CN105037363B - A kind of entecavir compound prepared novel synthesis - Google Patents
A kind of entecavir compound prepared novel synthesis Download PDFInfo
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- CN105037363B CN105037363B CN201510406573.9A CN201510406573A CN105037363B CN 105037363 B CN105037363 B CN 105037363B CN 201510406573 A CN201510406573 A CN 201510406573A CN 105037363 B CN105037363 B CN 105037363B
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- 229960000980 entecavir Drugs 0.000 title claims abstract description 38
- -1 entecavir compound Chemical class 0.000 title claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 title abstract description 19
- 238000003786 synthesis reaction Methods 0.000 title abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims abstract description 24
- 238000010189 synthetic method Methods 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 150000002576 ketones Chemical class 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 230000000977 initiatory effect Effects 0.000 claims abstract description 5
- 238000006228 Dieckmann condensation reaction Methods 0.000 claims abstract description 3
- 125000004185 ester group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 91
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- 238000003756 stirring Methods 0.000 claims description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- 239000000243 solution Substances 0.000 claims description 40
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 36
- 208000035126 Facies Diseases 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000000376 reactant Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 239000012043 crude product Substances 0.000 claims description 21
- 238000010898 silica gel chromatography Methods 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
- 229940125782 compound 2 Drugs 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 229940126214 compound 3 Drugs 0.000 claims description 18
- 229940125898 compound 5 Drugs 0.000 claims description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 17
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 239000011230 binding agent Substances 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 16
- 229940125773 compound 10 Drugs 0.000 claims description 16
- 229940125797 compound 12 Drugs 0.000 claims description 16
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 16
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 16
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 16
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 12
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 11
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 10
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000000284 extract Substances 0.000 claims description 8
- 150000002460 imidazoles Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 238000012805 post-processing Methods 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 7
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000002024 ethyl acetate extract Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 5
- 230000008859 change Effects 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000002027 dichloromethane extract Substances 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- ADZJWYULTMTLQZ-UHFFFAOYSA-N tritylphosphane;hydrobromide Chemical compound [Br-].C=1C=CC=CC=1C(C=1C=CC=CC=1)([PH3+])C1=CC=CC=C1 ADZJWYULTMTLQZ-UHFFFAOYSA-N 0.000 claims description 4
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- QLFFCLRSMTUBEZ-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].[Na].OP(O)(O)=O QLFFCLRSMTUBEZ-UHFFFAOYSA-N 0.000 claims description 2
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000006228 supernatant Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- YVOMYDHIQVMMTA-BYPYZUCNSA-N (3s)-3-hydroxyhexanedioic acid Chemical compound OC(=O)C[C@@H](O)CCC(O)=O YVOMYDHIQVMMTA-BYPYZUCNSA-N 0.000 claims 1
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000006751 Mitsunobu reaction Methods 0.000 abstract 1
- 238000006946 Rubottom oxidation reaction Methods 0.000 abstract 1
- 238000007239 Wittig reaction Methods 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
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- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
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- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 3
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 2
- XICUCJZXYQGJIZ-UHFFFAOYSA-N P.[Br-].C1(=CC=CC=C1)C(C1=CC=CC=C1)(C1=CC=CC=C1)[PH3+] Chemical compound P.[Br-].C1(=CC=CC=C1)C(C1=CC=CC=C1)(C1=CC=CC=C1)[PH3+] XICUCJZXYQGJIZ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- GCSVCUMDOQKEMT-UHFFFAOYSA-N butan-1-amine;hydrofluoride Chemical compound [H+].[F-].CCCCN GCSVCUMDOQKEMT-UHFFFAOYSA-N 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000004383 yellowing Methods 0.000 description 2
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- DCSOPUDOZMRWRP-UHFFFAOYSA-N Cc1cc(C)cc([SiH2]Cl)c1 Chemical compound Cc1cc(C)cc([SiH2]Cl)c1 DCSOPUDOZMRWRP-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- SAXNTHPZJQFRIJ-ZCFIWIBFSA-N O[C@@H](C1(CC2)OCCO1)C2=O Chemical compound O[C@@H](C1(CC2)OCCO1)C2=O SAXNTHPZJQFRIJ-ZCFIWIBFSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011280 coal tar Substances 0.000 description 1
- NUUNDIOOYFEMQN-UHFFFAOYSA-N cyclopenta-1,3-diene;sodium Chemical compound [Na].C1C=CC=C1 NUUNDIOOYFEMQN-UHFFFAOYSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002019 doping agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000005822 methylenation reaction Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000011269 tar Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000007984 tetrahydrofuranes Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical synthesis field; relate to a kind of entecavir compound prepared and synthetic method of intermediate; with (S) 3 hydroxyl dimethyl adipate as initiation material, by hydroxyl TBS protection, Dieckmann condensation reaction, ketone protect into ketal, ester group is reduced into hydroxyl, hydroxyl protection, deprotection, ketone become silyl enol ether, Rubottom oxidation reaction prepares intermediate 9；Intermediate 9, through wittig reaction, Mitsunobu reaction, desiliconization protection group, basic hydrolysis, prepares Entecavir.Reaction condition gentleness of the present invention is easily-controllable, simple to operate, product yield is high, purity is high, is suitable for industrialized great production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of entecavir compound prepared novel synthesis.
