CN117616016A - 手性3-亚磺酰基苯甲酸 - Google Patents
手性3-亚磺酰基苯甲酸 Download PDFInfo
- Publication number
- CN117616016A CN117616016A CN202280045050.4A CN202280045050A CN117616016A CN 117616016 A CN117616016 A CN 117616016A CN 202280045050 A CN202280045050 A CN 202280045050A CN 117616016 A CN117616016 A CN 117616016A
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- Prior art keywords
- alkyl
- methyl
- group
- cycloalkyl
- formula
- Prior art date
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- CMUCIWUXKFQLKE-UHFFFAOYSA-N S(=O)=C1CC(C(=O)O)=CC=C1 Chemical compound S(=O)=C1CC(C(=O)O)=CC=C1 CMUCIWUXKFQLKE-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 36
- 229910052736 halogen Chemical group 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- -1 OR a Chemical group 0.000 claims description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 125000006217 methyl sulfide group Chemical group [H]C([H])([H])S* 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012190 activator Substances 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- PLVXZFMZGNGIPO-UHFFFAOYSA-N O=C(NC1=NN=CO1)C1=CC=CC=C1 Chemical compound O=C(NC1=NN=CO1)C1=CC=CC=C1 PLVXZFMZGNGIPO-UHFFFAOYSA-N 0.000 claims description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 5
- APKZPKINPXTSNL-UHFFFAOYSA-N 1,3,4-oxadiazol-2-amine Chemical compound NC1=NN=CO1 APKZPKINPXTSNL-UHFFFAOYSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 230000002363 herbicidal effect Effects 0.000 abstract description 4
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Chemical group 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- UZDDXUMOXKDXNE-QMMMGPOBSA-N (1s)-1-(4-methylphenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(C)C=C1 UZDDXUMOXKDXNE-QMMMGPOBSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- RHLSTBAZUYRNTK-UHFFFAOYSA-N n-(1,2,5-oxadiazol-3-yl)benzamide Chemical class C=1C=CC=CC=1C(=O)NC=1C=NON=1 RHLSTBAZUYRNTK-UHFFFAOYSA-N 0.000 description 3
