CN107698580A - A kind of benzothiazole sulfone compound, its preparation method and application - Google Patents
A kind of benzothiazole sulfone compound, its preparation method and application Download PDFInfo
- Publication number
- CN107698580A CN107698580A CN201710897907.6A CN201710897907A CN107698580A CN 107698580 A CN107698580 A CN 107698580A CN 201710897907 A CN201710897907 A CN 201710897907A CN 107698580 A CN107698580 A CN 107698580A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- independently
- group
- compound
- alkenyl
- 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
Links
- -1 benzothiazole sulfone compound Chemical class 0.000 title claims abstract description 56
- IOJUPLGTWVMSFF-UHFFFAOYSA-N cyclobenzothiazole Natural products C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 229940125904 compound 1 Drugs 0.000 claims description 28
- 239000000758 substrate Substances 0.000 claims description 28
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052710 silicon Inorganic materials 0.000 claims description 14
- 239000010703 silicon Substances 0.000 claims description 14
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 13
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 4
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 109
- 150000001875 compounds Chemical class 0.000 abstract description 56
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract description 11
- 239000002904 solvent Substances 0.000 description 50
- 239000002585 base Substances 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 238000000034 method Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- 238000006467 substitution reaction Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 0 C*CC1CC(C)CCC1 Chemical compound C*CC1CC(C)CCC1 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical group C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 150000008282 halocarbons Chemical class 0.000 description 12
- 239000011230 binding agent Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003223 protective agent Substances 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 6
- 229960000987 paricalcitol Drugs 0.000 description 6
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 5
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 102000003982 Parathyroid hormone Human genes 0.000 description 4
- 108090000445 Parathyroid hormone Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 239000000199 parathyroid hormone Substances 0.000 description 4
- 229960001319 parathyroid hormone Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 210000002990 parathyroid gland Anatomy 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 238000009933 burial Methods 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- MWKXCSMICWVRGW-UHFFFAOYSA-N calcium;phosphane Chemical compound P.[Ca] MWKXCSMICWVRGW-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- YGZSVWMBUCGDCV-UHFFFAOYSA-N chloro(methyl)silane Chemical compound C[SiH2]Cl YGZSVWMBUCGDCV-UHFFFAOYSA-N 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical class [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 102000009310 vitamin D receptors Human genes 0.000 description 2
- 108050000156 vitamin D receptors Proteins 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- PWIBNNTXJKKHBW-UHFFFAOYSA-N CC(CCC1)(C(CC=O)CC2)C2C1O Chemical compound CC(CCC1)(C(CC=O)CC2)C2C1O PWIBNNTXJKKHBW-UHFFFAOYSA-N 0.000 description 1
- XUTMVIZHESYGMK-AVVAXGLSSA-N C[C@H](CC(C)(C)O)/C=C\[C@@H](C)[C@@H](CC1)[C@@](C)(CCCC2O)[C@@]12N Chemical compound C[C@H](CC(C)(C)O)/C=C\[C@@H](C)[C@@H](CC1)[C@@](C)(CCCC2O)[C@@]12N XUTMVIZHESYGMK-AVVAXGLSSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical compound CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
The invention discloses a kind of benzothiazole sulfone compound, its preparation method and application.The invention provides a kind of benzothiazole sulfone compound or its salt as shown in Equation 1, wherein, R1For R1‑1Substituted C1‑C6Alkyl or R1‑2Substituted C2‑C8Alkenyl；All R1‑1And R1‑2It independently is：Hydroxyl, amino, halogen, cyano group, O PG1Or, NH PG2；All PG1It independently is hydroxyl protecting group, all PG2It independently is amino protecting group.The high income for the Julia reactions that the compound and parent nucleus aldehyde are carried out, based on product purity is high and trans.
Description
Technical field
The present invention relates to a kind of benzothiazole sulfone compound, its preparation method and application.
Background technology
Novel vitamin D analogues have a variety of therapeutic activities, and theirs is complicated, and structure is difficult.For example, paricalcitolSide chain contain unsaturated double-bond, it is difficult to build.
Paricalcitol is a kind of artificial synthesized novel vitamin D analogues with bioactivity.Paricalcitol can be with
Vitamin D receptor in selectivity up-regulation parathyroid gland is without increasing the vitamin D receptor in enteron aisle, to intestines and stomach Calcium and phosphorous absorption
Influence it is smaller.Paricalcitol can also raise the calcium sensitivity acceptor (CaSR) in parathyroid gland.Therefore, paricalcitol energy
It is enough preferably to suppress parathyroid gland propagation, reduce parathyroid hormone (PTH) synthesis and secretion and reduce PTH levels while right
The horizontal influence of patient's calcium phosphorus is smaller.Paricalcitol can also directly act on osteocyte to maintain bone volume and improve bone mineralising
Surface.It is horizontal to correct abnormal PTH, so as to recover calcium phosphorus stable state, can prevent or treat the metabolic relevant with CKD
Osteopathy.It is mainly used in the Secondary cases first that treatment receives the patients of chronic renal failure of haemodialysis after FDA approval listings
Gland hyperfunction by shape.
In the prior art, on side chain on paricalcitol D rings structure mainly by following two methods (see
CN102131773A)：1st, parent nucleus aldehyde and side chain (phenyl tetrazole sulfone compound) carry out Julia reactions；2nd, parent nucleus aldehyde and side
Chain (ylide class compound) carries out wittig reactions.But the yield and purity of coupling are very low, cause Material Cost drastically
Rise, be also unfavorable for the large-scale production of product.
Meanwhile Tetrahedron Letters 2016, vol 57, Iss 12,1309-1312 also disclose that the structure of side chain
Construction method, but its yield is relatively low, product is cis-configuration.
Therefore, this area needs a kind of reagent that efficiently can be coupled with parent nucleus aldehyde badly.
The content of the invention
The technical problems to be solved by the invention are the reaction efficiencies for the reagent being coupled in the prior art with parent nucleus aldehyde
Low, the defects of causing yield and (configuration) purity relatively low, so, the invention provides a kind of benzothiazole sulfone compound, its
Preparation method and application, the high income for the Julia reactions that the compound is carried out with parent nucleus aldehyde, product purity is high and trans to be
It is main.
