles transformation.Different according to reagent concentration and temperature of reaction, the reaction times can be from about several minutes to several days.Reaction can obtain the about 70%-85% of overall yield in about 16 hours under about 105 ℃.
After reaction was finished, product can separate and purifies by methods known in the art, these methods comprise precipitation and filter, concentrate, extraction, crystallization or chromatography.The aftertreatment of mixture of reaction products preferably is cooled to about 50 ℃, use successively then caustic solution (5%NaOH, 10%NaOH then) destroy any excessive methyl-sulfate and in and organic phase.Further use salt solution (1 0%) washed product mixture then.By adding methyl alcohol stripping toluene under the vacuum toluene solvant is replaced by methyl alcohol then.Separate 3-aryl regional isomer by the following method, add water (16: 1 methyl alcohol: water), be cooled to about 5-10 ℃ and centrifugally make required 3-aryl isomer crystallizes and unwanted 5-aryl isomer is stayed in the solution.
In most preferred concrete scheme, prepare the alkylation 3-arylpyrazole of general formula I Id from the phenyl diketone of general formula I Ib by following reaction:
This reaction is undertaken by the above-mentioned method for preparing general formula I d compound, and further illustrate in embodiment 1 (step B) substantially.Step C
The benzene compound that step C relates to the alkyl replacement is oxidized to corresponding phenylformic acid.The substrate of this reaction is preferably 2,4-dihalo-5-pyrazoles toluene.Method for oxidation of the present invention also is particularly suitable for other alkyl substituted benzene substrate, for example comprise unsubstituted toluene, the toluene that replaces, having a substituting group at least is the toluene of the replacement of the toluene of 6 yuan of heterocyclic replacements at the most that replace or unsubstituted and the pyrazoles that at least one substituting group is pyrazoles or replacement.Specifically, method for oxidation of the present invention can be used for preparing the phenylformic acid pyrazoles of the replacement of general formula III g by following reaction from the replacement toluene of general formula III f,
Wherein in following formula, R
5And R
6Be that halogen and Pyr are that replace or unsubstituted pyrazoles.Used herein term " pyrazoles of replacement " is the pyrazoles of the replacement of general formula Pyr-1,
Wherein in following formula, R
1Be hydrogen, alkyl or the alkyl that replaced by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide base or alkylphosphines acyl group; And R
3It is hydrogen or halogen.1-alkyl-5-aryl isomer of the special preferred formula Pyr-2 of pyrazoles that replaces
Wherein in following formula, R
1Be hydrogen or C
1-5Alkyl; R
2Be hydrogen or C
1-3Haloalkyl; And R
3It is hydrogen or halogen.
The replacement toluene oxidation of general formula III f becomes the benzoic method of general formula III g, and the concrete grammar by following preparation general formula I e and general formula I Ie compound carries out substantially.
In the preferred version of a step C, press following reaction by 2 of oxidation general formula I d, the benzoic acid compounds of 4-dihalo--5-pyrazoles-toluene compound general formula I e:
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, and R
5And R
6It is halogen.This reaction is preferred in the presence of metal salt catalyst or their mixture, catalyst promoting agent and free-radical initiator, is undertaken by compound and the molecular oxygen direct oxidation of general formula I d.As described below, use benzoyl peroxide as the initiator of this reaction the more durable and safety and reliability of initiator than prior art.
Various metal salt catalysts for example cobalt salt, manganese salt, nickel salt, cesium salt and zirconates can use or unite use separately.The example of this salt comprises cobaltous acetate (II), cobaltous formate, caproic acid cobalt, cobalt chloride, cobaltous carbonate, acetylacetone cobalt, manganous acetate (II), Manganous chloride tetrahydrate, cesium acetate (III), methyl ethyl diketone zirconium (IV), zirconium chloride, nickelous chloride etc.Cobaltous acetate (Co (OAc)
2), manganous acetate (Mn (OAc)
2) or its promotor be preferred catalyst.The total amount of using single catalyst or blended united catalyst with respect to the amount of general formula I d compound approximately less than 1% to about 100% molar equivalent.
Catalyst promoting agent uses with metal salt catalyst.Comprised alkylogen, halide salts, lithium salts, carboxylate salt by preferred catalyst promoting agent, preferred especially halide salts is alkali metal halide and ammonium halide for example.As catalyst promoting agent for example Sodium Bromide, hydrogen bromide and brometo de amonio of bromide most preferably.The usage quantity of halide salts promotor is preferably about 0.1%-10% mole with respect to the amount of general formula I d compound.Ketone for example acetone also can be used as promotor as catalyst promoting agent or with halide salts.Bound by theory not, acetone can typically quicken the reaction of slow inductive phase, therefore can shorten the 20%-30% of total reaction time.
Any known initiator is hydrogen peroxide for example, is suitable for causing this oxidizing reaction, and preferred initiator is a benzoyl peroxide.Use benzoyl peroxide than using hydrogen peroxide to make reacting phase to stronger, more reliable and safer, in fact, the oxidizing reaction that hydrogen peroxide causes is general dangerous and frequent unstable.Bound by theory not believes that the impurity that benzoyl peroxide makes reaction pair hinder reaction to carry out usually is insensitive.The benzoyl peroxide preferable amount is about 0.1%-10% mole with respect to the amount of the toluene compound of the replacement of general formula I d, more preferably from about 0.1%-5% mole and most preferably from about 0.3%-0.7% mole.
This reaction is preferably carried out in any suitable reagent that can not hinder this reaction process; Yet this reaction also can be carried out under solvent-free.Preferred solvent comprises aliphatic carboxylic acid and acid anhydrides for example acetate and diacetyl oxide.Most preferred solvent is an acetate.
The substrate compounds of general formula I d preferably mixes in suitable containers with catalyzer, catalytic promoter and initiator.Most preferred reaction mixture comprises substrate and following promotor, catalyst promoting agent and the initiator that is blended in the acetate: about 0.9%-1.1% mole Co (OAc)
2, about 0.09%-0.11% mole Mn (OAc)
2, about 2.7%-3.3% mole Sodium Bromide, about 4.5%-5.5% mole of acetone and 0.6%-0.8% mole benzoyl peroxide.The molecular oxygen that provides in reaction mixture is the excessive pure oxygen of stoichiometric calculation, air or oxygen and the AIR MIXTURES in other gas.Bound by theory not, speed of reaction seems to be subjected to the restriction of mass transfer.Therefore, this mixture is answered thorough mixing or is stirred in reaction process and makes oxygen obtain maximum dispersion.This reaction can be carried out under normal pressure, or if desired, carries out adding to depress.When in compression system, using oxygen, oxygen pressure preferably about 1 * 10
5Pa-70 * 10
5Pa (about 1 normal atmosphere to about 1000Psig) and more preferably from about 1 * 10
5Pa-18 * 10
5Pa (about 1 normal atmosphere is to about 250Psig).Oxygen pressure most preferably from about 1.7 * 10
5Pa (about 10Psig).When using air, above-mentioned force value is meant the dividing potential drop of oxygen in the air.High pressure is to the favourable influence of speed of reaction, but the investment cost of reacting required under the high pressure whole benefits that may to negate it bring.Carry out this react preferred temperature be about 80 ℃ to solvent boiling point.When using acetate to make solvent, temperature of reaction is preferably about 80 ℃-120 ℃, more preferably from about 110 ℃.Reaction times according to the concentration of reagent different with temperature of reaction from several minutes to several days.About 110 ℃ of reactions about 5-50 hour, the typical yields of acquisition was about 90%.
After reaction is finished, can separate and purified product with customary way.But the phenylformic acid of the general formula I e that obtains will be used for the subsequent step of entire method, and preferably next step (step D) is preceding not to be separated from solution this product being used for.When subsequent step that expectation is used for, this reaction mixture remains on greater than under 70 ℃, reduces to minimum so that form sedimentary possibility.
In most preferred concrete scheme, prepare the phenylformic acid of general formula I Ie from the arylpyrazole of general formula I Id by following reaction process:
This reaction is undertaken by the above-mentioned method for preparing general formula I e compound substantially, further illustrates in embodiment 1 (step C).In this reaction, the methyl on the preferential and pyrazoles of the methyl on the aryl of general formula I Id is oxidized.Typically, only there is the methyl on its pyrazoles of product of 1-2% oxidized.For preventing the further oxidation of pyrazoles methyl, as long as be stopped reaction after all arylmethyls have reacted.For example, in case after HPLC measured all substrate compounds reactions, if can be by cutting off oxygen supply and being compression system, then open container comes termination reaction.Step D
Step D relates to the halogenation of heterogeneous ring compound.This reacts preferred substrate is 1-alkyl-3-aryl-5-halogen alkyl pyrazole, and bromination process of the present invention more is usually used in other heterocycle substrate, comprises the heterogeneous ring compound of maximum six-rings, the pyrazoles of unsubstituted pyrazoles or replacement.Specifically, the pyrazoles that bromination process of the present invention can replace from the phenyl of the compound general formula III h of general formula III d by following reaction,
Wherein: Ar be phenyl or with steps A in the phenyl of the identical replacement of definition; R
1Be hydrogen, alkyl or the alkyl that replaced by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group.More preferably R
1Be hydrogen or C
1-5Alkyl and R
2Be C
1-3Haloalkyl.The bromination reaction of these substrates is undertaken by the method for the compound of following preparation general formula I f and Iif substantially.
Step D especially preferably relates to 1-alkyl-3-aryl-5-halogen alkyl pyrazole halogenation formation 4-halo pyrazoles.By the halogenation pyrazoles of following reaction by the compound general formula I f of halogenation general formula I e
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl and R
3, R
5And R
6It is halogen.Suitable halogenating agent known in the art comprises chlorine, N-chlorosuccinimide, SULPHURYL CHLORIDE, bromine, N-bromosuccinimide etc.The amount of halogenating agent can be for extremely excessive less than a molar equivalent with respect to the amount of the 3-aryl pyrazole compound of general formula I e.Any inert solvent be can use, organic acid, mineral acid, hydrocarbon, halohydrocarbon, aromatic hydrocarbons, ether, sulfide, sulfoxide and sulfone comprised.Temperature of reaction can be from about 10 ℃ to about 100 ℃ and according to reacting condition times such as the concentration of reagent and temperature of reaction.