- DIYVRCCXGRMXGF-UHFFFAOYSA-N n-(2h-triazol-4-yl)benzamide Chemical class C=1C=CC=CC=1C(=O)NC1=CN=NN1 DIYVRCCXGRMXGF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- NURQLCJSMXZBPC-UHFFFAOYSA-N 3,4-dimethylpyridine Chemical compound CC1=CC=NC=C1C NURQLCJSMXZBPC-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- NWYYWIJOWOLJNR-RXMQYKEDSA-N l-valinol Chemical compound CC(C)[C@H](N)CO NWYYWIJOWOLJNR-RXMQYKEDSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- PLTCINJSRCMVPL-UHFFFAOYSA-N n-(2h-tetrazol-5-yl)benzamide Chemical class C=1C=CC=CC=1C(=O)NC=1N=NNN=1 PLTCINJSRCMVPL-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VDMAQVANUGNDOM-LLVKDONJSA-N (2r)-3-methyl-2-phenylbutan-1-amine Chemical compound CC(C)[C@@H](CN)C1=CC=CC=C1 VDMAQVANUGNDOM-LLVKDONJSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 description 1
- HWIYPLYOPCWLKR-UHFFFAOYSA-N 2-chloro-3-methylsulfanyl-4-(trifluoromethyl)benzoic acid Chemical compound ClC1=C(C(=O)O)C=CC(=C1SC)C(F)(F)F HWIYPLYOPCWLKR-UHFFFAOYSA-N 0.000 description 1
- SWKPKONEIZGROQ-UHFFFAOYSA-N 4-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1 SWKPKONEIZGROQ-UHFFFAOYSA-N 0.000 description 1
- XPXWYVCQCNFIIJ-UHFFFAOYSA-N 5-methyl-1,3,4-oxadiazol-2-amine Chemical compound CC1=NN=C(N)O1 XPXWYVCQCNFIIJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical group F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Abstract
本发明涉及式(I‑R)和式(I‑S)中规定的绝对构型的手性3‑亚磺酰基苯甲酸,其作为用于制备除草化合物的前体。在式(I‑R)和式(I‑S)中,X、Z和R’表示基团如烷基、环烷基、卤代烷基和卤素。
Description
本发明涉及手性3-亚磺酰基苯甲酸、其用途以及一种制备手性N-(1,2,5-噁二唑-3-基)苯甲酰胺、N-(1,3,4-噁二唑-2-基)苯甲酰胺、N-(四唑-5-基)和N-(三唑-5-基)苯甲酰胺的方法。
WO 2021/078174 A1公开了具有除草活性的手性N-(1,2,5-噁二唑-3-基)苯甲酰胺、N-(1,3,4-噁二唑-2-基)苯甲酰胺、N-(四唑-5-基)苯甲酰胺和N-(三唑-5-基)苯甲酰胺。EP 21162218同样公开了具有除草活性的手性N-(1,3,4-噁二唑-2-基)苯甲酰胺。其中所述具有除草活性的手性化合物在苯环的3号位带有手性亚磺酰基。这些化合物通过N-(1,2,5-噁二唑-3-基)苯甲酰胺、N-(1,3,4-噁二唑-2-基)苯甲酰胺、N-(四唑-5-基)苯甲酰胺和N-(三唑-5-基)苯甲酰胺的对映体分离以复杂的方式进行制备。
本发明的目的是克服现有技术中已知的缺点。
本发明提供了式(I-R)和(I-S)中给出的绝对构型的手性3-亚磺酰基苯甲酸
其中取代基定义如下:
R’为(C1-C6)-烷基、(C3-C6)-环烷基、(C1-C6)-烷基-O-(C1-C6)-烷基或(C3-C6)-环烷基-(C1-C6)烷基,
X为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基、ORa、S(O)nRb或(C1-C6)-烷基-ORa,