The invention provides a kind of benzothiazole sulfone compound or its salt as shown in Equation 1：
Wherein, R1For R1-1Substituted C1-C6Alkyl (described R1-1Number for one or more<Such as 1,2,3
It is individual or 4>, when multiple R being present1-1When, any two R1-1It is identical or different；Described " C1-C6Alkyl " such as C1-C5Alkyl,Or, " the C in addition to 2,3- dimethylbutyls6Alkyl "；Described " C1-C5Alkyl " is for example
C1-C4Alkyl orDescribed " C1-C4Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or the tert-butyl group；All R1-1Can independently be connected on tertiary carbon atom or not be connected on tertiary carbon atom) or R1-2
Substituted C2-C8Alkenyl (described R1-2Number for one or more<Such as 1,2,3 or 4>, it is multiple when existing
R1-2When, any two R1-2It is identical or different；Described " C2-C8Alkenyl " such as C2-C6Alkenyl orIt is described
" C2-C6Alkenyl " such as C2-C4Alkenyl；Described " C2-C4Alkenyl " such as vinyl, propylene -1- bases or propylene -2- bases；Institute
The R stated1-2It can independently be connected on tertiary carbon atom or not be connected on tertiary carbon atom)；
All R1-1And R1-2It independently is：Hydroxyl, amino, halogen (such as fluorine, chlorine, bromine or iodine), cyano group ,-O-PG1、
Or ,-NH-PG2；All PG1It independently is hydroxyl protecting group, all PG2It independently is amino protecting group；
But described compound 1 is not
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
R1Can be R1-1Substituted C1-C6Alkyl.
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All " hydroxyl protecting groups " can independently be the conventional hydroxyl protecting group of such reaction of this area, and (just " hydroxyl is protected
The implication of shield base ", classification, the present invention quote what publishing house of East China University of Science published in October, 2004《Guarantor in organic synthesis
Protect base》Full content), such as methyl, substitution methyl (in another example tetrahydrofuran base, THP trtrahydropyranyl or dihydropyran
Base), ethyl, substitution ethyl, benzyl, substitution benzyl,(such as trimethyl silicon substrate, triethyl group silicon substrate,
Or, t-Butyldimethylsilyl), acyl group (in another example formoxyl,<Such as acetyl group>, substitution alkyl-carbonyl<Again
Such as trifluoroacetyl group>, substitution aryl carbonyl, substitution Heteroarylcarbonyl, methoxycarbonyl, substitution alkoxy carbonyl<
Such as 9-fluorenylmethyloxycarbonyl again>, benzyloxycarbonyl group or, the benzyloxycarbonyl of substitution) or, sulfonyl is (in another example mesyl, benzyl
Base sulfonyl or p-toluenesulfonyl)；
All R1-1-1、R1-1-2、R1-1-3And R1-1-4It independently is C1-C6Alkyl (such as C1-C4Alkyl；All " C1-C4
Alkyl " independently such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example first
Base or ethyl).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All " hydroxyl protecting groups " can independently be(such as trimethyl silicon substrate, triethyl group silicon substrate,
Or, t-Butyldimethylsilyl),(such as acetyl group) or oxinane -2- bases；
All R1-1-1、R1-1-2、R1-1-3And R1-1-4It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4
Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or second
Base).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All " hydroxyl protecting groups " can independently be(such as trimethyl silicon substrate, triethyl group silicon substrate,
Or, t-Butyldimethylsilyl) or oxinane -2- bases；
All R1-1-1、R1-1-2And R1-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All "-O-PG1" can not be ester group.Described ester group refers to containing acyl group, substituted acyl, sulfonyl etc. and oxygen
The group of formation, such as acetoxyl group, tolysulfonyl epoxide etc..
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All " amino protecting groups " can independently be the conventional amino protecting group of such reaction of this area, and (just " amino is protected
The implication of shield base ", classification, the present invention quote what publishing house of East China University of Science published in October, 2004《Guarantor in organic synthesis
Protect base》Full content), such as acyl group (in another example formoxyl, acetyl group, methoxycarbonyl or, substitution alkoxy carbonyl<
Such as 9-fluorenylmethyloxycarbonyl again>).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All R1-1And R1-2- O-PG can independently be1Or ,-NH-PG2。
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
All R1-1And R1-2It can independently be：-O-PG1。
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
R1For R1-1Substituted C1-C6Alkyl；
All R1-1It independently is：-O-PG1；All PG1It independently is hydroxyl protecting group；
All " hydroxyl protecting groups " independently are(such as trimethyl silicon substrate, triethyl group silicon substrate or,
T-Butyldimethylsilyl) or oxinane -2- bases；
All R1-1-1、R1-1-2And R1-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
R1For R1-1Substituted C1-C6Alkyl；
All R1-1It independently is：-O-PG1；All PG1It independently is hydroxyl protecting group；
All " hydroxyl protecting groups " independently are(such as trimethyl silicon substrate, triethyl group silicon substrate or, uncle
Butyldimethyl silicon substrate)；
All R1-1-1、R1-1-2And R1-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
R1Can be
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
Work as R1ForWhen, described hydroxyl protecting group can be(such as trimethyl silicon substrate,
Triethyl group silicon substrate or, t-Butyldimethylsilyl),(such as acetyl group) or oxinane -2- bases；
Described R1-1-1、R1-1-2、R1-1-3And R1-1-4It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4
Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or second
Base).
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
Work as R1ForWhen, described hydroxyl protecting group can beOr oxinane -2- bases；
Described R1-1-1、R1-1-2And R1-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, described compound 1 can be following any structure：
In a certain technical scheme, the definition of each group can (definition not annotated be such as described below in described compound 1
It is preceding any described)：
Described " salt " can be the conventional salt in this area, such as hydrochloride or sulfate.
Present invention also offers one kindCrystal formation, it is made by the following method：WillRecrystallized, obtain crystal formation；The solvent of described recrystallization is that (it can for esters solvent
For the conventional esters solvent in this area, such as ethyl acetate and/or isopropyl acetate, in another example ethyl acetate) and varsol
(it can be the conventional varsol in this area, such as the one or more in petroleum ether, n-hexane and normal heptane, in another example just
Heptane).
In above-mentioned recrystallization, the volume ratio of described varsol and esters solvent can be 5~15, can be 10 again
~12.
In above-mentioned recrystallization, the solvent of described recrystallization withVolume mass ratio
It can be 10mL/g~20mL/g, can be 14mL/g~20mL/g again.
The operation of described recrystallization can be the conventional operation in this area, such as：Will be described
It is dissolved in described esters solvent, adds described varsol, cooling crystallization, obtain crystal formation.Described dissolving
Temperature can be 30 DEG C~40 DEG C.The final temperature of described cooling can be 10 DEG C~20 DEG C.
Present invention also offers a kind of preparation method of above-mentioned compound 1, as all R1-1Or R1-2It independently is and appoints
During one group, it is method one；As all R1-1Or R1-2In it is at least one be-O-PG1When, it is method two；When all
R1-1Or R1-2In it is at least one be-NH-PG2When, it is method three：
Described method one comprises the steps：Compound 2 and oxidant are subjected to oxidation reaction, obtain compound 1 i.e.