R
3Preferred bromine, in preferred concrete scheme, the bromination that step D relates to heterogeneous ring compound is 1-alkyl-3-aryl-5-halogen alkyl pyrazole for example.Can react with bromide anion by the compound by general formula I e, be the bromination pyrazoles (R of general formula I f with the compound bromination of general formula I e
3Be bromine).Bromide anion preferably produces by the oxidation bromide salt.Organic and inorganic bromide salt all is fit to, and preferred inorganic bromine salt is alkali metal bromide (for example Sodium Bromide) for example.Preferred oxygenant comprises separately independently aqueous sodium hypochlorite solution and chlorine.Bromide anion also can be used bromine chloride (BrCl) expression, for example makes by mixing bromine and chlorine.The bromide anion that produces from bromide salt under oxidizing condition generally has more reactive behavior and has more selectivity than liquid bromine.Reaction times with this system can shorten an order of magnitude than the reaction times of using liquid bromine.In addition, bromide reagent used herein is generally cheap than liquid bromine, and the method for this paper can reduce to minimum with the waste of the bromide that produces.
This reaction can be carried out in any suitable solvent, but preferably uses aliphatic acid solution for example to carry out in the acetate.Use acetic acid solution can help minimum is reduced in unwanted side reaction, for example benzene halide formic acid becomes acyl halide.
Preferably excessive Sodium Bromide is added in the acetic acid solution that contains general formula I e compound.The total amount of Sodium Bromide is preferably about 1.0-1.6 molar equivalent with respect to the amount of the phenylformic acid substrate of general formula I e in reaction mixture, more preferably from about 1.15-1.5 molar equivalent, most preferably from about 1.4 molar equivalents.Note, when general formula I e compound directly when the oxidation step of front provides, existing mixture may contain the NaBr that uses as promotor of relatively small amount in oxidizing reaction.In the case, when determining to add the amount of NaBr, the NaBr in solution should be counted.Preferably add Sodium Bromide with the aqueous solution form of its formation by NaBr being dissolved in distilled water or the deionized water (water of about 17-25 molar equivalent, preferred about 21 molar equivalents).When adding NaBr and carrying out subsequent reactions with the reaction mixture thorough mixing, so that obtain high bromination rate and minimum is reduced in side reaction.Preferably add Sodium Bromide lentamente to avoid producing bulk precipitation and controlled temperature about below 70 ℃.Add oxygenant and reaction mixture is heated to desired reaction temperature, temperature of reaction is preferably about room temperature to about 100 ℃, especially preferably about 70-90 ℃ and most preferably from about 75-85 ℃.
When using chlorine, slowly in reaction mixture, add excessive chlorine and mixing as oxygenant.The amount of excess chlorine is preferably about 1.0-1.5 molar equivalent with respect to the amount of the heterocycle substrate of general formula I e.When the arylpyrazole product of the oxidation that obtains as step C then carries out bromination reaction in this step without separation, the amount of excess chlorine is preferably about 1.0-1.3 molar equivalent, most preferably from about 1.15 molar equivalents with respect to the amount of the toluene substrate of the replacement of general formula I d (step C).Bound by theory not it is believed that the reaction of chlorine and sodium bromide solution forms bromide anion, HCl and NaCl, and the substrate of bromide anion bromination reaction.Follow chlorination, exothermic heat of reaction.Along with the progress of reaction, the reaction mixture more and more thickness that generally becomes can elevated temperature and/or add more water so that thorough mixing.If pass through HPLC or fluorine NMR assaying reaction imperfect tense, again chlorination (about 0.1 molar equivalent).
When with clorox during, after adding Sodium Bromide, add excessive clorox and mix with substrate compounds as oxygenant.Be preferably maintained in the range of from about 70 ℃ and stirred reaction mixture simultaneously, clorox added with the form of the aqueous solution.The amount of excessive clorox is preferably about 1.0-3.0 molar equivalent with respect to the amount of the heterocycle substrate of general formula I e.When the arylpyrazole product of the oxidation that obtains as step C directly carries out bromination reaction without separation, the amount of excessive clorox is preferably about 1.5-3.5 molar equivalent, most preferably from about 2.5 molar equivalents with respect to the amount of the toluene substrate of the replacement of general formula I d (step C).React as the method for oxygenant with chlorine by above-mentioned then.By performance characteristic, clorox and chlorine as oxygenant equally by preferably.But, these oxygenants preferably also can be according to other factors, operability for example.Also can use other oxygenant well known by persons skilled in the art.Do not consider employed oxygenant, bromination reaction preferably carries out under normal pressure.Reaction times can be from several minutes by several days, and about 75-85 ℃ was reacted 2-4 hour down, obtain the productive rate greater than about 90%.
After reaction is finished, reaction mixture is cooled to about room temperature or a little higher than room temperature.Destroy excessive oxygenant then and required bromination pyrazoles product is settled out from solution.When using NaOCl/NaBr or chlorine system, for example sodium sulfite aqueous solution can destroy residual oxidizer and the formation product precipitates by add the reductive agent aqueous solution in reaction mixture.Can add other a certain amount of water precipitates required product fully and helps and mix.When inorganic salt are dissolved in reaction mixture after for some time (approximately 15-30 minute), can be from solution the filtering-depositing product, use deionized water wash and drying then.If the halo pyrazole compound of the general formula I f that obtains will be used for follow-up esterif iotacation step, should be with the product thorough drying.
In a most preferably concrete scheme, press the bromination arylpyrazole of following reaction from general formula I Ie compound general formula I If:
This reaction is undertaken by the above-mentioned method for preparing general formula I f compound substantially, and will further illustrate in embodiment 1 (step D-1 and D-2).Step e
Step e relates to the esterification of carboxylic acid.Though this reacts preferred substrate is 2,4-dihalo--5-pyrazoles phenylformic acid, but esterification process of the present invention also more is widely used for other carboxylic acid, and what comprise ester group carboxylic acid, longer chain fatty acid, heterocyclic carboxylic acid, replacement is to replace or the phenylformic acid of the replacement of unsubstituted maximum hexa-member heterocycles with unsubstituted phenylformic acid and at least one substituting group.Specifically, can use the esterification process of this paper, by the benzoic ether of following reaction from the compound general formula III i of general formula III g,
Wherein Pyr is pyrazoles or the substituted pyrazolecarboxylic as step C definition, R
5And R
6Be halogen and R
10Be C
1-5Alkyl.The esterification of these substrates is undertaken by one of two kinds of esterification schemes, and these two kinds of schemes will be described in detail in the preparation of the compound of following general formula I and general formula I I.
In a special preferred method, a kind of by in two kinds of schemes, 2 of the compound general formula I by esterification general formula I f, 4-dihalo--5-pyrazoles-benzoic ether:
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
1-5Alkyl.In brief, in first esterification scheme, the phenylformic acid of general formula I f and halogenating agent reaction form corresponding acyl halide.Then, this acyl halide wants the excessive esterifying agent of the pure and mild acyl halide formation of esterification to stir with premix.In the scheme of benzoic ether of another preparation general formula I, with the phenylformic acid of trialkyl ortho ester esterification general formula I f.These two kinds of esterification schemes are suitable for that all steric hindrance is arranged-esterification of OR group, for example sec.-propyl.
In first esterification scheme, prepare the acyl halide intermediate by methods known in the art.A typical method comprises for example reactions such as thionyl chloride, phosphorus pentachloride, oxalyl chloride of phenylformic acid substrate and halogenating agent.The inert solvent that can use not overslaugh halogenating reaction is toluene for example, can be by for example accelerated reactions such as triethylamine, pyridine or dimethyl formamide of amine alkali that add catalytic amount.The halogenation of phenylformic acid substrate preferably at room temperature, mixes the toluene solution of substrate with excessive halogenating agent (1.1-1.7 equivalent), adds several dimethyl formamides, slowly is heated to about 75 ℃ and at the about 1-3 of this thermotonus hour.Other temperature of reaction and reaction times also suit.After forming the acyl halide intermediate, under keeping about 75 ℃, remove toluene solvant and excessive halogenating agent by coupling vacuum stripping.
The acyl halide intermediate with by mixing a spot of acyl halide and general formula R
10The esterifying agent reaction that the alcohol of OH makes.Acyl halide is preferably C
1-3Acyl halide, preferred especially acetyl halide.The halogen atom of acyl halide is general identical with the halogen atom of esterified acyl halide intermediate, and is preferably chlorine.Most preferred acyl halide is an Acetyl Chloride 98Min..Add acyl halide and make the weight that forms esterifying agent make the weight that forms esterifying agent, be preferably about 0.1-10%, be preferably about 2-5% especially and most preferably be about 4% with respect to adding alcohol.Bound by theory not, acyl halide for example Acetyl Chloride 98Min. it is believed that the trace water that can remove in the pure reagent that may be present in deposit, therefore avoided competing reaction potentially when wanting esterified acyl halide intermediate reaction at esterifying alcohol.Acyl halide show with the water reaction than with the alcohol reaction more preferably, particularly when this alcohol be that hindered alcohols is for example during Virahol.Use acyl halide/pure esterifying agent to allow to use low-level alcohol (rank that promptly contains about 1-2% water) that the ester products productive rate and the purity of gained are improved.When acyl halide and alcohol mix to form esterifying agent, as heat release and emit HCl gas expecting.Excessive esterifying agent (about 5-15 molar equivalent and preferred about 10 molar equivalents) added the acyl halide intermediate and under normal pressure, react, temperature of reaction maintain about 0 ℃ to the boiling point of alcohol approximately.When using Virahol as esterifying alcohol, temperature of reaction is preferably about 0-80 ℃, most preferably from about 75 ℃.Esterification obtains HCl gas and washs in reaction process.Can change reaction time, at about 75 ℃ of productive rates that reaction can obtain greater than about 90% in about 1-2 hour.The esterification products of gained also has very high purity (greater than about 90%), has simplified product postprocessing and has improved useful load and loop cycle.The benzoic ether product that obtains can be removed excessive alcohol or precipitated product separates by vacuum.In preceding a kind of separation method, reaction mixture preferably heats and is maintained at about under 80-90 ℃, decompression stripping alcoholic solvent and other volatile matter.The remaining mixture that will contain product then is cooled to room temperature.In addition, also can be by being cooled to about 50 ℃ and aqueous precipitation product, filtering separation then.
In another esterification scheme, the benzoic ether of phenylformic acid by general formula I f and the trialkyl ortho ester prepared in reaction general formula I of general formula F1
In following formula, R
10Be C
1-5Alkyl and R
11It is hydrogen or alkyl.R
10Be preferably C
3-5Alkyl.R
11Be preferably hydrogen, the trialkyl ortho ester is preferably the trialkyl ortho-formiate.Trialkyl ortho ester for example trialkyl ortho-formiate provides the required alkyl ester of high productive rate.