Background technology
Entecavir (Entecavir), chemical name is: [1-S-(1 α, 3 α, 4 β)]-2-amino-1,
9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylenecyclopentyl]-6H-purine-6-one, be a kind of effective,
The deoxyguanosine analog of Selective depression hepatitis B replication is many to hepatitis B virus (HBV)
Poly-enzyme is inhibited, U.S. Bristol-MyersSquibb (Bristol Myers Squibb) company research and develop,
In April, 2005 lists in the U.S., and its structural formula is as follows:
In vitro tests shows, Entecavir is more more effective than other nucleoside analogs.Animal model and human clinical grind
Studying carefully result to show, Entecavir has extremely strong suppression hepatitis B replication, reduces serum-virus DNA
The effect of level, the mutated viruses strain to resistance to lamivudine is still effective, and has no obvious untoward reaction and line
Plastochondria toxicity.A large amount of clinical experiments show, it is many to reverse transcriptase in hepatocyte and hepatitis B virus DNA
Poly-enzyme has direct inhibitory action, has the strongest anti-virus ability, and the selectivity ratios of this compound is higher simultaneously,
Its cytotoxicity is the 1/8000 of anti-hepatitis B activity, effectively can treat chronic viral hepatitis B and not disturb influenza
Virus and inhibition of HIV.And owing to its mechanism of action is different, the drug resistance that life-time service produces is low.Due to it
Have rapid-action, resist that hepatitis B virus is strong, the feature of low drug resistance, be the head of Chronic Hepatitis B antiviral therapy
Choosing, the market demand is bigger.
A lot of document and patent is had to describe the synthetic method of Entecavir and intermediate thereof, such as at present:
1, patent WO2004052310 reports and synthesize entecavir using 16 and 17 as key intermediate respectively
Two kinds of new methods of Wei.
Wherein the synthetic method with intermediate 16 as key intermediate is to first pass through asymmetric synthesis to build containing outside ring
The chirality five-membered ring intermediate 16 of double bond, then be combined with purine compound, obtain grace through three-step reaction and replace
Card Wei, reaction scheme is as follows:
The synthetic route of this intermediate (16) is short, and productivity is higher, but reagent price is much more expensive, and cost is too
Height, severe reaction conditions, the reagent environmental pollution such as mesyl chloride is relatively big, is not suitable for industrialized production.
Synthetic method with intermediate 17 as key intermediate is first with chain type silane (-SiR2 bRa) protect as configuration
Protect group, build five-membered ring racemic compound (24), then obtain chirality five-membered ring by the method for chemical resolution,
Thus synthesis obtains key intermediate 17 further, is combined with purine compound the most again, anti-through three steps
Should obtain Entecavir, reaction scheme is as follows:
At present, the defect that the synthesis of such intermediate (17) there is also generates substantial amounts of tar in reacting exactly, makes
Obtain product purification difficult, also affect yield simultaneously.In order to solve this difficult problem, 2005, Maotang X.Zhou
Carry out further base group modification to 17, devise and synthesize grace using intermediate 30 and 31 as key intermediate
For the method (US20050272932) of card Wei, it is coal-tar middle oil that the use of the two intermediate decreases late phase reaction
Producing, and productivity is higher, but its synthesis step is oversize, whole economic efficiency is the highest.
The problem that above method exists all leverages the industrialization development of Entecavir.For presently, there are
Problem, a kind of reaction condition gentleness of exploration is easily-controllable, synthesis step simple, product purifies easily, applicable industrialization
The key intermediate and the synthetic method thereof that produce are significant.