Z为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基或S(O)nRb,
Ra为(C1-C6)-烷基或(C3-C6)-环烷基,
Rb为(C1-C6)-烷基或(C3-C6)-环烷基,
n为0、1或2。
本发明的化合物为通式(I-S)的那些,其根据Cahn-Ingold-Prelog规则为S构型,条件是R’具有比苯环更低的优先级。例如,对于其中R’为甲基或环丙基的通式(I)的化合物就是如此。本发明的其他化合物为通式(I)的那些,其根据Cahn-Ingold-Prelog规则为R构型,条件是R’具有比苯环更高的优先级。例如,对于其中R’为甲氧基甲基的通式(I)的化合物就是如此。
在式(I-R)和式(I-S)及下文所有的式中,具有两个以上碳原子的烷基可以是直链的或支链的。烷基基团为例如甲基、乙基、正丙基或异丙基、正丁基、异丁基、叔丁基或2-丁基、戊基、己基,如正己基、异己基和1,3-二甲基丁基。环烷基为具有三至六个碳原子的碳环饱和环体系,例如环丙基、环丁基、环戊基或环己基。卤素取代的烷基是指这样的直链或支链烷基,其中这些基团中的一些或所有氢原子可以被卤素原子取代,例如,C1-C2-卤代烷基,如氯甲基、溴甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基、氯氟甲基、二氯氟甲基、氯二氟甲基、1-氯乙基、1-溴乙基、1-氟乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、2-氯-2-氟乙基、2-氯-2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基、五氟乙基和1,1,1-三氟丙-2-基。
卤素表示氟、氯、溴或碘。
如果一个基团被基团多取代,则这应被理解为该基团被选自上述基团的一个或多个相同或不同的基团取代。
优选通式(I-R)和(I-S)的化合物,其中
X为F、Cl、Br、甲基、乙基、i-Pr、c-Pr、OMe、SMe、Set、CH2OMe或CF3,
R’为甲基、乙基、c-Pr、CH2-cPr、CH2CH2OMe、c-Pr、CH2-cPr或CH2CH2OMe,
Z为F、Cl、Br、I、甲基、乙基、c-Pr、i-Pr、SMe、S(O)Me、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2。
特别优选通式(I-R)和(I-S)的化合物,其中
X为F、Cl、Br、甲基、乙基、c-Pr、OMe、SMe、SEt、CH2OMe或CF3,
R’为Me、Et、c-Pr、CH2-cPr或CH2CH2OMe,
Z为Cl、Br、甲基、乙基、c-Pr、i-Pr、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2。
非常特别优选通式(I-R)和(I-S)的化合物,其中
X为Cl或甲基,
R’为甲基或c-Pr,
Z为CF3或CHF2。
除非有不同的定义,在下文规定的所有式中,取代基和符号具有与式(I-R)和式(I-S)中所述的相同含义。OMe表示O-甲基;SMe表示S-甲基;SEt表示S-乙基;CH2OMe表示CH2O-甲基;i-Pr表示异丙基;c-Pr表示环丙基。
例如,本发明通式(I-R)和(I-S)的化合物可以由各自的外消旋化合物(I-rac)通过下文描述的方法制备。这些方法同样构成了本发明主题的一部分。
外消旋化合物(I-rac)及其制备方法原则上是已知的,例如由WO2021/078174A1和WO2012/126932A1已知。使外消旋化合物(I-rac)与对映体纯的通式(II)的胺反应;在合适的条件下,两种可能的非对映体盐(III-dR)和(III-dS)中只有一种结晶出来并可以分离出来用于进一步后处理。另一种非对映体盐可以从母液中分离出来。
结晶可以在各种合适的溶剂或溶剂混合物中进行,使用甲醇、甲醇/水(1:1至10:1)、乙醇/水(1:1至10:1)、异丙醇,优选异丙醇/水(范围为1:1至10:1)、丙酮/水(1:1至20:1)、乙酸乙酯、THF、THF/水(3:1至20:1)或甲苯。使用已知方法通过过滤从母液中分离得到盐晶体,并用所用的溶剂或溶剂混合物洗涤,在减压下干燥。在进一步的反应步骤中,然后将分离的通式(III-dR)或(III-dS)的非对映体化合物在0℃至20℃的温度下与水混合,任选地在有机溶剂(如甲醇、乙醇、异丙醇、THF、丙酮等)的存在下进行,并与强酸(如HCl或H2SO4)混合以达到pH 1-2。将通式(I-R)或(I-S)的对映体纯化合物沉淀出来并通过过滤从母液中分离出来,洗涤并在减压下干燥。
式(I-rac)的化合物和式(II)的胺通常以等摩尔量使用。此步骤通常在室温下进行。
合适的手性胺为多种可商购的通式(II)的胺,例如,那些化合物,其中