Can be with trialkyl ortho ester esterification phenylformic acid solvent-free or in suitable solvent, carry out.The solvent systems that uses have aromatic hydrocarbon solvent for example toluene, dimethylbenzene and cymene for example methoxy ethyl ether, diethoxy ether Huo diox are suitable solvents with relative high boiling ether.Preferably phenylformic acid substrate and excessive trialkyl ortho ester (about 1.1-1.5 molar equivalent, preferred about 1.3 molar equivalents) are mixed and be heated to about 80-150 ℃, especially preferably about 130-140 ℃ and most preferably from about 135 ℃.Reaction mixture is heated to about 110 ℃, begins from reaction mixture, to remove volatile by product.Reaction is preferably carried out under normal pressure.Reaction times changes according to temperature of reaction and reagent concentration; Can obtain about 90% productive rate in about 1-2 hour 135 ℃ of reactions.After the reaction, can remove excessive trialkyl ortho-formiate, solvent and volatile by product, esterification products is separated with dissolved matter, then cooling by stripping.On the other hand, can add Virahol, add water then and make esterification products form precipitation by being cooled to about 50 ℃.The filtering separation precipitated product at random washs with isopropanol in addition again, and dry.
In most preferred concrete scheme, use the esterification arylpyrazole of the compound general formula I I of general formula I If by following reaction:
This reaction can be substantially undertaken by arbitrary method of two kinds of esterification schemes of the compound of above-mentioned preparation general formula I.When using first kind of esterification scheme, the preferred esterifying agent of preparation isopropyl esters is formed by the Acetyl Chloride 98Min. and the Virahol mixing of 4% (weight).When using second kind of esterification scheme, trialkyl ortho ester esterifying agent is preferably orthoformic acid triisopropyl ester, about general formula F1, R
10Be sec.-propyl (CH (CH
3)
2) and R
11Be hydrogen.The method that forms the isopropyl esters of general formula I I will illustrate respectively in acyl halide/pure and mild trialkyl ortho ester scheme of embodiment 1 (step e-1 and E-2).Sequence of steps
The step of the compound of preparation general formula I or II is preferably undertaken by the order of aforesaid A-E: the formation of diketone (steps A), cyclisation (condensation) and alkylation (step B), oxidation (step C), halogenation (step D) and esterification (step e).This order of determining is not immutable, and those of ordinary skill in the art can make corresponding change.
For example, the order of halogenation step can change.Halogenating reaction can be carried out between alkylation and oxidation step.With reference to above-mentioned steps, the phenyl diketone that makes from methyl phenyl ketone can prepare aryl pyrazole compound (steps A), condensation of phenyl diketone and alkylation form alkyl pyrazole (step B), halogenation pyrazoles part (step D), methyl on the Oxybenzene base section (step C) and esterification (step e).By the compound (steps A) of this concrete scheme by acidylate general formula I a
Form the compound of general formula I b,
The compound of general formula I b and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I d,
The compound (step D) of halogenation general formula I d forms the compound of general formula I g
The compound (step C) of oxidation general formula I g form general formula I f compound and
The compound (step e) of esterification general formula I f forms the compound of general formula I.
In addition, can be after oxidation and esterif iotacation step halogenation pyrazoles part.In this case, by forming phenyl diketone (steps A) preparation arylpyrazole, condensation of phenyl diketone and alkylation form alkylation pyrazoles (step B), and the methyl on the Oxybenzene base section forms phenylformic acid pyrazoles (step C), esterification phenylformic acid (step e) and halogenation pyrazoles part (step D).Compound (steps A) by acidylate general formula I a
Form the compound of general formula I b,
The compound of general formula I b and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I d,
The compound (step C) of oxidation general formula I d forms the compound of general formula I e,
The compound (step e) of esterification general formula I e form general formula I h compound and
The compound (step D) of halogenation general formula I h forms the compound of general formula I.
The variation of the sequence of steps of another preparation arylpyrazole is included in and forms preceding oxidation of pyrazoles and esterification phenyl moiety.For example, can form carboxylic acid-methyl phenyl ketone (step C) by the initial oxidation methyl-acetophenone, esterification (step e) forms phenyl diketone (steps A), and condensation of phenyl diketone and alkylation form alkylation pyrazoles (step B) and halogenation pyrazoles part (step D) preparation arylpyrazole.Specifically, can be by the compound (step C) of oxidation general formula I a
Form the compound of general formula I i,
The compound (step e) of esterification general formula I i forms the compound of general formula I j
The compound (steps A) of acidylate general formula I j forms the compound of general formula I k
The compound of general formula I k and hydrazine condensation form alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) form general formula I h compound and
The compound (step D) of halogenation general formula I h forms the compound of general formula I.
Another example, arylpyrazole can form phenyl diketone (steps A) by elder generation, the methyl (step C) on the oxidation phenyl diketone phenyl moiety, esterification (step e) forms alkylation pyrazoles (step B) and halogenation (step D) and prepares.According to said method, can be by the compound (steps A) of acidylate general formula I a
Form the compound of general formula I b,
The compound (step C) of oxidation general formula I b forms the compound of general formula I l,
The compound (step e) of esterification general formula I l form general formula I k compound and
The compound of general formula I k and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I h,
The compound (step D) of halogenation general formula I h forms the compound of general formula I.
In another changes in proper order, can before forming, pyrazoles carry out oxidation step, after forming, pyrazoles carries out esterif iotacation step.For example, arylpyrazole can form carboxylic acid-methyl phenyl ketone (step C) by the initial oxidation methyl-acetophenone, form phenyl diketone (steps A) then, condensation of phenyl diketone and alkylation form alkylation pyrazoles (step B), and halogenation pyrazoles part (step D) and esterification (step e) prepare.Specifically, can be by the compound (step C) of oxidation general formula I a
Form the compound of general formula I i,
The compound (steps A) of acidylate general formula I i forms the compound of general formula I l
The compound of general formula I l and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I e,
The compound (step D) of halogenation general formula I e form general formula I f compound and
The compound (step e) of esterification general formula I f forms the compound of general formula I.
Another example, arylpyrazole can be by forming phenyl diketone (steps A) earlier, and oxidation (step C) forms alkylation pyrazoles (step B), and halogenation (step D) and esterification (step e) prepare.Can be by the compound (steps A) of acidylate general formula I a
Form the compound of general formula I b,
The compound (step C) of oxidation general formula I b forms the compound of general formula I l,
The compound of general formula I l and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I e,
The compound (step D) of halogenation general formula I e form general formula I f compound and
The compound (step e) of esterification general formula I f forms the 3-aryl pyrazole compound of general formula I.
In addition, in the end in two examples, halogenation step can be carried out after esterification.Utilize this to change, can be by the compound (steps A) of acidylate general formula I a
Form the compound of general formula I b,
The compound (step C) of oxidation general formula I b forms the compound of general formula I l,
The compound of general formula I l and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I e,
The compound (step e) of esterification general formula I e form general formula I h compound and
The compound (step D) of halogenation general formula I h forms the compound of general formula I.
Another can be by the compound (step C) of oxidation general formula I a by the example that preferred sequence of steps changes
Form the compound of general formula I i,
The compound (steps A) of acidylate general formula I i forms the compound of general formula I l
The compound of general formula I l and hydrazine condensation form the compound of alkyl pyrazole precursor intermediate and this intermediate of alkylation (step B) formation general formula I e,
The compound (step e) of esterification general formula I e form general formula I h compound and
The compound (step D) of halogenation general formula I h forms the arylpyrazole of general formula I.In each reaction above, R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
1-5Alkyl.
Those skilled in the art will appreciate that also having other order to change can be used to prepare arylpyrazole by method of the present invention.The following example principle and advantage of the present invention of explaining.
EXAMPLE Example 1:5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-preparation of 2-chloro-4-fluorobenzoic acid isopropyl ester.Steps A:
By the compound 1,1 of following reaction from general formula I Ia, 1-three fluoro-4-[4-chloro-2-fluoro-5-methyl-phenyl-1-yls]-2,4-dimethyl diketone (general formula I Ib):
Under-5 ℃, with trifluoroacetyl chloride (2.6kg, relatively and the compound of general formula I Ia be 1.5 molar equivalents) blast in the methanol solution that contains 25% sodium methylate (4.24kg NaMeO is 1.5 molar equivalents with respect to the compound of general formula I Ia).Control adding speed makes temperature be no more than 40 ℃, exothermic heat of reaction.Joining day amounts to about 1.5 hours.The 4-chloro-2-fluoro-5-methyl acetophenone (2.434kg, 13.092 moles) that adds general formula I Ia then.Add the sodium methylate/methanol solution (4.24kg, 1.5 molar equivalents) of amount in addition, gentle heat release is heated to 60 ℃ and keep this temperature in reaction process with reaction mixture.Reaction process is monitored by gas-chromatography, shows that this reacts to finish in about 45 minutes.
For carrying out the cyclization of step B, the compound treatment of the general formula I Ib that makes is as follows.Add the 10%HCl aqueous solution (5.0kg) neutralization reaction.Stripped methanol obtains slurry under 45-50 ℃ and slight vacuum then.Add toluene solvant (11.62kg) and remove water layer.Wash the toluene solution of the product compound that contains general formula I Ib and be directly used in step B with deionized water (6.63kg) without further handling.
Other treatment processs about the product compound of general formula I Ib are used in other experiment.In an other method, for example, earlier stripped methanol obtains slurry under 45-50 ℃ and slight vacuum.Be cooled to room temperature then and add toluene solvant (11.62kg).With the 10%HCl aqueous solution (5.0kg) with use deionized water (6.63kg) washing toluene solution then.Remove water layer and toluene solution is directly used in step B without further handling.In another post-treating method, earlier reaction is cooled to 50 ℃, use the 10%HCl aqueous solution (7.0kg) neutralization then.Solution further is cooled to about 10 ℃, causes the product precipitation.By filtering separation precipitation, then with deionized water wash to filtrate pH greater than about 2.For in step B, using isolated compound, isolating precipitation is directly formed slurry without further drying in toluene (about 11kg).Step B:
By the compound 1-methyl-3-[4-chloro-2-fluoro-5-methyl-phenyl-1-yl of following reaction from general formula I Ib]-5-trifluoromethyl pyrazol (general formula I Id):
Under the room temperature, contain 1,1,1-three fluoro-4-[4-chloro-2-fluoro-5-methyl-phenyl-1-yls to what aforesaid method made]-2, add the 35% hydrazine aqueous solution (1.1 molar equivalent) in the toluene solution of 4-two butanone (general formula I Ib).Gentle heat release and to keep temperature in whole condensation reaction be about 40 ℃.Reaction mixture was stirred 30 minutes and passed through gas-chromatography monitoring reaction process at 40 ℃.In some experiments, some midbody products are precipitated out from solution in reaction process.