Can；
Described method two comprises the steps：By R1-1Or R1-2With protective agent protect instead for-OH compound 1
Should, obtain compound 1；
Described method three comprises the steps：By R1-1Or R1-2For-NH2Compound 1 and protective agent protect it is anti-
Should, obtain compound 1.
In method one, the reaction condition of described oxidation reaction can be the conventional reaction condition of such reaction of this area, example
Such as following reaction conditions：
Described oxidation reaction can be carried out in halogenated hydrocarbon solvent.Described halogenated hydrocarbon solvent can be this area such
React conventional halogenated hydrocarbon solvent, such as dichloromethane.Described halogenated hydrocarbon solvent and the volume matter of described compound 2
Measure the volume mass ratio that ratio can be such reaction routine of this area, such as 10mL/g~15mL/g.
In described oxidation reaction, described oxidant can be the conventional oxidant of such reaction of this area, such as between
Chloroperoxybenzoic acid.
In described oxidation reaction, the mol ratio of described oxidant and described compound 2 can be this area such
React conventional mol ratio, such as 2~3.
The temperature of described oxidation reaction can be 0 DEG C~30 DEG C (such as 0 DEG C~5 DEG C or 20 DEG C~30 DEG C).
The process of described oxidation reaction can use the routine monitoring method (such as TLC, HPLC or NMR) in this area to enter
Row monitoring, as reaction end when typically no longer being reacted using compound 2, the reaction time can be 10h~15h (such as 12h).
Described method one can also further comprise following step：By compound R1-LG1Carried out with 2-mercaptobenzothiazole
Substitution reaction, obtain described compound 2；LG1For leaving group；
Described " leaving group " can be the conventional leaving group of such reaction of this area (can by another functional group or
Atom passes through substitution reaction<Such as nucleophilic substitution>The functional group substituted or atom), such as halogen is (in another example chlorine, bromine
Or iodine), sulfonate group (in another example trifluoromethanesulfonic acid ester group, methanesulfonates, brosylate or p-methyl benzenesulfonic acid ester) or,
Acyloxy (in another example acetoxyl group or trifluoroacetyl epoxide), in another example sulfonate group is (in another example trifluoromethanesulfonic acid ester group, first sulphur
Acid esters, brosylate or p-methyl benzenesulfonic acid ester).
The reaction condition of described substitution reaction can be the conventional reaction condition of such reaction of this area, such as following reactions
Condition：
Described substitution reaction can be carried out in amide solvent.Described amide solvent can be such reaction of this area
Conventional amide solvent, such as DMF.Described amide solvent and described 2-mercaptobenzothiazole
Volume mass than can be the conventional volume mass ratio of such reaction of this area, such as 3mL/g~5mL/g.
Described substitution reaction can be carried out in the presence of acid binding agent.Described acid binding agent can be that such reaction of this area is normal
The acid binding agent (such as potassium tert-butoxide) of rule.The mol ratio of described acid binding agent and described 2-mercaptobenzothiazole can be this area
The conventional mol ratio of such reaction, such as 1.0~1.1.Described acid binding agent can be mixed first with described 2-mercaptobenzothiazole
Reaction, then with R1-LG1Reaction.
The temperature of described substitution reaction can be 80 DEG C~100 DEG C (such as 80 DEG C~90 DEG C).
The process of described substitution reaction can use the routine monitoring method (such as TLC, HPLC or NMR) in this area to enter
Row monitoring, as reaction end when typically no longer being reacted using 2-mercaptobenzothiazole, the reaction time can be 2h~3h.
In method two, the reaction condition of described protection reaction can be the conventional reaction condition of such reaction of this area, example
Such as following reaction conditions：
Described protection reaction can be carried out in a solvent, and described solvent can be that amide solvent and/or halogenated hydrocarbon are molten
It agent, can be amide solvent again, can also be halogenated hydrocarbon solvent.Described amide solvent can be that such reaction of this area is conventional
Amide solvent, such as DMF.Described halogenated hydrocarbon solvent can be that such reaction of this area is conventional
Halogenated hydrocarbon solvent, such as dichloromethane.Described solvent and described " R1-1Or R1-2For the volume matter of-OH compound 1 "
The volume mass ratio that ratio can be such reaction routine of this area, such as 5mL/g~15mL/g are measured, in another example 5mL/g~10mL/g.
Described protection reaction can be carried out in the absence of a solvent.
In described protection reaction, described protective agent can be the conventional protective agent of such reaction of this area (such as three
Methylchlorosilane, chlorotriethyl silane, dihydropyran or acetic anhydride).
In described protection reaction, described protective agent and described " R1-1Or R1-2For mole of-OH compound 1 "
Than the mol ratio that can be such reaction routine of this area, such as 1.5~2.0.
Acid binding agent can be used in described protection reaction.Described acid binding agent can tie up acid for such reaction routine of this area
Agent, such as imidazoles or pyridine.Described acid binding agent and described " R1-1Or R1-2Mol ratio for-OH compound 1 " can be this
The conventional mol ratio of such reaction of field, such as 2~3.
Catalyst can be used in described protection reaction.Described catalyst can be the conventional catalysis of such reaction of this area
Agent, such as to dimethylamino naphthyridine or pyridinium p-toluenesulfonate.
The temperature of described protection reaction can be 10 DEG C~30 DEG C (such as 20 DEG C~30 DEG C).
The process of described protection reaction can use the routine monitoring method (such as TLC, HPLC or NMR) in this area to enter
Row monitoring, typically with " R1-1Or R1-2Be reaction end when no longer being reacted for-OH compound 1 ", the reaction time can be 10h~
15h (such as 12h).
Described method two can also further comprise following step：According to the preparation method described in method one, it is made described
" R1-1Or R1-2For-OH compound 1 ".
In method three, the reaction condition of described protection reaction can be the conventional reaction condition of such reaction of this area, example
Such as following reaction conditions：
Described protection reaction can be carried out in a solvent, and described solvent can be that amide solvent and/or halogenated hydrocarbon are molten
It agent, can be amide solvent again, can also be halogenated hydrocarbon solvent.Described amide solvent can be that such reaction of this area is conventional
Amide solvent, such as DMF.Described halogenated hydrocarbon solvent can be that such reaction of this area is conventional
Halogenated hydrocarbon solvent, such as dichloromethane.Described solvent and described " R1-1Or R1-2For-NH2Compound 1 " volume matter
The volume mass ratio that ratio can be such reaction routine of this area, such as 5mL/g~15mL/g are measured, in another example 5mL/g~10mL/g.