2, Entecavir is Carbocyclic nucleoside analogues, and its synthetic method is extremely complex.In prior art, China
It is [1S-(1 α, 2 α, 3 β, 5 α)]-2-[(benzene that patent ZL03135304.5 discloses the chiral starting materials of a kind of use
Methoxyl group) methyl]-6-oxabicyclo [3.1.0] hex-3-alcohol, this compound is not easy to obtain, expensive；And also
Former reaction uses palladium-carbon catalyst, expensive.Chinese patent application 200610088464.8 discloses and makes
With chiral starting materials [1S-(1 α, 2 α, 3 β, 5 α)]-3-(benzyloxy)-2-[(benzyloxy) methyl]-6-oxa-
Bicyclo-[3.1.0] hexane, expensive and be difficult to obtain；The methylene of costliness is used in methylenation
Change reagent N YSTED reagent.
3, Chinese patent application ZL200610003451.6, ZL200610130565.7 disclose and employ chirality
These method steps of initiation material are long, complex operation, and it is initial for all employ similar expensive chipal compounds
Raw material and catalyst, reaction yield is low, and course of reaction isomerization is serious, and a lot of intermediate needs to use post
Chromatographic purification.CN91110831, CN1747959, WO2004052310 have had very in these synthetic methods
Big improvement.Have employed sodium cyclopentadiene is raw material, obtains final products by series reaction.Its shortcoming is
Have employed expensive 3,5-dimethylphenyl chlorosilane as protection group.
In order to solve problems of the prior art, applicant proposes the present invention through numerous studies, spy.
Summary of the invention
Present invention aim at providing a kind of entecavir compound prepared and synthetic method of intermediate, existing to solve
There are the problems such as process route cost intensive in technology, raw material are rare, method and technology requirement is high.
Present invention provide the technical scheme that
A kind of entecavir compound prepared synthetic method, it is characterised in that the method is with compound 9 for initial former
MaterialComprise the following steps:
A) compound 9 is through wittig reacting generating compound 10；
B) compound 10 and compound 11 mix, through Mitsunobu reacting generating compound 12；
C) compound 12 desiliconization protection group generates compound 13；
D) compound 13 hydrolyzed under basic conditions generates Entecavir,
Preferably, described entecavir compound prepared synthetic method, it is characterised in that comprise the steps:
A) by compound 9 in a solvent, and Witting reagent effect, post-treated compound 10；
B) by compound 10 depositing at triphenylphosphine, diethyl azodiformate or diisopropyl azodiformate
React with compound 11 lower, post-treated compound 12；
C) by compound 12 in a solvent, add tetrabutyl ammonium fluoride and carry out desiliconization protection group reaction, reaction knot
Bundle, post-treated compound 13；
D) compound 13 is joined in alkaline solution, reactant liquor is heated to 70 DEG C, stirring reaction, instead
After should terminating, post-treated Entecavir.
It is furthermore preferred that described entecavir compound prepared synthetic method:
Being prepared as of the described Witting reagent of step a): under nitrogen protection, adds triphenylmethylphosphonium bromide
Enter in solvent, be cooled at 0 DEG C, add base catalyst, finish, be warmed to room temperature reaction, thus prepare
Witting reagent；Described solvent be dichloromethane, oxolane, toluene, ether one or more；Institute
Stating base catalyst is Feldalat NM, Sodium ethylate, potassium tert-butoxide or n-BuLi；Described post processing is: cancellation,
Concentrating under reduced pressure, ethyl acetate extracts, and washing organic facies, anhydrous sodium sulfate are dried, filter, concentrating under reduced pressure, slightly
Product purify to obtain compound 10 through silica gel column chromatography；
The described reaction of step b) is to carry out in solvents tetrahydrofurane, described in be added thereto to triphenylphosphine and
The temperature of the suspension of DEAD is 0 DEG C, and the temperature of described stirring reaction is 0 DEG C, the time is 1-5 hour, institute
The post processing stated is: after having reacted, and adds ethyl acetate, use 0.5M sodium hydroxide solution in reactant liquor
Washing, anhydrous sodium sulfate is dried organic facies, filtration, concentrating under reduced pressure, and crude product purifies to obtain chemical combination through silica gel column chromatography
Thing 11；
The described reaction of step c) is to carry out in solvents tetrahydrofurane, and described stirring reaction temperature is room temperature, stirs
Mixing the response time is 12 hours, and described post processing is: after reaction terminates, cancellation, and ethyl acetate extracts, water
Washing organic facies, anhydrous sodium sulfate is dried, filtration, concentrating under reduced pressure；
Alkaline solution described in step d) is 2M sodium hydroxide solution, and the described stirring response time is 4 little
Time, described post processing is: after reaction terminates, reactant liquor is cooled to 0 DEG C, adjusts pH extremely with 1M hydrochloric acid solution
6.8, and at 0 DEG C, stir 2h, filter to obtain Entecavir.