After reaction is finished, in case of necessity reaction mixture is heated to 70 ℃ and sedimentary intermediate is redissolved and/or to be convenient to make organic phase and water to be divided into different two-layer.Remove water layer and with 10% salt solution (2 * 2.77kg) washing toluene solutions.Discard salts solution then.
Slowly add methyl-sulfate (1.94kg, about 1.2 equivalents) in the toluene solution that contains alkyl pyrazole precursor intermediate that aforesaid method makes, control adding speed makes very exothermic reduce to minimum.After adding methyl-sulfate,, make azeotropic removal of water at 105 ℃ of reflux solution.By gas-chromatography monitoring reaction process.In experiment,, add methyl-sulfate (about 150-170 gram) in addition when reacting imperfect tense.After refluxing about 10 hours, cooling solution with the 10%NaOH aqueous solution (5.16kg) washing, with the 5%NaOH aqueous solution (5.16kg) washing, is used 10% salt solution (5.16kg) washing then.Stripping toluene also replaces with methyl alcohol (2.95kg) from solution.Add water (184 grams are 1: 16 weight ratio with respect to methyl alcohol) and make alkyl pyrazole reaction product precipitation, be cooled to about 5 ℃ then.The centrifugal precipitated product (about 2.858kg, light gray solid) of removing.The overall yield of steps A and step B is about 75%.Step C:
By compound 5-[1-methyl-5-(the trifluoromethyl)-1H-pyrazole-3-yl of following reaction from general formula I Id]-2-chloro-4-fluorobenzoic acid (general formula I Ie):
1-methyl-3-[4-chloro-2-fluoro-5-methyl-phenyl-1-yl of the general formula I Id that aforesaid method is made]-the 5-trifluoromethyl pyrazol (2.853kg, 9.755mol), Co (OAc)
24H
2O (24.16g, 0.098mol), Mn (OAc)
2H
2O (2.4g, 0.0097mol) and NaBr (30.24g 0.277mol) is added in the reactor.(11.00kg 184mol), then adds benzoyl peroxide (22.87g, 0.094mol in succession to add Glacial acetic acid then ... the hydration solid that contains 70% benzoyl peroxide for 32.67g) and acetone (27.66g, 0.49mol).Mixing substrate, catalyzer, catalytic promoter and initiator is reaction mixture, causes and carry out this reaction then.In reaction mixture, press air usually.Reaction mixture is heated to about 110 ℃ and keep this temperature in reaction process.With HPLC monitoring reaction process, this reaction was generally finished in 10-20 hour.The reaction mixture that contains product need not separate or other aftertreatment, and expection is used in following bromination reaction.
Carry out the variation of above-mentioned oxidation experiment.Except replacing the benzoyl peroxide with hydrogen peroxide, this reaction is carried out as stated above, and the initiation of oxidizing reaction is irregular and wants six hours sometimes.In experimentation, carry out this reaction the acetone as stated above except that in reaction mixture, not adding, reaction proceeds to the about 20%-30% of the time lengthening of finishing.In further experiment, use preferred reaction mixture, replace air, depress with air and oxygen as purge gas adding with oxygen.In addition, in some experiments, by cooling with add the water sepn reaction product.The productive rate of the Oxybenzene formic acid product that this reflection typically obtains greater than about 90% and purity be about 93%-97%.Step D-1:
By compound 5-[4-bromo-1-methyl-5-(the trifluoromethyl)-1H-pyrazole-3-yl of following reaction from general formula I Ie]-2-chloro-4-fluorobenzoic acid (general formula I If):
In four parts of acetate, contain 5-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl by the preparation of the method for above-mentioned steps C]-2-chloro-4-fluorobenzoic acid slurry.(1.36kg 1.35mol) is dissolved in the deionized water (3.69kg, about 21mol) and add the acetate substrate solution lentamente with Sodium Bromide.Under violent the mixing, add NaBr and carefully maintain the temperature at approximately more than 70 ℃, make formation bulk is sedimentary and may reduce to minimum.(789g 1.15mol), causes heat release to logical chlorine.Reactant becomes dense thick in reaction process, maintains the temperature at about 85 ℃ and helps stirring.Reaction process is independently by HPLC and fluorine NMR monitoring.As the reaction do not finish, add other amount chlorine (74g, 0.1mol).Reaction in about 3 hours is finished behind the chlorination terminal point.
Then reaction mixture is cooled to chamber Gentle 25% sodium sulfite aqueous solution (about 2.8kg, 0.15mol) quenching reaction.(3.69kg 20mol) helps to mix and bromizate product to precipitate fully to add water.After leaving standstill about 30 minutes, the filtering separation product is with being used for step e after deionized water wash and the thorough drying.Isolating the bromination arylpyrazole product (general formula I If) of about 3.50kg, is about 80%-90% with respect to the productive rate of the alkylation pyrazole compound of general formula I Id, the about 93-97% of purity.Step D-2:
Except using clorox to replace chlorine as the oxygenant, bromination process is undertaken by above-mentioned (step D-1).With Sodium Bromide (1.36kg, 1.35mol) be dissolved in deionized water (3.69kg, about 21mol) and adding contain 5-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-the acetate slurry of 2-chloro-4-fluorobenzoic acid after, keep temperature be about 70 ℃ and stir under slowly add the NaOCl aqueous solution (1.5-2.4mol).By HPLC monitoring reaction process, about 3 hours internal reactions are finished behind the adding NaOCl.After reaction is finished, cooling solution and reacting with the S-WAT all standing as stated above.Separated product has similar productive rate as stated above.Step e-1:
By compound 5-[4-bromo-1-methyl-5-(the trifluoromethyl)-1H-pyrazole-3-yl of following reaction from general formula I If]-2-chloro-4-fluorobenzoic acid isopropyl ester (general formula I I):
Under the room temperature, with above-mentioned 5-[4-bromo-1-methyl-5-(the trifluoromethyl)-1H-pyrazole-3-yl that makes]-2-chloro-4-fluorobenzoic acid (3.50kg) thorough drying and be dissolved in toluene (7.38kg, 9mol).25 ℃ add down thionyl chloride (1.58kg, 1.5mol) and dimethyl formamide (9.2g 0.01mol) and with reaction mixture slowly is heated to 75 ℃.The control heating rate is with the solution foaming of avoiding of maximum possible.React and finish at 75 ℃ at about 2 hours internal reactions.Under keeping 75 ℃, coupling vacuum stripping toluene solvant and excessive thionyl chloride stay corresponding acyl halide intermediate (about 3.8kg), are oily matter.
(5.53kg 10.6mol) mixes the formation esterifying agent with Acetyl Chloride 98Min. (221g) with the SILVER REAGENT Virahol.Observe heat release and emit HCl gas.Under 75 ℃, esterifying agent is added in the chloride of acid intermediate.Stirred reaction mixture and to keep temperature in reaction process be 75 ℃, and the washing HCl gas of emitting.By gas-chromatography monitoring reaction process, in about 2 hours, finish.
Reaction mixture is cooled to 50 ℃ then.In sedimentary product, add water (11kg) lentamente.The filtering separation product obtains brown to white waxy solid, and purity is greater than about 92% and the about 90-94% of productive rate.
In other experiment, other product postprocessing method comprise decompression down the stripped product mixture and at about 80-90 ℃ down except that desolvating and all volatile matters.Melt is cooled to room temperature forms blocks of solid.Step e-2:
In another esterification scheme, above-mentioned 5-[4-bromo-1-methyl-5-(the trifluoromethyl)-1H-pyrazole-3-yl that makes]-2-chloro-4-fluorobenzoic acid (300g, 0.747mol) (186g 1.3mol) mixes, and is heated to about 135-140 ℃ then to remove low-boiling by-products with orthoformic acid three isopropyl esters.HPLC monitors this reaction, finishes in about 1.5 hours.
Decompression is excessive orthoformic acid three isopropyl esters and the volatile byproducts of stripping down, with the gained oily matter cooling of fusing with separate.In other experiment, come precipitated product by cooling off this reaction mixture to about 50 ℃, add Virahol (480g), add water (600g).Further water/aqueous isopropanol (240g, 1: 0.8 weight, water: washing precipitation product Virahol).Filtering separation product and drying.Product purity is greater than about 92%, productive rate about 90%.The preparation of embodiment 23 (5)-[4-chloro-2-fluoro-5-aminomethyl phenyl-1-yl]-5 (3)-(trifluoromethyl)-1H-pyrazoles.
With 1,1,1-three fluoro-4-[2-chloro-4-fluoro-5-aminomethyl phenyl-1-yls]-2, the 4-dimethyl diketone prepares 3 (5) of general formula I IC-[4-chloro-2-fluoro-5-aminomethyl phenyl-1-yl]-5 (3)-(trifluoromethyl)-pyrazoles.
Dimethyl diketone (20.6g) is dissolved in the 100ml acetate in the 500ml flask that has magnetic stirring bar.Once add all hydrazines (2.85g) and heat release to about 45 ℃.Solution is heated to 110 ℃ and kept 15 minutes under this temperature.Then this reaction mixture is cooled to room temperature and pours in the water (200ml), obtain the white solid precipitation.Filtering separation precipitated product, air-dry overnight then.With this solid of 200ml hexane wash with through dry air momently, obtain the aryl pyrazole compound (19.6g) of general formula I IC, be (m.p.159-160 ℃ of white solid; Analyze .C
11H
7N
2F
4Cl
1Calculated value .:C-47.42, H-2.53, N-10.05; Measured value: C-47.36, H-2.58, N-10.07).Productive rate is about 97%.Alkylating 3 (5)-aryl-5 of N-(3)-haloalkyl pyrazoles of embodiment 3 regioselectivities.
By following reaction, prepare the alkylation pyrazoles of the regiospecificity of general formula III e with the phenyl diketone of general formula III b
Wherein in following formula, Ar is 2,5-difluorophenyl and R
2Be CF
3The compound of general formula III b and hydrazine cyclisation, and with the intermediate and the various methylating agent (CH of gained
3X) under different solvents and reaction conditions, react.In several differential responses, the percentages show of gained 3-aryl and 5-aryl isomer is in table 3-1.