Described protection reaction can be carried out in the absence of a solvent.
In described protection reaction, described protective agent can be the conventional protective agent of such reaction of this area (such as three
Methylchlorosilane, chlorotriethyl silane, dihydropyran or acetic anhydride).
In described protection reaction, described protective agent and described " R1-1Or R1-2For-NH2Compound 1 " rub
Your ratio can be the conventional mol ratio of such reaction of this area, such as 1.5~2.0.
Acid binding agent can be used in described protection reaction.Described acid binding agent can tie up acid for such reaction routine of this area
Agent, such as imidazoles or pyridine.Described acid binding agent and described " R1-1Or R1-2For-NH2Compound 1 " mol ratio can be this
The conventional mol ratio of such reaction of field, such as 2~3.
Catalyst can be used in described protection reaction.Described catalyst can be the conventional catalysis of such reaction of this area
Agent, such as to dimethylamino naphthyridine or pyridinium p-toluenesulfonate.
The temperature of described protection reaction can be 10 DEG C~30 DEG C (such as 20 DEG C~30 DEG C).
The process of described protection reaction can use the routine monitoring method (such as TLC, HPLC or NMR) in this area to enter
Row monitoring, typically with " R1-1Or R1-2For-NH2Compound 1 " be reaction end when no longer reacting, the reaction time can be 10h~
15h (such as 12h).
Described method three can also further comprise following step：According to the preparation method described in method one, it is made described
" R1-1Or R1-2For-NH2Compound 1 ".
As it was previously stated, the preparation method of described compound 1 can be following reaction scheme；
As it was previously stated, the preparation method of described compound 1 can also be following reaction scheme；
Present invention also offers a kind of compound as shown in Equation 2；
Wherein, R1It is defined as described above, but it is not
Present invention also offers a kind of benzothiazole sulfone compound as shown in Equation 5With containingThe compound 6 of structure carries out the application in Julia reactions；
Wherein, in ringRepresent singly-bound or double bond；Outside ringRepresent singly-bound or double bond；
R5For R5-1Substituted C1-C6Alkyl (described R5-1Number for one or more<Such as 1,2,3 or 4
It is individual>, when multiple R being present5-1When, any two R5-1It is identical or different；Described " C1-C6Alkyl " such as C1-C5Alkyl,Or, " the C in addition to 2,3- dimethylbutyls6Alkyl "；Described " C1-C5Alkyl " is for example
C1-C4Alkyl orDescribed " C1-C4Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or the tert-butyl group；All R5-1Can independently be connected on tertiary carbon atom or not be connected on tertiary carbon atom) or R5-2
Substituted C2-C8Alkenyl (described R5-2Number for one or more<Such as 1,2,3 or 4>, it is multiple when existing
R5-2When, any two R5-2It is identical or different；Described " C2-C8Alkenyl " such as C2-C6Alkenyl orIt is described
" C2-C6Alkenyl " such as C2-C4Alkenyl；Described " C2-C4Alkenyl " such as vinyl, propylene -1- bases or propylene -2- bases；Institute
The R stated5-2It can independently be connected on tertiary carbon atom or not be connected on tertiary carbon atom)；
All R5-1And R5-2It independently is：Hydroxyl, amino, halogen (such as fluorine, chlorine, bromine or iodine), cyano group ,-O-PG4、
Or ,-NH-PG5；All PG4It independently is hydroxyl protecting group, all PG5It independently is amino protecting group.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described compound 5 is not
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
R5Can be R5-1Substituted C1-C6Alkyl.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All " hydroxyl protecting groups " can independently be the conventional hydroxyl protecting group of such reaction of this area, and (just " hydroxyl is protected
The implication of shield base ", classification, the present invention quote what publishing house of East China University of Science published in October, 2004《Guarantor in organic synthesis
Protect base》Full content), such as methyl, substitution methyl (in another example tetrahydrofuran base, THP trtrahydropyranyl or dihydropyran
Base), ethyl, substitution ethyl, benzyl, substitution benzyl,(such as trimethyl silicon substrate, triethyl group silicon substrate,
Or, t-Butyldimethylsilyl), acyl group (in another example formoxyl,<Such as acetyl group>, substitution alkyl-carbonyl<Again
Such as trifluoroacetyl group>, substitution aryl carbonyl, substitution Heteroarylcarbonyl, methoxycarbonyl, substitution alkoxy carbonyl<
Such as 9-fluorenylmethyloxycarbonyl again>, benzyloxycarbonyl group or, the benzyloxycarbonyl of substitution) or, sulfonyl is (in another example mesyl, benzyl
Base sulfonyl or p-toluenesulfonyl)；
All R5-1-1、R5-1-2、R5-1-3And R5-1-4It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4
Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or second
Base).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All " hydroxyl protecting groups " can independently be(such as trimethyl silicon substrate, triethyl group silicon substrate,
Or, t-Butyldimethylsilyl),(such as acetyl group) or oxinane -2- bases；
All R5-1-1、R5-1-2、R5-1-3And R5-1-4It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4
Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or second
Base).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All " hydroxyl protecting groups " can independently be(such as trimethyl silicon substrate, triethyl group silicon substrate,
Or, t-Butyldimethylsilyl) or oxinane -2- bases；
All R5-1-1、R5-1-2And R5-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All "-O-PG4" can not be ester group.Described ester group refers to containing acyl group, substituted acyl, sulfonyl etc. and oxygen
The group of formation, such as acetoxyl group, tolysulfonyl epoxide etc..