R1为甲基、乙基、正丙基、异丙基、正丁基、异丁基,并且
R2为羟甲基、苯基、4-甲基苯基。
例如,下列式(II)的胺具有良好的适用性:
(S)-(-)-α,4-二甲基苄胺(CAS编号27298-98-2),
(R)-(-)-3-甲基-2-苯基丁胺(CAS编号67152-35-6),
(S)-(+)-2-氨基-3-甲基-1-丁醇(CAS编号2026-48-4)。
优选(S)-(-)-α,4-二甲基苄胺(CAS编号27298-98-2)。
本发明式(I-R)和式(I-S)的3-亚磺酰基苯甲酸在上述方法中获得,通常其对映体过量(ee)为至少94%,经常甚至为至少99%。
优选对映体过量(ee)为至少94%的式(I-R)和式(I-S)的3-亚磺酰基苯甲酸。特别优选对映体过量(ee)为至少99%的式(I-R)和式(I-S)的3-亚磺酰基苯甲酸。
本发明通式(I-S)的3-亚磺酰基苯甲酸特别适合于制备如EP 21162218中所述的具有除草活性的化合物。因此,本发明还提供了一种通过使通式(III)的2-氨基-1,3,4-噁二唑与本发明的通式(I-S)的3-亚磺酰基苯甲酸反应来制备具有式(I*)中给出的绝对构型的N-(1,3,4-噁二唑-2-基)苯甲酰胺的方法,
其特征在于,所述方法在以下条件下进行:
a)在选自亚硫酰氯、光气、双光气、甲磺酰氯、对甲苯磺酰氯、POCl3、PC15、草酰氯和C1-C8烷基-OC(O)Cl的活化试剂(活化剂)的存在下,和
b)在通式(IV)的碱的存在下,
和
c)其中取代基定义如下:
R为氢、(C1-C6)-烷基、(C3-C7)-环烷基、甲氧基甲基或甲氧基乙基,
R’为(C1-C6)-烷基、(C3-C6)-环烷基、(C1-C6)-烷基-O-(C1-C6)-烷基或(C3-C6)-环烷基-(C1-C6)-烷基,
X为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基、OR1、S(O)nR2或(C1-C6)-烷基-OR1,
Z为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基或S(O)nR2,
R1为(C1-C6)-烷基或(C3-C6)-环烷基,
R2为(C1-C6)-烷基或(C3-C6)-环烷基,
R5为C1-C12-烷基或苯基,
n为0、1或2。
本发明通式(I-R)的3-亚磺酰基苯甲酸特别适合于制备如WO 2021/078174A1中所述的具有除草活性的化合物。因此,本发明还提供了一种通过使通式(V)的2-氨基-1,3,4-噁二唑与本发明的通式(I-R)的3-亚磺酰基苯甲酸反应来制备具有式(I**)中给出的绝对构型的N-(1,3,4-噁二唑-2-基)苯甲酰胺的方法,
其特征在于,所述方法在以下条件下进行:
a)在选自亚硫酰氯、光气、双光气、甲磺酰氯、对甲苯磺酰氯、POCl3、PC15、草酰氯和C1-C8烷基-OC(O)Cl的活化试剂(活化剂)的存在下,和
b)在通式(IV)的碱的存在下,
和
c)其中取代基定义如下:
R为氢、(C1-C6)-烷基、(C3-C7)-环烷基、甲氧基甲基或甲氧基乙基,
R’为(C1-C6)-烷基、(C3-C6)-环烷基、(C1-C6)-烷基-O-(C1-C6)-烷基或(C3-C6)-环烷基-(C1-C6)-烷基,
X为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基、OR1、S(O)nR2或(C1-C6)-烷基-OR1,
Z为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基或S(O)nR2,
R1为(C1-C6)-烷基或(C3-C6)-环烷基,
R2为(C1-C6)-烷基或(C3-C6)-环烷基,
R5为C1-C12-烷基或苯基,
n为0、1或2。
在上述两种由式(V)和(I-S)的化合物制备式(I*)的化合物或由式(V)和(I-R)的化合物制备式(I**)的化合物的方法中,基团优选如下:
R为氢或甲基,
X为F、Cl、Br、甲基、乙基、i-Pr、c-Pr、OMe、SMe、SEt、CH2OMe或CF3,
R’为甲基、乙基、c-Pr、CH2-cPr、CH2CH2OMe、c-Pr、CH2-cPr或CH2CH2OMe,
Z为F、Cl、Br、I、甲基、乙基、c-Pr、i-Pr、SMe、S(O)Me、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2;
更优选地:
R为氢或甲基,
X为F、Cl、Br、甲基、乙基、c-Pr、OMe、SMe、SEt、CH2OMe或CF,
R’为Me、Et、c-Pr、CH2-cPr或CH2CH2OMe,
Z为Cl、Br、甲基、乙基、c-Pr、i-Pr、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2;