Table 3-1
| Alkylating agent | Condition (solvent, temperature) | %N-methyl product | |
| The 3-aryl | The 5-aryl | ||
| ??CH 3I | Acetone, K 2CO 3, room temperature | ????70 | ????30 |
| ??CH 3I | ????DMF，K 2CO 3, room temperature | ????70 | ????30 |
| ??CH 3I | ????DMSO，K 2CO 3, room temperature | ????65 | ????35 |
| ??(CH 3) 2SO 4 | ????50％NaOH/CH 2Cl 2, room temperature | ????64 | ????36 |
| ??CH 3BR | Acetone, K 2CO 3, room temperature | ????78 | ????24 |
| ??(CH 3) 2SO 4 | Acetone, K 2CO 3, room temperature | ????77 | ????23 |
| ??CH 3BR | Acetone, K 2CO 3，0℃ | ????80 | ????20 |
| ??(CH 3) 2SO 4 | Toluene refluxes | ????96 | ????4 |
| ??(CH 3) 2SO 4 | Toluene, K 2CO 3, room temperature | ????55 | ????45 |
Under alkaline condition, carry out this reaction, with salt of wormwood or sodium hydroxide as alkali, in the N-methylpyrazole gross product that makes, the about 55-80% of percentage 5-aryl isomery height of the 3-aryl isomer that selectivity forms, the methylating reagent of use low reactivity for example methyl bromide and lower temperature of reaction can obtain better choice.Yet, under acidic conditions, react and can improve selectivity significantly.The methyl-sulfate of use in backflow toluene is as methylating reagent (forming methylsulfonic acid) in reaction process, about 96% alkylating arylpyrazole product is required 3-aryl isomer.Under acidic conditions, repeat this reaction and can similar highly selective obtain 3-aryl isomer,, the results are shown among the table 3-2 when using the substituting group on the different phenyl at (methyl-sulfate in the dry toluene that is refluxing) under the identical reaction conditions.
Table 3-2
| Aryl | %N-methyl product | |
| The 3-aryl | The 5-aryl | |
| 2,5-two fluoro-phenyl | ????96 | ????4 |
| 2,4-two fluoro-phenyl | ????96 | ????4 |
| 2,4-two chloro-phenyl | ????88 | ????12 |
| 4-chloro-2-fluoro-5-methyl-phenyl | ????91 | ????9 |
In above-mentioned each reaction, the regional chemistry of alkylation haloalkyl pyrazoles distributes by 3 and 5 carbon of pyrazoles ring
13The chemical shift of C nmr is relatively measured.In brief, for aryl substituent, the C3 carbon of 3-aryl isomer has significant hydrazone feature and about 143ppm, and the C5 carbon of 5-aryl isomer has significant alkene hydrazine feature and be shown in the about 133ppm in upfield.These distribute consistent with the X-ray structure of long scope coupling experimental result and 3-aryl isomer.The preparation of embodiment 4:3 (5)-aryl-5 (3)-difluoro chloromethyl pyrazoles
It is alkylating decomposition simultaneously under alkaline condition, and successfully alkylation under acidic conditions.
The 3-aryl-5-halogen alkyl pyrazole of general formula III c,
Wherein Ar is 4-chloro-phenyl-and R
2Be by 1,1-two fluoro-1-chloro-4-[4-chloro-phenyl--1-yls]-2, the CF of 4-dimethyl diketone preparation
2Cl.(60.0g, also (0.253mol 8ml) handles this solution to Glacial acetic acid 0.240mol) (250ml) solution with hydrazine to stir dimethyl diketone.Temperature has increase slightly.This mixture was refluxed one hour, after the cooling, add water (500ml).Use the extracted with diethyl ether product, merge extract and also wash with water, then with 10% sodium hydrogen carbonate solution washing also vacuum concentration get the aryl pyrazole compound of general formula III c.
At alkaline condition (K
2CO
3, the arylpyrazole of MeI) alkylation general formula III c.Yet basic alkylation is not just decomposed when forming any alkylation pyrazoles.CF
2The incoordination of Cl group and alkali is by being proved to be with processes of carbonate treatment intermediate (general formula III c) lacking alkylating agent.In the case, at room temperature decomposed less than one hour.But, under acidic conditions successfully alkylation 3-aryl-5-halogen alkyl pyrazole analogue (wherein Ar is 4-chloro-2-fluoro-5-methoxyl group-phenyl and R
2Be CF
2Cl).5-[4-chloro-2-fluoro-5-methoxyl group-phenyl-1-yl that will be in toluene]-(14.50g 0.0466mol) refluxed one hour in dean stark trap, but does not collect moisture 3-(chlorodifluoramethyl-)-pyrazoles.(5.61g 0.0445mol) and with this mixture refluxed 3.5 hours to add methyl-sulfate by syringe.With isopyknic NaOH (2.5N) washed product mixture and filtration organic layer.Solvent removed in vacuo and with products therefrom continuous recrystallization four times from hexane, alkylated aryl pyrazoles (9.22g, 73% productive rate), be white crystalline solid (fusing point 73-74; Analyze. calculated value C
12H
9N
2OF
3Cl
2Calculated value .:C-44.33, H-2.79, N-8.62; Measured value: C-44.32, H-2.77, N-8.60).
According to detailed description of the present invention and the foregoing description, several purposes of the present invention all realize.
The explanation of this paper and example are attempted to allow and be those skilled in the art are afamiliar with its principle and practical application.For being more suitable for indivedual needs that use, those skilled in the art can adapt to and use the present invention in a variety of forms.Therefore, the illustrated concrete scheme of the present invention is not in order to limit the present invention.
Claims (151)
1. method for preparing general formula III b compound,
This method comprises, the methyl phenyl ketone of general formula III a,
With the halo acyl halide acidylate of general formula A1,
This halo acyl halide has complete halogenated alpha-carbon, and wherein Ar is the phenyl of phenyl or replacement; R
2Be C
1-3Haloalkyl; With Z be halogen.
2. the process of claim 1 wherein that Ar is general formula Ar-2
Wherein, R
5And R
6Be halogen and R
7Be low alkyl group, haloalkyl or
, the W here be hydrogen, hydroxyl, halogen or-OC
1-5Alkyl.
3. the method for claim 2, wherein R
7It is low alkyl group.
4. the method for claim 2, wherein R
2Be trifluoromethyl, R
5Be fluorine, R
6Be chlorine and R
7It is methyl.
5. the process of claim 1 wherein that this halo acyl halide is a trihalogen acetyl halogen.
6. the process of claim 1 wherein that this halo acyl halide is a trihalogen acetyl chlorine.
7. the process of claim 1 wherein that this halo acyl halide is three fluoro ethanoyl chlorine.
8. the process of claim 1 wherein methyl phenyl ketone under alkaline condition by acidylate.
9. the process of claim 1 wherein the methyl phenyl ketone of general formula I Ia,
By acidylate is the compound of general formula I Ib,
Its method is, adds the halo acyl halide in the solution that contains alkoxide and alcohol, forms reagent mixture, then, adds methyl phenyl ketone in this reagent mixture.
10. the method for claim 9, wherein the halo acyl halide is a trifluoroacetyl group chlorine, alkoxide is that methylate and alcohol are methyl alcohol.
11. the process of claim 1 wherein the methyl phenyl ketone of general formula I j,
By acidylate is the compound of general formula I k.
12. the process of claim 1 wherein the methyl phenyl ketone of general formula I i
By acidylate is the compound of general formula I l.
13. a method for preparing general formula III d compound,
This method comprises, the phenyl diketone of general formula III b,
In reaction mixture with the hydrazine condensation, generate alkyl pyrazole precursor intermediate, hydrazine exists so that stoichiometric calculation is excessive with respect to the phenyl diketone in reaction mixture, the amount of excessive hydrazine be normal content at least about 15% mole, normal content is the summation of molar weight of the intermediate of unreacted phenyl diketone molar weight and generation, from reaction mixture, remove excessive hydrazine and with this intermediate of alkylating agent alkylation, wherein Ar is the phenyl of phenyl or replacement; R
1It is the alkyl that alkyl or halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio replace; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group.
14. the method for claim 13, wherein R
1Be C
1-5Alkyl and R
2Be C
1-3Haloalkyl.
15. the method for claim 13, wherein Ar is general formula Ar-2,
R wherein
5And R
6Be halogen and R
7Be low alkyl group, haloalkyl or
, wherein W is a hydrogen, hydroxyl, halogen or-OC
1-5Alkyl.
16. the method for claim 15, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl and R
7It is low alkyl group.
17. the method for claim 15, wherein R
1Be methyl, R
2Be trifluoromethyl, R
5Be fluorine, R
6Be chlorine and R
7It is methyl.
18. the method for claim 13, wherein the amount of excessive hydrazine is about 15% to about 25% of a normal content.
19. a method for preparing general formula III d compound,
This method comprises, the phenyl diketone of general formula III b
In reaction mixture, generate alkyl pyrazole precursor intermediate with the hydrazine condensation, reaction mixture has organic phase and water, hydrazine is with respect to phenyl diketone stoichiometric calculation excessive existence in the reaction mixture, from reaction mixture, remove excessive hydrazine by from reaction mixture, removing water, with with this intermediate of alkylating agent alkylation, wherein Ar is the phenyl of phenyl or replacement; R
1It is the alkyl that alkyl or halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio replace; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group.
20. the method for claim 19, wherein R
1Be C
1-5Alkyl and R
2Be C
1-3Haloalkyl.
21. the method for claim 19, wherein Ar is general formula Ar-2,
R wherein
5And R
6Be halogen and R
7Be low alkyl group, haloalkyl or
, wherein W is a hydrogen, hydroxyl, halogen or-OC
1-5Alkyl.
22. the method for claim 21, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl and R
7It is low alkyl group.
23. the method for claim 21, wherein R
1Be methyl, R
2Be trifluoromethyl, R
5Be fluorine, R
6Be chlorine and R
7It is methyl.
24. the method for claim 19, wherein reaction mixture is that single-phase and excessive hydrazine is removed from reaction mixture by liquid-liquid extraction.
25. the method for claim 19 is wherein removed excessive hydrazine from reaction mixture, be to be dissolved in by any amount precipitation that the reacting by heating mixture will generate telling water in the organic phase and from organic phase and removing water and finish from reaction mixture again.
26. the method for claim 19, wherein the amount of excessive hydrazine is about 15% (mole) of normal content at least in the reaction mixture, and said normal content is the summation of molar weight of the intermediate of the molar weight of unreacted phenyl diketone and generation.
27. the method for a bromination heterocycle substrate, this method comprise that heterocycle substrate and bromide salt react under oxidizing condition.