The most preferred:
In step a), compound 9 with the mol ratio of triphenylmethylphosphonium bromide, base catalyst is
1:1.4-1.6:1.4-1.6；
Compound 10 and compound 11, triphenylphosphine, diethyl azodiformate or azo two in step b)
The mol ratio of formic acid diisopropyl ester is 1:1.5-2.5:1.5-2.5:1.5-2.5；
In step c), compound 12 is 1:1.5-3 with the mol ratio of tetrabutyl ammonium fluoride；
In step a), the eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=50:1-10:1.
Present invention also offers the synthetic method of a kind of entecavir midbodies compound.
A kind of synthetic method of entecavir midbodies as claimed in claim 1, it is characterised in that the method with
(S)-3-hydroxyl dimethyl adipate (compound 1) is initiation materialIncluding
The following step:
(1) compound 1 protects to obtain compound 2 through hydroxyl TBS；
(2) compound 2 generates compound 3 through Dieckmann condensation reaction；
(3) compound 3 protects into ketal through ketone, generates compound 4；
(4) compound 4 is reduced into hydroxyl through ester group, generates compound 5；
(5) compound 5 is through hydroxyl protection, generates compound 6；
(6) compound 6 deprotection generates compound 7；
(7) compound 7 becomes silyl enol ether through ketone, generates compound 8；
(8) compound 8 metachloroperbenzoic acid aoxidizes to obtain compound 9；
Preferably, the synthetic method of described entecavir midbodies, it is characterised in that comprise the steps:
1) compound 1 is generated compound 2 with TBSCl in the presence of organic solvent, acid binding agent；
2) by step 1) in gained compound 2 in a solvent, alkaline matter be catalyzed under cyclization；Locate after through
Manage to obtain compound 3；
3) in the presence of organic solvent and catalyst, by step 2) in gained compound 3 anti-with ethylene glycol
Compound 4 should be prepared；
4) by step 3) in gained compound 4 be dissolved in anhydrous tetrahydro furan, at sodium borohydride and lithium chloride
Effect under react, post-treated compound 5；
5) by step 4) gained compound 5 generates chemical combination with TBSCl in the presence of organic solvent, acid binding agent
Thing 6；
6) by step 5) gained compound 6 is dissolved in methanol, and add hydrochloric acid and carry out ketal deprotection reaction,
Post-treated compound 7；
7) by step 6) gained compound 7 in organic solvent, in the presence of organic base and TMSOTf react
Prepare compound 8；
8) by step 7) gained compound 8 through metachloroperbenzoic acid oxidation reaction, post-treated chemical combination
Thing 9；
Further preferred, the synthetic method of described entecavir midbodies, specifically comprise the following steps that
1) compound 1 is dissolved in organic solvent, is sequentially added into acid binding agent, TBSCl, stirring reaction under room temperature
3-5 hour, adding shrend and go out, separatory, organic phase washed with water, anhydrous sodium sulfate is dried, and filters, decompression
Concentrate, obtain compound 2；Described organic solvent is selected from dichloromethane, dimethylformamide, chloroform, tetrahydrochysene furan
One or more in muttering；Described acid binding agent is imidazoles or pyridine；
2) by step 1) in gained compound 2 be dissolved in solvent, add alkaline matter, be heated to reflux 2-5 little
Time, question response terminates, concentrating under reduced pressure；Residue adds 0.5M hydrochloric acid solution, extracts with dichloromethane, has
Machine is washed twice with water mutually, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, and crude product purifies through silica gel column chromatography
Obtain compound 3；Described solvent is methanol, ethanol, the tert-butyl alcohol, oxolane, dimethylformamide；Described
Alkaline matter is sodium alkoxide or potassium alcoholate, Sodamide., sodium hydride, hydrofining or calcium hydride；
3) by step 2) in gained compound 3 be dissolved in organic solvent, add ethylene glycol and catalyst, add
Hot reflux divides water, reacts 4-10 hour, after not having moisture to produce, stops heating, is cooled to room temperature, adds
Saturated sodium bicarbonate solution stirs 10 minutes, separatory, organic phase washed with water twice, and anhydrous sodium sulfate is dried,
Filtering, concentrating under reduced pressure obtains compound 4；Described catalyst is p-methyl benzenesulfonic acid, pyridine hydrochloride or pyridinium tribromide
Change hydrogen salt；Described organic solvent is toluene, benzene, dichloromethane, chloroform or oxolane.