非常特别地:
R为氢或甲基,
X为氯或甲基,
R’为甲基或c-Pr,
Z为CF3或CHF2。
在上述两种由式(V)和(I-S)的化合物制备式(I*)的化合物或由式(V)和(I-R)的化合物制备式(I**)的化合物的方法中,式(V)和(I-S)或(V)和(I-R)的化合物通常以0.8至1.5的摩尔比使用。优选地,式(V)的化合物相对于式(I-S)或(I-R)的化合物过量10%使用。
活化剂和式(I-S)或(I-R)的化合物通常以0.5至3,优选1至2,更优选1.2至1.9的摩尔比使用。
所用活化剂优选为亚硫酰氯、光气或双光气,更优选亚硫酰氯。
式(IV)的碱和式(I-S)或(I-R)的化合物通常以0.5至10,优选1至3,更优选1至2.5的摩尔比使用。
本发明的上述两种制备式(I*)和(I**)的化合物的方法通常在溶剂中进行。合适的溶剂为惰性有机溶剂,优选脂族、脂环族或芳族烃类,如石油醚、己烷、庚烷、环己烷、甲基环己烷、苯、甲苯、二甲苯和萘烷;卤代烃类,如氯苯、二氯苯、二氯甲烷、氯仿、四氯甲烷、二氯乙烷和三氯乙烷;酯类,如乙酸乙酯和乙酸异丙酯;醚类,如乙醚、异丙基醚、甲基叔丁基醚、甲基叔戊基醚、二氧六环、四氢呋喃、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷和苯甲醚;酮类,如丙酮、丁酮、甲基异丁基酮和环己酮;腈类,如乙腈、丙腈、正丁腈或异丁腈和苯甲腈;酰胺类,如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基甲酰苯胺、N-甲基吡咯烷酮和六甲基磷酰三胺;吡啶类,如2-甲基吡啶、3-甲基吡啶、4-甲基吡啶、2,3-二甲基吡啶、2-甲基-5-乙基吡啶、2,6-二甲基吡啶、2,4-二甲基吡啶、3,4-二甲基吡啶和2,4,6-三甲基吡啶。上述溶剂的混合物也是合适的。
所使用的溶剂优选为四氢呋喃、乙腈、3-甲基吡啶或2-甲基-5-乙基吡啶。特别优选3-甲基吡啶。
这些方法通常在-5至50℃,优选0至25℃的温度范围内进行。
这些方法通常以这样的方式进行,即在搅拌下缓慢滴加活化剂,或者在光气的情况下将活化剂引入到式(III)、(I-S)和(IV)的化合物于溶剂中的初始进料中。通过HPLC监测反应的进展。反应通常在10至20小时后完成。
反应完成后,冷却反应混合物,产物通常几乎定量地沉淀出来。或者,反应混合物可以用极性溶剂(如水)或醇(如异丙醇)来稀释。式(I*)或(I**)的反应产物以较高的纯度获得,如有需要可进一步纯化。特别有利的是在20至35℃的温度下经3至6小时向反应混合物中加入水。这获得了可快速过滤形式的产物。使用氢氧化钠溶液处理母液后,可回收约95%的式(IV)的碱。
下文的实施例用于说明本发明。
实施例1:2-氯-3-[(S)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸的制备
步骤1:2-氯-3-[(S,R)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸的制备
首先在搅拌的3L夹套反应器中加入1L冰乙酸,然后加入0.2kg2-氯-3-甲基硫基-4-(三氟甲基)苯甲酸。将浑浊的混合物加热至60℃,在该温度下,在130分钟内滴加35%的过氧化氢水溶液,并在70℃的内部温度下搅拌21小时。将混合物冷却至20℃,并滴加100mL39%的亚硫酸氢钠溶液。然后将混合物在旋转蒸发仪中浓缩至约20%的残余体积。将残余物溶于1L水中,并用120mL 45%的氢氧化钠溶液(pH 13-14)碱化。然后用二氯甲烷洗涤水溶液,将移除的水相冷却至5℃并用280mL 32%的盐酸酸化。产物以油状物沉淀出来并在几分钟后结晶。通过吸滤器进行冷过滤,过滤出固体,用水洗涤并干燥。得到194g米黄色固体。
HPLC(H3PO4):logP=0.96;
质谱:287.0(M+H)+,328.1(M+H+CH3CN)+,573.0(2M+H)+;
1H NMR[DMSO-D6]:14.2(br s,1H),7.96-8.00(m,2H),3.14(s,3H)。
步骤2:制备2-氯-3-[(S,R)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸
2-氯-3-[(S)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸[(1S)-1-(对甲苯基)乙基]铵