28. the method for a bromination heterocycle substrate, this method comprise heterocycle substrate and BrCl reaction.
29. the method for claim 27, wherein the heterocycle substrate is that replace or unsubstituted pyrazole compound.
30. the method for claim 27, wherein the heterocycle substrate of general formula III d is the compound of general formula III h by bromination,
Wherein Ar is the phenyl of phenyl or replacement; R
1Be hydrogen, alkyl or the alkyl that replaces by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group.
31. the method for claim 30, wherein R
1Be C
1-5Alkyl; And R
2Be C
1-3Haloalkyl.
32. the method for claim 30, wherein Ar is general formula Ar-2,
R wherein
5And R
6Be halogen and R
7Be low alkyl group, haloalkyl or
, wherein W is a hydrogen, hydroxyl, halogen or-OC
1-5Alkyl.
33. the method for claim 32, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl and R
7It is low alkyl group.
34. the method for claim 32, wherein R
1Be methyl, R
2Be trifluoromethyl, R
5Be fluorine, R
6Be chlorine and R
7It is methyl.
35. the method for claim 27, wherein bromide salt is used as the clorox or the chlorine oxidation of oxygenant.
36. the method for claim 27 wherein is reflected at pH less than taking place under about 5.0 the acidic conditions.
37. the method for claim 27, the heterocycle substrate of general formula I Ie wherein,
Become the compound of general formula I If by bromination,
With this bromide salt with clorox or chlorine oxidation, this bromination carries out under less than about 5.0 acidic conditions at pH.
38. the method for claim 27, wherein the heterocycle substrate of general formula I d is become the compound of general formula I g by halogenation.
39. the method for claim 27, wherein the heterocycle substrate of general formula I h is become the compound of general formula I by halogenation.
40. the method for an esterification carboxylic acid substrate, this method comprise that carboxylic acid and halogenating agent reaction generate acyl halide and this carboxylic acid halides and esterifying agent reaction and generate carboxylicesters, esterifying agent is generated by alcohol mixture and acyl halide.
41. the method for claim 40, wherein substrate is that replace or unsubstituted phenylformic acid.
42. the method for claim 40, wherein substrate is to have a substituent phenylformic acid at least, and this substituting group is the replacement or the unsubstituted heterocycle of 6 yuan of rings at the most.
43. the method for claim 40, the carboxylicesters of the esterified one-tenth general formula III of the substrate of general formula III g i wherein,
Wherein Pyr is that replace or unsubstituted pyrazoles; R
5And R
6It is halogen; And R
10Be C
1-5Alkyl.
44. the method for claim 43, wherein Pyr is general formula Pyr-1,
R wherein
1Be hydrogen, alkyl or the alkyl that replaces by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group and R
3It is hydrogen or halogen.
45. the method for claim 44, wherein R
1Be hydrogen or C
1-5Alkyl; R
2It is haloalkyl; And R
3It is hydrogen or halogen.
46. the method for claim 44, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine and R
6Be chlorine.
47. the method for claim 40, wherein acyl halide is an ethanoyl halogen.
48. the method for claim 40, wherein alcohol is hindered alcohols.
49. the method for claim 40, wherein esterifying agent generates by mixing secondary alcohol and Acetyl Chloride 98Min..
50. the method for claim 40, wherein esterifying agent generates by mixing Virahol and Acetyl Chloride 98Min..
51. the method for claim 40, wherein esterifying agent generates by mixing quantitative acetyl halide and quantitative hindered alcohols, and the amount of acetyl halide is about 0.5%-10% (weight) with respect to the amount of alcohol.
52. the method for claim 40, the wherein substrate of general formula I If
Become acyl halide by halogenation, the esterifying agent that mixed quantitative Virahol of this acyl halide and quantitative Acetyl Chloride 98Min. generate, the amount of Acetyl Chloride 98Min. is about 2%-5% (weight) with respect to the amount of Virahol, generates the compound of general formula I I.
53. the method for claim 40, the substrate of general formula I e wherein,
Become acyl halide by halogenation, the compound of the esterified one-tenth general formula I of this acyl halide h.
54. the method for claim 40, the substrate of general formula I i wherein,
Become the compound of the esterified general formula I j of one-tenth of acyl halide and this acyl halide by halogenation.
55. the method for claim 40, the substrate of general formula I 1 wherein,
Become the compound of the esterified general formula I k of one-tenth of acyl halide and this acyl halide by halogenation.
56. the method for an esterification carboxylic acid substrate, this method comprise the trialkyl ortho ester reaction of carboxylic acid and general formula F1,
Generate carboxylicesters, wherein R
10Be C
3-5Alkyl and R
11It is hydrogen or alkyl.
57. the method for claim 56, wherein substrate is that replace or unsubstituted phenylformic acid.
58. the method for claim 56, wherein substrate is the phenylformic acid that at least one substituting group replaces, and this substituting group is the replacement or the unsubstituted heterocycle of 6 yuan of rings at the most.
59. the method for claim 56, the substrate of general formula III g wherein,
The carboxylicesters of esterified one-tenth general formula III i,
Wherein Pyr is that replace or unsubstituted pyrazoles; R
5And R
6It is halogen; And R
10Be C
3-5Alkyl.
60. the method for claim 59, wherein Pyr is general formula Pyr-1,
R wherein
1Be hydrogen, alkyl or the alkyl that replaces by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group and R
3It is hydrogen or halogen.
61. the method for claim 60, wherein R
1Be hydrogen or C
1-5Alkyl; R
2It is halogen; And R
3It is hydrogen or halogen.
62. the method for claim 60, wherein R
1It is methyl; R
2Be trifluoromethyl, R
3Be bromine, R
5It is fluorine; R
6Be chlorine and R
10It is sec.-propyl.
63. the method for claim 56, wherein R
10It is sec.-propyl.
64. the method for claim 56, wherein the trialkyl ortho ester is orthoformic acid three isopropyl esters.
65. the method for claim 56, wherein the compound of general formula I If becomes the compound of general formula I I with orthoformic acid three isopropyl ester esterifications.
66. the method for claim 56, the wherein compound of the esterified one-tenth general formula I of the substrate of general formula I e h.
67. the method for claim 56, the wherein compound of the esterified one-tenth general formula I of the substrate of general formula I i j.
68. the method for claim 56, the wherein compound of the esterified one-tenth general formula I of the substrate of general formula I l k.
69. a method for preparing compound of Formula I,
This method comprises the compound of general formula I f,
Become acyl halide and this acyl halide and esterifying agent reaction with the halogenating agent halogenation, this esterifying agent is by mixing general formula R
10The pure and mild acyl halide of OH forms, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6It is halogen; And R
10Be C
3-5Alkyl.
70. the method for claim 69, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5It is fluorine; R
6Be chlorine and R
10It is sec.-propyl.
71. the method for claim 69, wherein the compound of general formula I f is by the compound of halogenation general formula I e.
72. the method for claim 71, wherein R
3Be the compound of bromine and general formula I e under oxidizing condition with the bromide salt bromination.
73. the method for claim 71, wherein the compound of general formula I e is by the compound of oxidation general formula I d.
74. the method for claim 73, wherein the compound of general formula I d is by the compound of general formula I b,
In reaction mixture, prepare with hydrazine condensation generation alkyl pyrazole precursor intermediate with this intermediate of alkylating agent alkylation.
75. the method for claim 74, wherein in reaction mixture, exist and this method also comprises so that stoichiometric calculation is excessive with respect to general formula I b compound hydrazine, after condensation general formula I b compound and before the alkylation intermediate, from reaction mixture, remove excessive hydrazine.
76. the method for claim 74, wherein general formula I b compound is by acidylate general formula I a compound.
77. the method for claim 76, wherein general formula I a compound is with the halo acyl halide acidylate of general formula A1,
This halo acyl halide has whole halogenated alpha-carbon, wherein R
2Be C
1-3Haloalkyl and Z are halogens.
78. a method for preparing compound of Formula I,
This method comprises the compound with the trialkyl ortho ester esterification general formula I f of general formula F1
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen, R
10Be C
3-5Alkyl and R
11It is hydrogen or alkyl.
79. the method for claim 78, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine, R
6Be chlorine and R
10It is sec.-propyl.
80. the method for claim 78, wherein the compound of general formula I f is by the compound of halogenation general formula I e.
81. the method for claim 80, wherein R
3Be the compound of bromine and general formula I e under oxidizing condition by the bromide salt bromination.
82. the method for claim 80, wherein the compound of general formula I e is by the compound of oxidation general formula I d.
83. the method for claim 82, wherein the compound of general formula I d generates alkyl pyrazole precursor intermediate by the compound of general formula I b and the hydrazine condensation in the reaction mixture and prepares with this intermediate of alkylating agent alkylation.
84. the method for claim 83, wherein the hydrazine in reaction mixture calculates excessive the existence with the compound chemistry with respect to general formula I b, also comprise with this method, behind general formula I b compound condensation and before this intermediate of alkylation, from reaction mixture, remove excessive hydrazine.
85. the method for claim 83, wherein the compound of general formula I b is by the compound of acidylate general formula I a.
86. the method for claim 85, wherein the compound of general formula I a is by the halo acyl halide acylations of general formula A1,
This halo acyl halide has whole halogenated alpha-carbon, wherein R
2Be C
1-3Haloalkyl and Z are halogens.
87. method for preparing compound of Formula I
This method comprises, the compound of general formula I e
Under oxidizing condition, generate the compound of general formula I f with the bromide salt bromination,
With the compound of esterification general formula I f, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3Be bromine, R
5And R
6Be halogen and R
10Be C
3-5Alkyl.
88. the method for claim 87, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine, R
6Be chlorine and R
10It is sec.-propyl.
89. the method for claim 87, wherein the compound of general formula I e is by the compound of oxidation general formula I d.
90. the method for claim 89, wherein the compound of general formula I d generates alkyl pyrazole precursor intermediate by the compound of general formula I b and the hydrazine condensation in the reaction mixture and prepares with this intermediate of alkylating agent alkylation.
91. the method for claim 90, wherein the hydrazine that exists in the reaction mixture is that excessive and this method of stoichiometric calculation also comprises behind the condensation general formula I b compound and before the alkylation intermediate, removes excessive hydrazine from reaction mixture with respect to general formula I b compound.
92. the method for claim 90, wherein general formula I b compound is by acidylate general formula I a compound.
93. the method for claim 92, wherein general formula I a compound is with general formula A1 halo acyl halide acidylate
This halo acyl halide has fully halogenated alpha-carbon, wherein R
2Be C
1-3Haloalkyl and Z are halogens.
94. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I a
With the halo acyl halide acidylate of general formula A1,
This halo acyl halide has the alpha-carbon of perhalogeno, generates general formula I b compound,
General formula I b compound and hydrazine condensation generate alkyl pyrazole precursor intermediate and generate general formula I d compound with this intermediate of alkylating agent alkylation,
Oxidation general formula I d compound generates general formula I e compound,
Halogenation general formula I e compound generates general formula I f compound,
Esterification general formula I f compound, R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
3-5Alkyl.
95. the method for claim 94, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine, R
6Be chlorine and R
10It is sec.-propyl.
96. the method for the benzene substrate that it is alkyl that a direct oxidation has at least two substituting groups and substituting group, this method is included in metal salt catalyst and Benzoyl Peroxide exists down, and this substrate reacts with molecular oxygen.
97. the method for claim 96, wherein alkyl is a methyl.
98. the method for claim 96, wherein alkyl is that another substituting group on methyl and the substrate is to replace or the unsubstituted heterocycle that mostly is 6 yuan of rings most.
99. the method for claim 96, the substrate of general formula III f wherein,
Be oxidized to the compound of general formula III g,
Wherein Pyr is the pyrazoles of pyrazoles or replacement, and R
5And R
6It is halogen.
100. the method for claim 99, wherein Pyr replaces or unsubstituted N-methylpyrazole.
101. the method for claim 99, wherein Pyr is general formula Pyr-1,
R wherein
1Be hydrogen, alkyl or the alkyl that replaces by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group and R
3It is hydrogen or halogen.
102. the method for claim 101, wherein R
1Be C
1-5Alkyl and R
2Be C
1-3Haloalkyl.
103. the method for claim 101, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be hydrogen or bromine, R
5Be fluorine and R
6Be chlorine.
104. the method for claim 96, wherein in the presence of metal salt catalyst, promotor and Benzoyl Peroxide, substrate and molecular oxygen react.
105. the method for claim 104, wherein promotor comprises acetone.
106. the method for claim 96, wherein the substrate of general formula I Id in the presence of metal salt catalyst, bromide salt and acetone promotor and benzoyl peroxide, becomes the compound of general formula I Ie with molecular oxygen oxidation.
107. the method for claim 96, wherein the substrate of general formula I g is oxidized to the compound of general formula I f.
108. the method for claim 96, wherein the substrate of general formula I a is oxidized to the compound of general formula I i.
109. the method for claim 96, wherein the substrate of general formula I b is oxidized to the compound of general formula I l.
110. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I f,
Become acyl halide and this acyl halide and esterifying agent reaction with the halogenating agent halogenation, this esterifying agent is by mixing general formula R
10The pure and mild acyl halide of OH generates, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen, and R
10Be C
3-5Alkyl; Wherein general formula I f compound is by halogenation general formula I e compound,
With general formula I e compound by in the presence of metal salt catalyst, promotor and Benzoyl Peroxide, with molecular oxygen oxidation general formula I d compound.
111. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I f
With the trialkyl ortho ester esterification of general formula F1,
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen, R
10Be C
3-5Alkyl and R
11It is hydrogen or alkyl; Wherein the compound of general formula I f is by halogenation general formula I e compound,
Wherein general formula I e compound is by at metal salt catalyst, and promotor and benzoyl peroxide exist down with molecular oxygen oxidation general formula I d compound.
112. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I e
Under oxidizing condition, generate general formula I f compound with the bromide salt bromination,
With esterification general formula I f compound, wherein R
1Be C
3-5Alkyl, R
2Be C
1-3Haloalkyl, R
3Be bromine, R
5And R
6Be halogen and R
10Be C
3-5Alkyl the and wherein compound of general formula I e is by at metal salt catalyst, promotor and benzoyl peroxide exist down, with molecular oxygen oxidation general formula I d compound.
113. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I d
At metal salt catalyst, promotor and benzoyl peroxide exist down, with the compound of molecular oxygen oxidation general formula I e,
The compound halogenation of general formula I e becomes the compound of general formula I f,
Compound with esterification general formula I f; R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
3-5Alkyl.
114. the method for claim 113, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine, R
6Be chlorine and R
10It is sec.-propyl.
115. the method for claim 113, wherein the compound of general formula I d is prepared by following method, the compound of general formula I b
Be condensed into alkyl pyrazole precursor intermediate with hydrazine in the reaction mixture and with the alkylating agent alkylation.
116. the method for claim 115, wherein the hydrazine that exists in the reaction mixture is that stoichiometric calculation is excessive and also be included in behind the general formula I b compound condensation and remove excessive hydrazine before this intermediate of alkylation from reaction mixture with respect to the compound of general formula I b.
117. the method for claim 115, wherein alkylated reaction takes place under acidic conditions.
118. the method for claim 115, wherein general formula I b compound is prepared by acylations general formula I a compound.
119. the method for claim 118, wherein general formula I a compound is with the halo acyl halide acylations of general formula A1,
This halo acyl halide has whole halogenated alpha-carbon, wherein R
2Be C
1-3Haloalkyl and Z are halogens.
120. a method for preparing the alkylation pyrazole compound of general formula III e,
This method comprises the phenyl diketone of general formula III b
Generate alkyl pyrazole precursor intermediate and use this intermediate of alkylating agent alkylation under acidic conditions with the hydrazine condensation in reaction mixture, wherein Ar is the phenyl of phenyl or replacement; R
1Be alkyl or the alkyl that replaces by halogen, amino, nitro, cyano group, hydroxyl, carboxyl, alkoxyl group, sulphur, mercaptoalkyl or alkylthio; And R
2Be alkyl, hydroxyl, alkoxyl group, acyl group, carboxylic acid and its aldehyde, acid amides and ester derivative, halogen, haloalkyl, amino, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group.
121. the method for claim 120, wherein R
2Be the alkyl that is selected from replacement, acyl group, carboxylic acid and aldehyde thereof, acid amides and ester derivative, halogen, haloalkyl, nitro, cyano group, mercaptoalkyl, alkylthio, alkyl sulfinyl, the alkane alkylsulfonyl, alkylphosphine oxide acyl group or alkylphosphines acyl group drive electron group.
122. the method for claim 120, wherein R
1Be C
1-5Alkyl and R
2Be C
1-3Haloalkyl.
123. the method for claim 120, wherein Ar is general formula Ar-2,
R wherein
5And R
6Be halogen and R
7Be low alkyl group, haloalkyl or
, wherein W is a hydrogen, hydroxyl, halogen or-OC
1-5Alkyl.
124. the method for claim 123, wherein R
1Be C
1-5Alkyl and R
2Be C
1-3Haloalkyl and R
7It is low alkyl group.
125. the method for claim 123, wherein R
1Be methyl, R
2Be trifluoromethyl, R
5Be fluorine, R
6Be chlorine and R
7It is methyl.
126. the method for claim 120, wherein the hydrazine that exists in the reaction mixture is that excessive and this method of stoichiometric calculation also is included in after the condensation of phenyl diketone and removes excessive hydrazine before this intermediate of alkylation from reaction mixture with respect to the phenyl diketone.
127. the method for claim 126, wherein in the reaction mixture amount of excessive hydrazine be normal content at least about 15% mole, normal content is the summation of molar weight of the intermediate of unreacted phenyl diketone molar weight and generation.
128. the method for claim 120, wherein the alkylation pyrazoles of general formula III e is the 3-aryl isomer of general formula III d compound,
Also generate its corresponding 5-aryl isomer with this alkylated reaction, wherein 3-aryl isomer be the 3-aryl that generates and 5-aryl isomer total amount at least about 90%.
129. the method for claim 120, wherein acidic conditions is to be neutral but along with the tart solvent that becomes of reaction produces when being begun by alkylated reaction.
130. the method for claim 120, wherein acidic conditions is to produce in reaction mixture by the acid that adds catalytic amount.
131. the method for claim 120, wherein alkylating agent is a dialkylsulfates.
132. the method for claim 120, wherein alkylating agent is a methyl-sulfate.
133. the method for claim 120, wherein the phenyl diketone of general formula I Ib
With the hydrazine condensation in reaction mixture with organic phase and water, this hydrazine that exists in reaction mixture is that stoichiometric calculation is excessive with respect to the phenyl diketone, with this method also comprise remove from reaction mixture by after condensation phenyl diketone and before this intermediate of alkylation, from reaction mixture, removing water excessive hydrazine and wherein this intermediate be alkylated into the compound of general formula I Id with methyl-sulfate.
134. the method for claim 120, wherein the phenyl diketone of general formula I k
Generate the compound that alkyl pyrazole precursor intermediate and this intermediate are alkylated into general formula I h with the hydrazine condensation.
135. the method for claim 120, wherein the phenyl diketone of general formula I l
Generate the compound that alkyl pyrazole precursor intermediate and this intermediate are alkylated into general formula I e with the hydrazine condensation.
136. the method for regioselective alkylation 3 (5)-aryl-5 (3)-haloalkyl pyrazoles, this method comprises the compound of general formula III c
With the alkylating agent alkylation, the N-hydrogen of general formula III c compound does not have deprotonation and generates the 3-aryl isomer and the 5-aryl isomer of 1-alkyl-3 (5)-aryl-5 (3)-haloalkyl pyrazoles, and 3-aryl isomer has general formula III e,
The amount of the 3-aryl isomer that generates be 1-alkyl-3 (5)-aryl-5 (3)-haloalkyl pyrazoles total amount of generating at least about 90%, wherein Ar is the phenyl of phenyl or replacement; R
1Be C
1-5Alkyl; And R
2Be C
1-3Haloalkyl.
137. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I f
Become acyl halide and this acyl halide and esterifying agent reaction with the halogenating agent halogenation, esterifying agent is by mixing general formula R
10The pure and mild acyl halide of OH and generating, wherein R
1Be C
1-5Alkyl; R
2Be C
1-3Haloalkyl; R
3, R
5And R
6It is halogen; And R
10Be C
3-5Alkyl, wherein the compound of general formula I f is to be prepared by the compound of halogenation general formula I e,
Wherein the compound of general formula I e is to be prepared by the compound of oxidation general formula I d,
With the compound of general formula I d be compound by general formula I b,
Generate alkyl pyrazole precursor intermediate with hydrazine condensation in the reaction mixture and under acidic conditions, prepare with this intermediate of alkylating agent alkylation.
138. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I f
With the trialkyl ortho ester esterification of general formula F1,
R wherein
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen, R
10Be C
3-5Alkyl and R
11It is hydrogen or alkyl; Wherein the compound of general formula I f is to be prepared by halogenation general formula I e compound,
Wherein general formula I e compound is to be prepared by oxidation general formula I d compound,
Wherein general formula I d compound is the compound by general formula I b
Be condensed into alkyl pyrazole precursor intermediate with hydrazine in the reaction mixture and at acidic conditions with this intermediate of alkylating agent alkylation.
139. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I e
Under oxidizing condition, become general formula I f compound with the bromide salt bromination,
With esterification general formula I f compound, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3Be bromine, R
5And R
6Be halogen and R
10Be C
3-5Alkyl; Wherein general formula I e compound is to be prepared by oxidation general formula I d compound
Wherein general formula I d compound is by general formula I b compound
Be condensed into alkyl pyrazole precursor intermediate with hydrazine in the reaction mixture and under acidic conditions with this intermediate of alkylating agent alkylation.
140. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I d
In the presence of metal catalyst, catalyst adjuvant and benzoyl peroxide, become general formula I e compound with molecular oxygen oxidation,
Halogenation general formula I e compound becomes general formula I f compound
With esterification general formula I f compound, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
3-5Alkyl; Wherein general formula I d compound is by general formula I b compound
Be condensed into alkyl pyrazole precursor intermediate with hydrazine in the reaction mixture and under acidic conditions with the alkylating agent alkylation.
141. a method for preparing compound of Formula I,
This method comprises, general formula I b compound
Be condensed into alkyl pyrazole precursor intermediate and under acidic conditions, generate general formula I d compound with the hydrazine in the reaction mixture with this intermediate of alkylating agent alkylation,
Oxidation general formula I d compound becomes general formula I e compound,
Halogenation general formula I e compound becomes general formula I f compound,
With esterification general formula I f compound, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
3-5Alkyl.
142. the method for claim 141, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine, R
6Be chlorine and R
10It is sec.-propyl.
143. the method for claim 141, wherein the compound of general formula I b is by the compound of general formula I a.
144. the method for claim 143, wherein the compound of general formula I a is with the halo acyl halide acidylate of general formula A1,
This halo acyl halide has whole halogenated alpha-carbon, wherein R
2Be C
1-3Haloalkyl and Z are halogens.
145. a method for preparing compound of Formula I,
This method comprises, the compound of general formula I a
Become general formula I b compound with halo acetyl halide or halo acetyl alkyl ester acidylate
Hydrazine in general formula I b compound and the reaction mixture is condensed into alkyl pyrazole precursor intermediate, and this reaction mixture has organic phase and water, and the hydrazine that exists in the reaction mixture is that stoichiometric calculation is excessive with respect to general formula I b compound,
Any amount resolution of precipitate that the reacting by heating mixture may form advance organic phase and from organic phase water phase separated,
From reaction mixture, remove excessive hydrazine by from reaction mixture, removing water,
Under acidic conditions,, generate general formula I d compound with this intermediate of alkylating agent alkylation
In the presence of metal salt catalyst, halide salts and acetone catalyst adjuvant and benzoyl peroxide, become general formula I e compound with molecular oxygen oxidation general formula I d compound,
Become general formula I f compound with halogenating agent halogenation general formula I e compound,
Become compound of Formula I with esterification general formula I f compound, wherein R
1Be C
1-5Alkyl, R
2Be C
1-3Haloalkyl, R
3, R
5And R
6Be halogen and R
10Be C
1-5Alkyl.
146. the method for claim 145, wherein R
1Be methyl, R
2Be trifluoromethyl, R
3Be bromine, R
5Be fluorine, R
6Be chlorine and R
10It is sec.-propyl.
147. the method for claim 145, wherein the compound of general formula I f is by generating corresponding benzoyl halogen and this benzoyl halogen and esterifying agent reaction and esterified with the halogenating agent reaction, and esterifying agent is formed by alcohol mixture and Acetyl Chloride 98Min..
148. the method for claim 145, wherein the compound of general formula I f is by esterified with the reaction of the trialkyl ortho ester of general formula F1,
R wherein
11Be hydrogen or alkyl, and R
10Be C
3-5Alkyl.
149. a method for preparing general formula I I compound,
This method comprises, the compound of general formula I Ia
Become general formula I Ib compound with trifluoro second halogen or Trifluoroacetic Acid Ethyl Ester acidylate,
Hydrazine in general formula I Ib compound and the reaction mixture is condensed into alkyl pyrazole precursor intermediate, and this reaction mixture has organic phase and water, and the hydrazine that exists in the reaction mixture is that stoichiometric calculation is excessive with respect to general formula I Ib compound,
The reacting by heating mixture makes any amount resolution of precipitate that may form advance organic phase and tell water from organic phase,
From reaction mixture, remove excessive hydrazine by from compound of reaction, removing water,
Under acidic conditions, make generation general formula I Id compound with this intermediate of methylating agent alkylation
In the presence of metal salt catalyst, halide salts, acetone and Benzoyl Peroxide, with molecular oxygen oxidation general formula I Id compound, make to generate general formula I Ie compound,
Under oxidizing condition, with bromide salt bromination general formula I Ie compound, make to generate general formula I If compound,
Generate general formula I I compound with esterification general formula I If compound.
150. the method for claim 149, wherein the compound of general formula I If is by generating corresponding benzoyl halogen and this benzoyl halogen and esterifying agent reaction and esterified with the halogenating agent reaction, and esterifying agent is to generate by mixing Virahol and Acetyl Chloride 98Min..
151. the method for claim 149, wherein the compound of general formula I If is by the esterification with the reaction of orthoformic acid three isopropyl esters.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/667,103 US5698708A (en) | 1996-06-20 | 1996-06-20 | Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
| US08/667,135 US5869688A (en) | 1994-07-20 | 1996-06-20 | Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
| US08/667,256 | 1996-06-20 | ||
| US08/667,135 | 1996-06-20 | ||
| US08/667,256 US5880290A (en) | 1994-01-31 | 1996-06-20 | Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
| US08/667,103 | 1996-06-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1228075A true CN1228075A (en) | 1999-09-08 |
Family
ID=27418163
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97197382.2A Pending CN1228075A (en) | 1996-06-20 | 1997-06-16 | Process for preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0923520A2 (en) |
| JP (1) | JP2000512656A (en) |
| CN (1) | CN1228075A (en) |
| AU (1) | AU720882B2 (en) |
| BR (1) | BR9710711A (en) |
| CA (1) | CA2258215A1 (en) |
| HU (1) | HUP0104324A3 (en) |
| NZ (1) | NZ333414A (en) |
| PL (1) | PL330718A1 (en) |
| WO (1) | WO1997048668A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114874144A (en) * | 2022-03-28 | 2022-08-09 | 曲靖师范学院 | Process for preparing 4-bromo-N-arylpyrazole compound |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5532416A (en) * | 1994-07-20 | 1996-07-02 | Monsanto Company | Benzoyl derivatives and synthesis thereof |
| ES2202189T3 (en) * | 1999-10-29 | 2004-04-01 | Boehringer Ingelheim Pharmaceuticals Inc. | PROCEDURE TO PREPARE SUBSTITUTED PIRAZOLS. |
| BR112015028751B1 (en) * | 2013-05-22 | 2021-01-12 | Bayer Cropscience Aktiengesellschaft | PROCESS FOR THE PREPARATION OF 3,5-BIS (FLUORALQUIL) PIRAZOL DERIVATIVES FROM ALPHA, ALPHA-DIHALOAMINES AND USE OF THESE FOR PREPARATION OF ACTIVE FUNGICID INGREDIENTS |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2578654A (en) * | 1950-01-28 | 1951-12-18 | Shell Dev | Preparation of tertiary-alkyl-substituted benzene carboxylic acids |
| FR1504431A (en) * | 1965-11-09 | 1967-12-08 | Inst Francais Du Petrole | Two-step paraxylene oxidation process |
| US3426035A (en) * | 1966-02-03 | 1969-02-04 | Dow Chemical Co | Halogenation of aromatic compounds |
| DE2922591A1 (en) * | 1979-06-02 | 1980-12-04 | Basf Ag | METHOD FOR PRODUCING PYRAZOLES |
| US4870109A (en) * | 1985-05-20 | 1989-09-26 | Eli Lilly And Company | Control of ectoparasites |
| US5281571A (en) * | 1990-10-18 | 1994-01-25 | Monsanto Company | Herbicidal benzoxazinone- and benzothiazinone-substituted pyrazoles |
| US5532416A (en) * | 1994-07-20 | 1996-07-02 | Monsanto Company | Benzoyl derivatives and synthesis thereof |
| JPH072798A (en) * | 1993-06-17 | 1995-01-06 | Sumika Fine Chem Kk | Production of 5-halogenopyrimidine derivative |
| US5587485A (en) * | 1994-07-20 | 1996-12-24 | Monsanto Company | Heterocyclic- and carbocyclic- substituted benzoic acids and synthesis thereof |
-
1997
- 1997-06-16 PL PL97330718A patent/PL330718A1/en unknown
- 1997-06-16 AU AU34919/97A patent/AU720882B2/en not_active Ceased
- 1997-06-16 NZ NZ333414A patent/NZ333414A/en unknown
- 1997-06-16 CA CA002258215A patent/CA2258215A1/en not_active Abandoned
- 1997-06-16 JP JP10503274A patent/JP2000512656A/en active Pending
- 1997-06-16 BR BR9710711A patent/BR9710711A/en unknown
- 1997-06-16 CN CN97197382.2A patent/CN1228075A/en active Pending
- 1997-06-16 WO PCT/US1997/010525 patent/WO1997048668A2/en not_active Application Discontinuation
- 1997-06-16 EP EP97931231A patent/EP0923520A2/en not_active Ceased
- 1997-06-16 HU HU0104324A patent/HUP0104324A3/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114874144A (en) * | 2022-03-28 | 2022-08-09 | 曲靖师范学院 | Process for preparing 4-bromo-N-arylpyrazole compound |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000512656A (en) | 2000-09-26 |
| BR9710711A (en) | 1999-08-17 |
| HUP0104324A2 (en) | 2002-02-28 |
| EP0923520A2 (en) | 1999-06-23 |
| CA2258215A1 (en) | 1997-12-24 |
| NZ333414A (en) | 2000-05-26 |
| HUP0104324A3 (en) | 2002-04-29 |
| PL330718A1 (en) | 1999-05-24 |
| AU720882B2 (en) | 2000-06-15 |
| WO1997048668A3 (en) | 1998-04-02 |
| WO1997048668A2 (en) | 1997-12-24 |
| AU3491997A (en) | 1998-01-07 |
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