4) sodium borohydride and lithium chloride are joined in anhydrous tetrahydro furan, under nitrogen protection stirring 30 minutes,
Stopping stirring allowing solid deposit, and the round bottom that the supernatant is added dropwise to the anhydrous tetrahydro furan equipped with compound 4 burns
In Ping, it is stirred at room temperature until reactionless thing, adds shrend and go out reaction, reactant liquor concentrating under reduced pressure removal oxolane,
Residue from dichloromethane extracts, organic phase washed with water twice, merges, and is dried, and filters, concentrating under reduced pressure,
Crude product column chromatography purifies to obtain compound 5；
5) by step 4) gained compound 5 is dissolved in organic solvent, is sequentially added into acid binding agent, TBSCl, room temperature
Lower stirring reaction 3-5 hour, adds shrend and goes out, separatory, organic phase washed with water, and anhydrous sodium sulfate is dried,
Filter, concentrating under reduced pressure, obtain compound 2；Described organic solvent is selected from dichloromethane, dimethylformamide, chlorine
One or more in imitative, oxolane；Described acid binding agent is imidazoles or pyridine；
6) by step 5) gained compound 6 is dissolved in methanol, and add 3N hydrochloric acid under room temperature, stir at 50 DEG C
Mix reaction 2-4 hour, until reactionless thing, be cooled to room temperature, in adjusting pH extremely with saturated sodium bicarbonate solution
Property, extracting with dichloromethane, organic facies is dried through anhydrous sodium sulfate, filters, and concentrating under reduced pressure, crude product is through post layer
Analysis purifies to obtain compound 7；
7) by step 6) compound 7 is dissolved in organic solvent, is cooled to 0 DEG C, drips organic base the most wherein
And TMSOTf, stir the mixture 1 hour of gained at 5 DEG C；After having reacted, add shrend and go out reaction, divide
From organic facies, washing with water, be dried through anhydrous sodium sulfate, filter, concentrating under reduced pressure obtains target compound 8；Institute
The organic base stated is one or more of pyridine, triethylamine, imidazoles or DBU；Described organic solvent is dichloro
Methane；
8) by step 7) gained compound 8 is dissolved in dichloromethane, is cooled to-25 DEG C, is sequentially added into phosphoric acid
Disodium hydrogen and the metachloroperbenzoic acid of 70%, at-25 DEG C, stirring reaction 2-4 hour, adds sodium sulfite
Solution and sodium bisulfate, reactant liquor is heated to room temperature, stirs 1-2 hour, and after having reacted, separation has
Machine phase, is washed twice with water, and is dried through anhydrous sodium sulfate, filters, and concentrating under reduced pressure, crude product is through silica gel column chromatography
Purify to obtain compound 9.
Further:
Step 1) in compound 1 be 1:1.1-1.3:1.0-1.2 with acid binding agent, the mol ratio of TBSCl；
Step 2) in the mol ratio of compound 2 and alkaline matter be 1:1-3；
Step 3) in compound 3 be 1:2-4:0.05-0.10 with ethylene glycol, the mol ratio of catalyst；
Step 4) in compound 4 be 1:1.1-1.2:1.1-1.2 with sodium borohydride, the mol ratio of lithium chloride；
Step 5) in compound 5 be 1:1.1-1.3:1.1-1.2 with acid binding agent, the mol ratio of TBSCl；
Step 7) in compound 7 be 1:3-5:1-2 with organic base, the mol ratio of TMSOTf；
Step 8) in compound 8 be 1:4-6:2-3 with disodium hydrogen phosphate, the mol ratio of metachloroperbenzoic acid.
Further: the developing solvent that silica gel column chromatography described in course of reaction uses is petrol ether/ethyl acetate:
Step 2) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1；
Step 4) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=60:1-40:1；
Step 6) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1；
Step 8) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=50:1-10:1.