在惰性化的和搅拌的夹套反应器中,将1.06kg外消旋的2-氯-3-[(S,R)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸溶于20L丙酮中并加热至55℃。在温和的回流下,在4小时内滴加519.4g(S)-(-)-α,4-二甲基苄胺,将所得悬浮液在52℃下搅拌过夜。将混合物在6小时内逐步冷却至20℃。通过吸滤器过滤悬浮液。然后用丙酮洗涤滤饼,随后在40℃下减压干燥。得到637g无色晶体。
HPLC(H3PO4):logP=0.50/1.00;
质谱:119.0(胺-M+H)+,286.9(酸-M+H)+;手性HPLC 95.1%ee;
1H NMR[DMSO-D6]:8.23(br s,3H),7.70-7.71(m,1H),7.45-7.46(m,1H),7.35-7.36(m,2H),7.22-7.23(m,2H),4.35(q,1H),3.07(s,3H),2.31(s,3H),1.47(d,3H)。
步骤3:制备2-氯-3-[(S)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸
首先向搅拌的夹套反应器中加入4.9L冰水,并将636g来自步骤2的盐悬浮于其中。然后,滴加入总计0.55L浓盐酸溶液,并将温度保持在0至5℃之间。将悬浮液逐渐加热至室温并持续搅拌过夜。然后通过吸滤器过滤悬浮液。然后用3L蒸馏水洗涤滤饼,随后在50℃下减压干燥。得到408.5g无色晶体。
HPLC(H3PO4):logP=1.00;
质谱:286.9(M+H)+;手性HPLC 98.0%ee;
1H NMR[DMSO-D6]:14.2(br s,1H)7.96-7.99(m,2H),3.14(s,3H)。
实施例2:制备2-氯-N-(5-甲基-1,3,4-噁二唑-2-基)-3-[((S)-甲基亚磺酰基)]-4-(三氟甲基)苯甲酰胺
将28.6g(0.1mol)2-氯-3-[(S)-甲基亚磺酰基]-4-(三氟甲基)苯甲酸、11g(0.11mol)2-氨基-5-甲基-1,3,4-噁二唑和28.7g(0.35mol)N-甲基咪唑溶于200mL乙腈中并搅拌30分钟。在冷却至5℃后,在60分钟内滴加18.9g(0.16mol)亚硫酰氯,使温度保持在5至10℃之间。然后在20℃下再搅拌15小时。在减压下去除溶剂,在40℃下将水加入到油性残余物中。使产物沉淀并在过滤后用冷盐酸和水洗涤。在干燥后,获得33.7g(92%)熔点为220℃的2-氯-N-(5-甲基-1,3,4-噁二唑-2-基)-3-[((S)-甲基亚磺酰基)]-4-(三氟甲基)苯甲酰胺。
旋光度:(-)-69°(MeOH)。
Claims (15)
1.式(I-R)和(I-S)中给出的绝对构型的手性3-亚磺酰基苯甲酸,
其中取代基定义如下:
R’为(C1-C6)-烷基、(C3-C6)-环烷基、(C1-C6)-烷基-O-(C1-C6)-烷基或(C3-C6)-环烷基-(C1-C6)烷基,
X为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基、ORa、S(O)nRb或(C1-C6)-烷基-ORa,
Z为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基或S(O)nRb,
Ra为(C1-C6)-烷基或(C3-C6)-环烷基,
Rb为(C1-C6)-烷基或(C3-C6)-环烷基,
n为0、1或2。
2.根据权利要求1所述的3-亚磺酰基苯甲酸,其中
X为F、Cl、Br、甲基、乙基、i-Pr、c-Pr、OMe、SMe、SEt、CH2OMe或CF3,
R’为甲基、乙基、c-Pr、CH2-cPr、CH2CH2OMe、c-Pr、CH2-cPr或CH2CH2OMe,
Z为F、Cl、Br、I、甲基、乙基、c-Pr、i-Pr、SMe、S(O)Me、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2。
3.根据权利要求1或2所述的3-亚磺酰基苯甲酸,其中
X为F、Cl、Br、甲基、乙基、c-Pr、OMe、SMe、SEt、CH2OMe或CF3,
R’为Me、Et、c-Pr、CH2-cPr或CH2CH2OMe,
Z为Cl、Br、甲基、乙基、c-Pr、i-Pr、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2。
4.根据权利要求1至3中任一项所述的3-亚磺酰基苯甲酸,其中
X为Cl或甲基,
R’为甲基或c-Pr,
Z为CF3或CHF2。
5.根据权利要求1至4中任一项所述的3-亚磺酰基苯甲酸,其对映体过量(ee)为至少94%。
6.根据权利要求5所述的3-亚磺酰基苯甲酸,其对映体过量(ee)为至少99%。
7.制备权利要求1至6中任一项所述的3-亚磺酰基苯甲酸的方法,其特征在于,
a)使式(I-rac)的外消旋化合物与对映体纯的通式(II)的胺反应,