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All " amino protecting groups " can independently be the conventional amino protecting group of such reaction of this area, and (just " amino is protected
The implication of shield base ", classification, the present invention quote what publishing house of East China University of Science published in October, 2004《Guarantor in organic synthesis
Protect base》Full content), such as acyl group (in another example formoxyl, acetyl group, methoxycarbonyl or, substitution alkoxy carbonyl<
Such as 9-fluorenylmethyloxycarbonyl again>).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All R5-1And R5-2- O-PG can independently be4Or ,-NH-PG5。
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
All R5-1And R5-2It can independently be：-O-PG4。
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
R5For R5-1Substituted C1-C6Alkyl；
All R5-1It independently is：-O-PG4.All PG4It independently is hydroxyl protecting group；
All " hydroxyl protecting groups " independently are(such as trimethyl silicon substrate, triethyl group silicon substrate or,
T-Butyldimethylsilyl) or oxinane -2- bases；
All R5-1-1、R5-1-2And R5-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
R5For R5-1Substituted C1-C6Alkyl；
All R5-1It independently is：-O-PG4.All PG4It independently is hydroxyl protecting group；
All " hydroxyl protecting groups " independently are(such as trimethyl silicon substrate, triethyl group silicon substrate or,
T-Butyldimethylsilyl)；
All R5-1-1、R5-1-2And R5-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
R5Can be
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Work as R5ForWhen, described hydroxyl protecting group can be(such as trimethyl silicane
Base, triethyl group silicon substrate or, t-Butyldimethylsilyl),(such as acetyl group) or oxinane -2- bases；
All R5-1-1、R5-1-2、R5-1-3And R5-1-4It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4
Alkyl " such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or second
Base).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Work as R5ForWhen, described hydroxyl protecting group can be(such as trimethyl silicon substrate,
Triethyl group silicon substrate or, t-Butyldimethylsilyl) or oxinane -2- bases；
All R5-1-1、R5-1-2And R5-1-3It independently is C1-C6Alkyl (such as C1-C4Alkyl；Described " C1-C4Alkyl "
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group, in another example methyl or ethyl).
In a certain technical scheme, described compound 5 can be following any structure：
DescribedCan be obtained crystal formation by the following method：Will
Recrystallized, obtain crystal formation；The solvent of described recrystallization is that (it can be that the conventional esters in this area are molten to esters solvent
Agent, such as ethyl acetate and/or isopropyl acetate, in another example ethyl acetate) and varsol (it can be the conventional hydrocarbon in this area
One or more in class solvent, such as petroleum ether, n-hexane and normal heptane, in another example normal heptane).
In above-mentioned recrystallization, the volume ratio of described varsol and esters solvent can be 5~15, can be 10 again
~12.
In above-mentioned recrystallization, the solvent of described recrystallization withVolume mass ratio
It can be 10mL/g~20mL/g, can be 14mL/g~20mL/g again.
The operation of described recrystallization can be the conventional operation in this area, such as：Will be described
It is dissolved in described esters solvent, adds described varsol, cooling crystallization, obtain crystal formation.Described dissolving
Temperature can be 30 DEG C~40 DEG C.The final temperature of described cooling can be 10 DEG C~20 DEG C.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure or
Person " containsThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
When described " containsThe compound 6 " of structure is " to containThe compound 6 " of structure
When, described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure " containsThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
When described " containsThe compound 6 " of structure is " to containThe compound 6 " of structure
When, described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure " containsThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
When described " containsThe compound 6 " of structure is " to containThe compound 6 " of structure
When, described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure " containsThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
When described " containsThe compound 6 " of structure is " to containThe compound 6 " of structure
When, described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure " containsThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure or
Person " containsThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
When described " containsThe compound 6 " of structure is " to containThe compound 6 " of structure
When, described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
When described " containsThe compound 6 " of structure is " to containThe compound 6 " of structure
When, described " containsThe compound 6 " of structure can be " to containThe compound 6 " of structure.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be Can be again
Wherein, PG6、PG7、PG8、PG9、PG10、PG11、PG12、PG13、PG14、PG15、PG16And PG17It independently is hydroxyl guarantor
Protect base (its is as defined above).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
Described " containsThe compound 6 " of structure can be Can be again
Wherein, PG6、PG7、PG8、PG9、PG10、PG11、PG12、PG13And PG14Independently being hydroxyl protecting group, (it is defined such as
It is upper described).
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan beCan be again
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan beCan be again
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan be
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan be
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan be
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan be
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
DescribedCan be
The reaction condition of described Julia reactions can be the conventional reaction condition of such reaction of this area, such as：
Described Julia reactions can be carried out in ether solvent.Described ether solvent can be that such reaction of this area is normal
The ether solvent of rule, such as tetrahydrofuran.Described ether solvent and the volume mass ratio of described compound 6 can be this area
The conventional volume mass ratio of such reaction, such as 15mL/g~45mL/g, in another example 30mL/g~45mL/g.
Described Julia reactions can be carried out in the presence of base.Described alkali can be the conventional alkali of such reaction of this area
(such as the one or more in LHMDS, potassium hexamethyldisilazide and lithium diisopropylamine, and example
Such as LHMDS).Described alkali and the molar ratio of described compound 6 can be that such reaction of this area is conventional
Molar ratio, such as 1.5~2.5, in another example 2.0~2.5.
The molar ratio of described compound 5 and described compound 6 can be the conventional mol ratio of such reaction of this area
Value, such as 1.2~2.5, in another example 2.0~2.5.
The feed way of described Julia reactions can be the conventional feed way of such reaction of this area, such as：
(1) described ether solvent is mixed with described compound 5；
(2) described alkali is added in the solution obtained to step (1)；
(3) described compound 6 is added in the mixture obtained to step (2) and carries out Julia reactions, is produced accordingly
Thing.
The temperature of described Julia reactions can be the conventional temperature of such reaction of this area, such as -80 DEG C~-30 DEG C (examples
Such as -80 DEG C~-70 DEG C or -40 DEG C~-30 DEG C).
The process of described Julia reactions can use the routine monitoring method (such as TLC, HPLC or NMR) in this area
It is monitored, as reaction end when typically no longer being reacted using compound 6, the reaction time can be 2h~5h.
In a certain technical scheme, the definition of each technical characteristic can the (definition not annotated as described below in described application
It is preceding it is any as described in)：
It can be cis and/or trans such as trans that described Julia, which reacts the double bond to be formed,.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：What the benzothiazole sulfone compound of the present invention was carried out with parent nucleus aldehyde
The high income of Julia reactions, based on product purity is high and trans.
Brief description of the drawings
Fig. 1 is the part hydrogen spectrogram of the end-product alcohol of embodiment 6.
Fig. 2 is the part hydrogen spectrogram of the end-product alcohol of comparative example 1.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Embodiment 1
2-mercaptobenzothiazole (26g, 0.156mol) is dissolved in 100ml DMF, and the lower addition t-BuOK of nitrogen protection consolidates
Body (18.3g, 1.05eq.), after stirring and dissolving is complete, after 5min, sulfonic acid ester side chain crude product
(41.0g, in theory 0.150mol) is added, and reaction system is warming up to 80 DEG C and stirred 2.5 hours, and TLC checks that raw material conversion is complete.
Cold house's temperature, add 100ml water, ethyl acetate/petroleum ether mixed extractant solvent 4 times.Organic phase is washed 2 times with 5%NaOH solution,
NH4Cl, NaCl are washed, and are dried to obtain crude product 37.0g, yield 92% or so.