Compared to prior art, technical solution of the present invention has a following significant advantage:
1) technical solution of the present invention provides the route that a kind of applicable domestic industry metaplasia is produced, and this route is with (S)-3-
Hydroxyl dimethyl adipate (compound 1) is initiation material, solves the problem that raw material in prior art is rare；
2) technical solution of the present invention is carried out all the time in the range of relatively stationary temperature, and step is few, simple and easy to control, instead
The consumption answering thing is easy to control, and reaction condition is gentle, and course of reaction is stable, and side reaction is few, solves prior art
Process route method and technology requires high problem topic；
3) reagent that technical solution of the present invention is used is cheap, and environmental pollution is little, solves prior art
The problem of process route cost intensive；
4) technical solution of the present invention gained Entecavir yield is high, and purity is high, and dopant species is few, suitable for industrialized
Big production.
Detailed description of the invention
Herein below is to combine concrete preferred implementation further description made for the present invention, it is impossible to
Assert the present invention be embodied as be confined to these explanations.Ordinary skill for the technical field of the invention
For personnel, without departing from the inventive concept of the premise, it is also possible to make some simple deduction or replace, all
Should be considered as belonging to protection scope of the present invention, the present invention uses but the technology that do not illustrates and indexing section,
It is prior art.
Embodiment 1:
1) synthesis of compound 2
(S)-3-hydroxyl dimethyl adipate (190.2g, 1mol) is dissolved in 2000ml dichloromethane, depends on
Secondary addition imidazoles (81.7g, 1.2mol) and TBSCl (165.8g, 1.1mol), reactant liquor at room temperature stirs
Mix 4 hours.Adding 1500ml shrend to go out reaction, separatory, organic facies 2000ml water washes twice, anhydrous
Sodium sulfate is dried, and filters, and obtains compound 2 (289.25g, productivity 95%) after concentrating under reduced pressure.
2) synthesis of compound 2
(S)-3-hydroxyl dimethyl adipate (190.2g, 1mol) is dissolved in 2000ml oxolane, depends on
Secondary addition pyridine (103.1g, 1.3mol) and TBSCl (180.9g, 1.2mol), reactant liquor is at room temperature
Stir 3 hours.Adding 1500ml shrend to go out reaction, separatory, organic facies 2000ml water washes twice, nothing
Aqueous sodium persulfate is dried, and filters, and obtains compound 2 (287.8g, productivity 94.5%) after concentrating under reduced pressure.
Embodiment 2:
1) synthesis of compound 3
Compound 2 (228.35g, 750mmol) is dissolved in 12500ml methanol, adds the Feldalat NM of 25%
Methanol solution (486g, 2250mmol), is heated to reflux 3 hours.After reaction terminates, concentrating under reduced pressure removes first
Alcohol.Residue adds 5000ml 0.5M hydrochloric acid solution, extracts with 2500ml dichloromethane, organic facies 2500ml
Washing twice, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate
=80:1) purify to obtain compound 3 (147.1g, productivity 72%).
2) synthesis of compound 3
Compound 2 (243.6g, 0.8mol) is dissolved in the 12500ml tert-butyl alcohol, adds the tert-butyl alcohol of 25%
The t-butanol solution (179.5g, 1.6mol) of potassium (t-BuOK), is heated to reflux 2 hours.After reaction terminates,
The concentrating under reduced pressure tert-butyl alcohol.Residue adds 5000ml 0.5M hydrochloric acid solution, extracts with 2500ml dichloromethane,
Organic facies 2500ml washes twice, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, crude product column chromatography (stone
Oil ether/ethyl acetate=80:1) purify to obtain compound 3 (169.0g, productivity 73%).
Embodiment 3:
1) synthesis of compound 4
Compound 3 (136.2g, 500mmol) is dissolved in 280ml toluene, addition ethylene glycol (93.1g,
1500mmol) with p-methyl benzenesulfonic acid monohydrate (7.6g, 40mmol), being heated to reflux a point water, reaction 8 is little
Time, after not having moisture to produce, stop heating, be cooled to room temperature.Add 750ml saturated sodium bicarbonate solution
Stirring 10 minutes, separate organic facies, wash twice with 1000ml water, anhydrous sodium sulfate is dried, and filters, subtracts
Pressure is concentrated to give compound 4 (145.6g, productivity 92%).
2) synthesis of compound 4
Compound 3 (136.2g, 500mmol) is dissolved in 280ml dichloromethane, addition ethylene glycol (62.1g,
1000mmol) with pyridine hydrochloride (5.8g, 50mmol), it is heated to reflux a point water, reacts 9 hours, treat not
After having moisture to produce, stop heating, be cooled to room temperature.Add 750ml saturated sodium bicarbonate solution stirring 10
Minute, separating organic facies, wash twice with 1000ml water, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure
Obtain compound 4 (147.2g, productivity 93%).