b)将两种结晶的非对映体盐(III-dr)或(III-ds)中的一种过滤、纯化并通过加入水和酸来释放,以得到式(I-R)或(I-S)的3-亚磺酰基苯甲酸,
c)通过加入水和酸来释放步骤a)的母液中的另一种非对映体盐,以得到式(I-R)或(I-S)的3-亚磺酰基苯甲酸,和
d)其中,在式(II)中,
R1为甲基、乙基、正丙基、异丙基、正丁基、异丁基,并且
R2为羟甲基、苯基、4-甲基苯基:
8.通过使通式(V)的2-氨基-1,3,4-噁二唑与本发明的通式(I-S)的3-亚磺酰基苯甲酸反应来制备具有式(I*)中给出的绝对构型的N-(1,3,4-噁二唑-2-基)苯甲酰胺的方法,
其特征在于,所述方法在以下条件下进行:
a)在选自亚硫酰氯、光气、双光气、甲磺酰氯、对甲苯磺酰氯、POCl3、PC15、草酰氯和C1-C8烷基-OC(O)Cl的活化试剂(活化剂)的存在下,和
b)在通式(IV)的碱的存在下,
和
c)其中取代基定义如下:
R为氢、(C1-C6)-烷基、(C3-C7)-环烷基、甲氧基甲基或甲氧基乙基,
R’为(C1-C6)-烷基、(C3-C6)-环烷基、(C1-C6)-烷基-O-(C1-C6)-烷基或(C3-C6)-环烷基-(C1-C6)烷基,
X为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基、OR1、S(O)nR2或(C1-C6)-烷基-OR1,
Z为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基或S(O)nR2,
R1为(C1-C6)-烷基或(C3-C6)-环烷基,
R2为(C1-C6)-烷基或(C3-C6)-环烷基,
R5为C1-C12-烷基或苯基,
n为0、1或2。
9.通过使通式(V)的2-氨基-1,3,4-噁二唑与本发明的通式(I-R)的3-亚磺酰基苯甲酸反应来制备具有式(I**)中给出的绝对构型的N-(1,3,4-噁二唑-2-基)苯甲酰胺的方法,
其特征在于,所述方法在以下条件下进行:
a)在选自亚硫酰氯、光气、双光气、甲磺酰氯、对甲苯磺酰氯、POCl3、PC15、草酰氯和C1-C8-烷基-OC(O)Cl的活化试剂(活化剂)的存在下,和
b)在通式(IV)的碱的存在下,
和
c)其中取代基定义如下:
R为氢、(C1-C6)-烷基、(C3-C7)-环烷基、甲氧甲基或甲氧基乙基,
R’为(C1-C6)-烷基、(C3-C6)-环烷基、(C1-C6)-烷基-O-(C1-C6)-烷基或(C3-C6)-环烷基-(C1-C6)烷基,
X为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基、OR1、S(O)nR2或(C1-C6)-烷基-OR1,
Z为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C3-C6)-环烷基或S(O)nR2,
R1为(C1-C6)-烷基或(C3-C6)-环烷基,
R2为(C1-C6)-烷基或(C3-C6)-环烷基,
R5为C1-C12-烷基或苯基,
n为0、1或2。
10.根据权利要求8或9所述的方法,其中
R为氢或甲基,
X为F、Cl、Br、甲基、乙基、i-Pr、c-Pr、OMe、SMe、SEt、CH2OMe或CF3,
R’为甲基、乙基、c-Pr、CH2-cPr、CH2CH2OMe、c-Pr、CH2-cPr或CH2CH2OMe,
Z为F、Cl、Br、I、甲基、乙基、c-Pr、i-Pr、SMe、S(O)Me、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2。
11.根据权利要求8至10中任一项所述的方法,其中
R为氢或甲基,
X为F、Cl、Br、甲基、乙基、c-Pr、OMe、SMe、SEt、CH2OMe或CF3,
R’为Me、Et、c-Pr、CH2-cPr或CH2CH2OMe,
Z为Cl、Br、甲基、乙基、c-Pr、i-Pr、S(O)2Me、S(O)2Et、CF3、C2F5或CHF2。
12.根据权利要求8至11中的任一项所述的方法,其中
R为氢或甲基,
X为Cl或甲基,
R’为甲基或c-Pr,
Z为CF3或CHF2。
13.根据权利要求8至12中的任一项所述的方法,其中式(V)和(I-S)或(V)和(I-R)的化合物以0.8至1.5的摩尔比使用。
14.根据权利要求8至13中任一项所述的方法,其中所述活化剂选自亚硫酰氯、光气、双光气、甲磺酰氯、对甲苯磺酰氯、POCl3、PC15、草酰氯和C1-C8-烷基-OC(O)Cl,并且该活化剂与式(I-S)或(I-R)的化合物以1至2的摩尔比使用。
15.根据权利要求8至14中任一项所述的方法,其中所述活化剂选自亚硫酰氯、光气和双光气。
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