Embodiment 2
The intermediate grease of embodiment 17.0g is dissolved in 70mL DCM, ice water cooling
But, mCPBA 12.0g (fuel factor clearly, pay attention to control charging rate) of the content more than 80% is added portionwise, after adding
Change and reaction is stirred at room temperature overnight.System separates out a large amount of solids.TLC is detected, and reaction is complete.1g sodium thiosulfate solids are added, are stirred
30min is mixed, is filtered, NaHCO3Wash organic phase.Drying is concentrated to give 7.90g brown liquids.The product, which is placed, slowly to be solidified.
Solid is added into the 40 degree of dissolvings of 10mL ethyl acetate, under stirring, 100mL normal heptanes is slowly added dropwise, cool to 10-20
Degree, separates out khaki crystal 6.66g, crystallization yield 85%.
HNMR(CDCl3):δ 8.21 (1H, d, J=8.0Hz), 8.02 (1H, d, J=8.0Hz), 7.61 (2H, m), 4.07
(1H, dd, J=3.2Hz, 14.4Hz), 3.25 (1H, dd, J=9.2Hz, 14.4Hz), 3.36 (1H, m), 1.28 (3H, s),
1.20 (3H, d, J=6.8Hz), 1.11 (3H, s)
Embodiment 3
The product sulfone of embodiment 21.0g is dissolved in 10ml dry DMFs, adds 3 equivalents
Imidazoles (Fw=68.07) and 2 equivalents TESCl (Fw=150.72, d=0.8977), then add the DMAP of catalytic amount, room temperature stirs
Mix overnight, raw material converts substantially completely.Product solvent petrol ether/ethyl acetate=10/1 or so.Column chromatography purifies yellowish
Color product 1.27g, yield 92%.
HNMR(CDCl3):δ 8.21 (1H, d, J=8.0Hz), 8.02 (1H, dd, J=0.8Hz, 8.0Hz), 7.61 (2H,
M), 4.05 (1H, d, J=14.0Hz), 3.17 (1H, dd, J=10.0Hz, 14.0Hz), 2.25 (1H, m), 1.23 (3H, s),
1.17 (3H, d, J=6.8Hz), 1.10 (3H, s), 0.84 (9H, t, J=8.0Hz), 0.50 (6H, q, J=8.0Hz)
Embodiment 4
The product sulfone of embodiment 21.0g is dissolved in 10ml dry DMFs, adds 2 equivalents
Imidazoles (Fw=68.07) and 1.5 equivalents TMSCl (Fw=108.64), then add catalytic amount DMAP, it is small to be stirred at room temperature 10
When, raw material conversion is complete.Product solvent petrol ether/ethyl acetate=10/1 or so.Column chromatography purifies to obtain faint yellow product
1.18g, yield 95%.
HNMR(CDCl3):δ 8.21 (1H, d, J=8.0Hz), 8.00 (1H, dd, J=0.8Hz, 8.0Hz), 7.60 (2H,
M), 3.99 (1H, d, J=14.4Hz), 3.15 (1H, dd, J=10.4Hz, 14.4Hz), 2.22 (1H, m), 1.23 (3H, s),
1.14 (3H, d, J=6.8Hz), 1.08 (3H, s), 0.00 (9H, s)
Embodiment 5
The product sulfone 1.0g of embodiment 2 is dissolved in 5.0mL dichloromethane, under ice-water bath add 5.0mL dihydropyran and
0.10g pyridinium p-toluenesulfonates, are stirred overnight at room temperature, and raw material largely converts, and column chromatography purifies to obtain pale yellow oil
0.91g, yield 71%.
Embodiment 6
The compound 5-1 (1.00g, 2.41mmol) that embodiment 3 obtains is dissolved in the anhydrous THF of 15ml, and dry ice is cooled to-
2.6ml LHMDS solution (2.6mmol) is added dropwise at 60 DEG C, after 30min, the THF that aldehyde 6-1 (0.392g, 1.21mmol) is added dropwise is molten
Liquid 3mL, low-temp reaction 30min, take from cold-trap, be warming up to -30 DEG C of reactions naturally and add NH in 2 hours4The processing of the Cl aqueous solution, extraction,
The very small product point of polarity is obtained, dodges post purifying, obtains 0.544g coupled products, yield 86%, purity is more than 90%.
Above-mentioned coupled product is dissolved in 5mL THF, adds 1.0g tetrabutyl ammonium fluorides, 45 DEG C of reactions desiliconization in 8 hours, rear place
Reason, ethyl acetate n-heptane system cross post purifying, obtain 0.28g solid products.The appraising datum of end-product alcohol is as follows：
HNMR(CDCl3):(2H, m, NMR peaks at this are difficult as shown in figure 1, proton peak overlaps by δ 5.34-5.30
Accurately to calculate coupling constant, but the collection of illustrative plates of comparative example 1, J values are combined, can unambiguously determine that double bond is anti-in the product
Formula), 3.95 (1H, m), 2.18-1.92 (3H, m), 1.95-1.80 (2H, m), 1.70-1.18 (9H, m), 1.17 (3H, s),
1.13(3H,s),1.03-0.99(6H,m),0.96(3H,s)。
Comparative example 1 is with reference to Tetrahedron Letters 2016, vol 57, Iss 12,1309-1312
With reference to TL, the sulfone of raw material aldehyde and end ester group is in THF/LHMDS systems, low-temp reaction, is prepared cis double
Key accounts for the coupled product of main body.
Take the cis coupled products of 1.0g to be dissolved in the anhydrous THF of 10mL, nitrogen protection, cool to -20~-30 degree, be added dropwise
Methyl-magnesium-bromide RMgBr, stirring reaction 2 hours, TLC conversions are complete.The saturated ammonium chloride solution that 5mL ice is added dropwise terminates instead
Should.The dilution of 20mL ethyl acetate is added, adds 50mL ammonium chloride solutions, liquid separation, the washing of 50mL sodium chloride solutions, organic phase drying
Concentration, obtains grignard product.
The crude product is directly dissolved in 10mL THF, adds 3.0g tetrabutyl ammonium fluorides, 45 DEG C of reaction desiliconizations, and product crosses post
Purifying, the appraising datum of end-product alcohol are as follows：
HNMR(CDCl3):δ 5.31-5.14 (2H, dt, J=10.8Hz), 4.07 (1H, m), 2.60-2.40 (2H, m),
1.19(3H,s),1.18(3H,s),0.98-0.93(9H,m)。
The NMR peaks (δ 5.3-5.1) of ethylene linkage are underlapped as shown in Fig. 2 it splits swarming separation degree height, and are computed, its
Coupling constant J=10.8Hz.With reference to the J of corresponding double bond in following embodiments 7 and 8ab=15.2Hz, it can unambiguously determine this
Locate double bond to be cis, correspondingly, the double bond of the product of the different embodiment 6 of appraising datum should be trans.