Embodiment 4:
The synthesis of compound 5
1) sodium borohydride (18.9g, 500mmol) and lithium chloride (21.2g, 500mol) are joined 250ml
In anhydrous tetrahydro furan, after stirring 30 minutes under nitrogen protection, stop stirring and allow solid deposit.By upper strata
Clear liquid is added dropwise to the round bottom of the 1400ml anhydrous tetrahydro furan equipped with compound 4 (142.4g, 450mmol) and burns
In Ping, it is stirred at room temperature until reactionless thing, adds 450ml shrend and go out reaction, reactant liquor concentrating under reduced pressure removal four
Hydrogen furan, residue 750ml dichloromethane extracts, and organic facies 150ml water washes twice, anhydrous slufuric acid
Sodium is dried, and filters, and concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1) purifies to obtain compound
5 (109.05g, productivity 84%).
2) sodium borohydride (20.4g, 540mmol) and lithium chloride (22.9g, 540mol) are joined 250ml
In anhydrous tetrahydro furan, after stirring 30 minutes under nitrogen protection, stop stirring and allow solid deposit.By upper strata
Clear liquid is added dropwise to the round bottom of the 1400ml anhydrous tetrahydro furan equipped with compound 4 (142.4g, 450mmol) and burns
In Ping, it is stirred at room temperature until reactionless thing, adds 450ml shrend and go out reaction, reactant liquor concentrating under reduced pressure removal four
Hydrogen furan, residue 750ml dichloromethane extracts, and organic facies 150ml water washes twice, anhydrous slufuric acid
Sodium is dried, and filters, and concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1) purifies to obtain compound
5 (119.2g, productivity 85%).
Embodiment 5:
1) synthesis of compound 6
Compound 5 (108.15g, 375mmol) is dissolved in 1000ml dichloromethane, is sequentially added into imidazoles
(30.65g, 450mmol) and TBSCl (62.15g, 415mmol), it is little that reactant liquor is stirred at room temperature 5
Time, until reactionless thing.Add 750ml shrend to go out reaction, separatory, organic facies 1000ml water washing two
Secondary, anhydrous sodium sulfate is dried, and filters, and obtains compound 6 (137.45g, productivity 91%) after concentrating under reduced pressure.
2) synthesis of compound 6
Compound 5 (115.36g, 400mmol) is dissolved in 1000 oxolanes, be sequentially added into pyridine (41.1g,
520mmol) with TBSCl (72.3g, 480mmol), reactant liquor is stirred at room temperature 5 hours, until without anti-
Answer thing.Adding 750ml shrend to go out reaction, separatory, organic facies 1000ml water washes twice, anhydrous slufuric acid
Sodium is dried, and filters, and obtains compound 6 (149.8g, productivity 93%) after concentrating under reduced pressure.
Embodiment 6: the synthesis of compound 7
1) compound 6 (125.00g, 310mmol) is dissolved in 600ml methanol, under room temperature, adds 100ml 3N
Hydrochloric acid, stirring reaction 3 hours at 50 DEG C, until reactionless thing.It is cooled to room temperature, uses unsaturated carbonate hydrogen
Sodium solution adjusts pH to neutral, extracts with 1000ml dichloromethane, and organic facies anhydrous sodium sulfate is dried, and filters,
Concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=80:1) purifies to obtain compound 7 (90.05g, product
Rate 81%).
2) compound 6 (141.1g, 350mmol) is dissolved in 800ml methanol, under room temperature, adds 120ml 3N
Hydrochloric acid, stirring reaction 2 hours at 50 DEG C, until reactionless thing.It is cooled to room temperature, uses unsaturated carbonate hydrogen
Sodium solution adjusts pH to neutral, extracts with 1000ml dichloromethane, and organic facies anhydrous sodium sulfate is dried, and filters,
Concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=80:1) purifies to obtain compound 7 (104.2g, product
Rate 83%).
Embodiment 7:
1) synthesis of compound 8
Compound 7 (89.65g, 250mmol) is dissolved in 900ml dichloromethane, is cooled to 0 DEG C, successively to
Wherein drip triethylamine (101.2g, 1000mmol) and TMSOTf (83.4g, 375mmol), stir at 5 DEG C
Mix the mixture 1 hour of gained.After having reacted, add 750ml shrend and go out reaction.Separate organic facies, use
750ml water washs, and anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure obtains compound 8 (93.7g, productivity 87%).