Embodiment 7
The compound 5-1 (1.17g, 2.83mmol) that embodiment 3 obtains is dissolved in the anhydrous THF of 20ml, and dry ice is cooled to-
2.9ml LHMDS solution (2.9mmol) is added dropwise at 70 DEG C, after 30min, aldehyde 7-1 (0.70g, 1.25mmol) THF solution is added dropwise
3mL, low-temp reaction 30min, take from cold-trap, be warming up to -30 DEG C of reactions naturally and add NH in 2 hours4The processing of the Cl aqueous solution, extraction, is obtained
The product point very small to polarity, EtOAc：PE<50:1 expansion, Rf>0.9.Post purifying is dodged, obtains 0.78g coupled products, yield
83%, purity is more than 90%.HNMR data are as follows：
HNMR(CDCl3):δ 6.12 (1H, d, J=11.2Hz), 5.76 (1H, d, J=11.2Hz), 5.26 (1H, dd, J=
8.0Hz, 15.2Hz), 5.16 (1H, dd, J=8.0Hz, 15.2Hz), 4.03 (2H, m), 2.76 (1H, m), 2.32 (2H, m),
2.22 (1H, m), 1.11 (3H, s), 1.06 (3H, s), 0.96 (3H, d, J=6.8Hz), 0.94-0.80 (30H, m), 0.56-
0.50(9H,m),0.00(12H,m)。
The feature coupling constant J of double bond hydrogenab=15.2Hz, can milli with reference to the J=10.8Hz of corresponding double bond in comparative example 1
Undoubtedly free burial ground for the destitute determines that double bond is trans at this.Therefore substantially without cis accessory substance.
Embodiment 8
The compound 5-2 (1.00g, 2.69mmol) that embodiment 4 obtains is dissolved in the anhydrous THF of 20ml, and dry ice is cooled to-
2.8ml LHMDS solution (2.8mmol) is added dropwise at 70 DEG C, after 30min, aldehyde 7-1 (0.70g, 1.25mmol) THF solution is added dropwise
3mL, low-temp reaction 30min, take from cold-trap, be warming up to -30 DEG C of reactions naturally and add NH in 2 hours4The processing of the Cl aqueous solution, extraction, is obtained
The product point very small to polarity, EtOAc：PE<50:1 expansion, Rf>0.9.Post purifying is dodged, obtains 0.76g coupled products, yield
85%, purity is more than 90%.HNMR data are as follows：
HNMR(CDCl3):δ 6.06 (1H, d, J=11.2Hz), 5.71 (1H, d, J=11.2Hz), 5.19 (1H, dd, J=
8.0Hz, 15.2Hz), 5.10 (1H, dd, J=8.0Hz, 15.2Hz), 3.95 (2H, m), 2.71 (1H, m), 2.26 (2H, m),
2.16 (1H, m), 1.07 (3H, s), 1.01 (3H, s), 0.91 (3H, d, J=6.8Hz), 0.84 (3H, d, J=6.8Hz) 0.77
(18H,s),0.45(3H,s),0.05-0.00(21H,m)
The feature coupling constant J of double bond hydrogenab=15.2Hz, can milli with reference to the J=10.8Hz of corresponding double bond in comparative example 1
Undoubtedly free burial ground for the destitute determines that double bond is trans at this.Therefore substantially without cis accessory substance.
Claims (10)
1. a kind of benzothiazole sulfone compound or its salt as shown in Equation 1：
Wherein, R1For R1-1Substituted C1-C6Alkyl or R1-2Substituted C2-C8Alkenyl；
All R1-1And R1-2It independently is：Hydroxyl, amino, halogen, cyano group ,-O-PG1Or ,-NH-PG2；All PG1It is independent
Ground is hydroxyl protecting group, all PG2It independently is amino protecting group；
But described compound 1 is not
2. benzothiazole sulfone compound as claimed in claim 1 or its salt, it is characterised in that described R1-1Number be
It is one or more；
And/or R1In, described " C1-C6Alkyl " is C1-C5Alkyl,Or, " remove 2,3- diformazans
C beyond base butyl6Alkyl "；
And/or all R1-1Independently it is connected on tertiary carbon atom or is not connected on tertiary carbon atom；
And/or described described R1-2Number for one or more；
And/or R1In, described " C2-C8Alkenyl " is C2-C6Alkenyl or
And/or all R1-2Independently it is connected on tertiary carbon atom or is not connected on tertiary carbon atom；
And/or all R1-1And R1-2In, all halogens independently are fluorine, chlorine, bromine or iodine；
And/or all R1-1And R1-2In, all " hydroxyl protecting group " independently is methyl, tetrahydrofuran base, oxinane
Base, dihydro pyranyl, ethyl, benzyl,Formoxyl,Trifluoroacetyl group, methoxycarbonyl, 9-
Fluorenylmethyloxycarbonyl or, benzyloxycarbonyl group；All R1-1-1、R1-1-2、R1-1-3And R1-1-4It independently is C1-C6Alkyl；
And/or all R1-1And R1-2In, all " amino protecting group " independently is formoxyl, acetyl group, methoxyl group carbonyl
Base or, 9-fluorenylmethyloxycarbonyl；
And/or described " salt " is hydrochloride or sulfate.
3. benzothiazole sulfone compound as claimed in claim 2 or its salt, it is characterised in that described R1-1Number be
One；
And/or as described R1-1Number for it is multiple when, it is described it is multiple be 2,3 or 4；
And/or R1In, as described " C1-C6Alkyl " is C1-C5Alkyl,Or, " remove 2,3- bis-
C beyond methyl butyl6During alkyl ", described " C1-C5Alkyl " is C1-C4Alkyl or
And/or described R1-2Number be one；
And/or as described R1-2Number for it is one or more when, it is described it is multiple be 2,3 or 4；
And/or R1In, as described " C2-C8Alkenyl " is C2-C6Alkenyl orWhen, described " C2-C6Alkenyl "
For C2-C4Alkenyl；
And/or all R1-1And R1-2In, all " hydroxyl protecting group " independently be tetrahydrofuran base,
And/or all R1-1-1、R1-1-2、R1-1-3And R1-1-4In, described C1-C6Alkyl independently is C1-C4Alkyl.
4. benzothiazole sulfone compound as claimed in claim 3 or its salt, it is characterised in that R1In, as described " C1-C6
Alkyl " is C1-C5Alkyl,Or, " the C in addition to 2,3- dimethylbutyls6It is alkyl ", described
“C1-C5Alkyl " is C1-C4Alkyl orWhen, described " C1-C4Alkyl " be methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, sec-butyl or the tert-butyl group；
And/or R1In, as described " C2-C8Alkenyl " is C2-C6Alkenyl orDescribed " C2-C6Alkenyl " is
C2-C4During alkenyl, described " C2-C4Alkenyl " is vinyl, propylene -1- bases or propylene -2- bases；
And/or all R1-1And R1-2In, all " hydroxyl protecting group " independently be tetrahydrofuran base or,
And/or as all R1-1-1、R1-1-2、R1-1-3And R1-1-4In, described C1-C6Alkyl independently is C1-C4During alkyl,
All " C1-C4Alkyl " independently is methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or the tert-butyl group.
5. benzothiazole sulfone compound as claimed in claim 4 or its salt, it is characterised in that as all R1-1And R1-2
In, all " hydroxyl protecting group " independently be tetrahydrofuran base or,When, it is allSolely
On the spot for trimethyl silicon substrate, triethyl group silicon substrate or, t-Butyldimethylsilyl.
6. benzothiazole sulfone compound as claimed in claim 1 or its salt, it is characterised in that R1For R1-1Substituted C1-C6
Alkyl；
And/or all R1-1And R1-2In, all "-O-PG1" it is not ester group；
And/or all R1-1And R1-2It independently is-O-PG1Or ,-NH-PG2。
7. benzothiazole sulfone compound as claimed in claim 6 or its salt, it is characterised in that all R1-1And R1-2It is independent
Ground is-O-PG1。
8. benzothiazole sulfone compound as claimed in claim 7 or its salt, it is characterised in that R1For
9. benzothiazole sulfone compound as claimed in claim 8 or its salt, it is characterised in that work as R1For
When, described hydroxyl protecting group isOr oxinane -2- bases；
Described R1-1-1、R1-1-2、R1-1-3And R1-1-4It independently is C1-C6Alkyl.
10. benzothiazole sulfone compound as claimed in claim 8 or its salt, it is characterised in that work as R1ForWhen, described hydroxyl protecting group isOr oxinane -2- bases；
Described R1-1-1、R1-1-2、R1-1-3And R1-1-4It independently is C1-C4Alkyl.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191655A (en) * | 2018-03-01 | 2018-06-22 | 西北农林科技大学 | The synthetic method of U.S.'s western corn rootworm sex pheromone and its application |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004067504A1 (en) * | 2003-01-31 | 2004-08-12 | Chugai Seiyaku Kabushiki Kaisha | 2-substituted vitamin d derivative |
| CN102070563A (en) * | 2011-01-21 | 2011-05-25 | 浙江大学 | Method for preparing 2-benzothiazolylethyl sulfone |
| CN102131773A (en) * | 2008-07-22 | 2011-07-20 | Azad药物成分股份公司 | Methods for producing paricalcitol |
| ES2380477A1 (en) * | 2010-10-13 | 2012-05-14 | Universidad De Vigo | Procedure for obtaining "25-hydroxycetone from windaus" that comprises the reaction of julia-kocienski. (Machine-translation by Google Translate, not legally binding) |
| CN103086937A (en) * | 2013-01-08 | 2013-05-08 | 上海朴颐化学科技有限公司 | Method for synthesizing paricalcitol |
| US20150376175A1 (en) * | 2014-06-30 | 2015-12-31 | Myongji University Industry And Academia Cooperation Foundation | C5 benzothiazolyl sulfone compound, method of preparing the same, method of preparing polyene dialdehyde compound using the same, and method of synthesizing lycopene using the same |
| CN105777665A (en) * | 2014-12-17 | 2016-07-20 | 上虞京新药业有限公司 | Calcipotriol intermediate compound and preparation method thereof |
-
2017
- 2017-09-28 CN CN201710897907.6A patent/CN107698580A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004067504A1 (en) * | 2003-01-31 | 2004-08-12 | Chugai Seiyaku Kabushiki Kaisha | 2-substituted vitamin d derivative |
| CN102131773A (en) * | 2008-07-22 | 2011-07-20 | Azad药物成分股份公司 | Methods for producing paricalcitol |
| ES2380477A1 (en) * | 2010-10-13 | 2012-05-14 | Universidad De Vigo | Procedure for obtaining "25-hydroxycetone from windaus" that comprises the reaction of julia-kocienski. (Machine-translation by Google Translate, not legally binding) |
| CN102070563A (en) * | 2011-01-21 | 2011-05-25 | 浙江大学 | Method for preparing 2-benzothiazolylethyl sulfone |
| CN103086937A (en) * | 2013-01-08 | 2013-05-08 | 上海朴颐化学科技有限公司 | Method for synthesizing paricalcitol |
| US20150376175A1 (en) * | 2014-06-30 | 2015-12-31 | Myongji University Industry And Academia Cooperation Foundation | C5 benzothiazolyl sulfone compound, method of preparing the same, method of preparing polyene dialdehyde compound using the same, and method of synthesizing lycopene using the same |
| CN105777665A (en) * | 2014-12-17 | 2016-07-20 | 上虞京新药业有限公司 | Calcipotriol intermediate compound and preparation method thereof |
Non-Patent Citations (6)
| Title |
|---|
| BIAO JIANG，ET AL.: ""The convergent synthesis of novel cytotoxic certonardosterol D2 from diosgenin"", 《TETRAHEDRON》 * |
| D. CHEVRIE，ET AL.: ""A convenient one-step synthesis of fluoroethylidene derivatives"", 《TETRAHEDRON LETTERS》 * |
| KAZUYUKI MIYASHITA，ET AL.: ""Total synthesis of leustroducsin B via a convergent route"", 《TETRAHEDRON LETTERS》 * |
| NORIHITO ARICHI，ET AL.: ""Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| PAUL R. BLAKEMORE: ""The modified Julia olefination: alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds"", 《J. CHEM. SOC., PERKIN TRANS. 1》 * |
| RAMAKRISHNA SAMALA，ET AL.: "A new metabolite of Paricalcitol: stereoselective synthesis of (22Z)-isomer of 1a,25-dihydroxy-19-norvitamin D2", 《TETRAHEDRON LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191655A (en) * | 2018-03-01 | 2018-06-22 | 西北农林科技大学 | The synthetic method of U.S.'s western corn rootworm sex pheromone and its application |
| CN108191655B (en) * | 2018-03-01 | 2021-05-28 | 西北农林科技大学 | Synthetic method and application of American western corn rootworm sex pheromone |
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