2) synthesis of compound 8
Compound 7 (89.65g, 250mmol) is dissolved in 900ml dichloromethane, is cooled to 0 DEG C, successively
Drip pyridine (79.1g, 1000mmol) and TMSOTf (111g, 500mmol) wherein, stir at 5 DEG C
The mixture of gained 1 hour.After having reacted, add 750ml shrend and go out reaction.Separate organic facies, use
750ml water washs, and anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure obtains compound 8 (94.8g, productivity 88%).
Embodiment 8: the synthesis of compound 9
1) compound 8 (75.00g, 175mmol) is dissolved in 1000ml dichloromethane, is cooled to-25 DEG C,
Be sequentially added into disodium hydrogen phosphate (124.2,875mmol) and 70% metachloroperbenzoic acid (94.9g,
385mmol), at-25 DEG C, stirring reaction 3 hours, add 200ml sodium sulfite solution and 400ml sulphuric acid
Hydrogen sodium solution, reactant liquor is heated to room temperature, stirs 1 hour.After having reacted, separate organic facies, use 1000ml
Water washes twice, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, crude product column chromatography (petroleum ether/acetic acid second
Ester=40:1～20:1) purify to obtain compound 9 (47.85g, productivity 73%).
2) compound 8 (75.00g, 175mmol) is dissolved in 1000ml dichloromethane, is cooled to-25 DEG C,
Be sequentially added into disodium hydrogen phosphate (141.9g, 875mmol) and 70% metachloroperbenzoic acid (129.4g,
525mmol), at-25 DEG C, stirring reaction 4 hours, add 200ml sodium sulfite solution and 400ml sodium bisulfate
Solution, reactant liquor is heated to room temperature, stirs 2 hours.After having reacted, separate organic facies, use 1000ml water
Washing twice, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate
=40:1～20:1) purify to obtain compound 9 (48.5g, productivity 74%).
Embodiment 9:
1) synthesis of compound 10
Under room temperature, triphenylmethylphosphonium bromide phosphine (56.25g, 155mmol) is joined 500ml anhydrous tetrahydrochysene furan
In muttering.Under nitrogen protection, it is cooled to 0 DEG C, in reactant liquor, adds potassium tert-butoxide (17.65,155mmol),
Finishing, be warmed to room temperature reaction 2 hours, reactant liquor is from milky yellowing.By compound 9 (40g, 105mmol)
It is dissolved in 250ml anhydrous tetrahydro furan, adds in reactant liquor, reaction 24 hour is stirred at room temperature.To reactant liquor
Middle addition 500ml shrend is gone out reaction, and concentrating under reduced pressure removes oxolane, and residue 500ml ethyl acetate extracts
Taking twice, merge organic facies, wash once with 500ml successively, 500ml saturated aqueous common salt washs successively, nothing
Aqueous sodium persulfate is dried, and filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1～30:1)
Purify to obtain target compound 10 (25.45g, productivity 65%).
2) synthesis of compound 10
Under room temperature, triphenylmethylphosphonium bromide phosphine (56.25g, 155mmol) is joined the anhydrous dichloromethane of 500ml
In alkane.Under nitrogen protection, it is cooled to 0 DEG C, in reactant liquor, adds the sodium methoxide solution (248mmol) of 25%,
Finishing, be warmed to room temperature reaction 2 hours, reactant liquor is from milky yellowing.By compound 9 (40g, 105mmol)
It is dissolved in 250ml anhydrous tetrahydro furan, adds in reactant liquor, reaction 24 hour is stirred at room temperature.To reactant liquor
Middle addition 500ml shrend is gone out reaction, and concentrating under reduced pressure removes oxolane, and residue 500ml ethyl acetate extracts
Taking twice, merge organic facies, wash once with 500ml successively, 500ml saturated aqueous common salt washs successively, nothing
Aqueous sodium persulfate is dried, and filters, concentrating under reduced pressure, crude product column chromatography (petrol ether/ethyl acetate=50:1～30:1)
Purify to obtain target compound 10 (25.8g, productivity 66%).
Embodiment 10: the synthesis of compound 12
1) triphenylphosphine (31.5g, 120mmol) is dissolved in 500ml oxolane, is cooled to 0 DEG C, to
Wherein add diethyl azodiformate (DEAD) (20.9g, 120mmol), stir 1 hour at 0 DEG C
To suspension.By compound 10 (22.5g, 60mmol) and the mixture of 11 (20.35g, 120mmol)
Dissolve with 450ml oxolane, at 0 DEG C, be added thereto to the suspension of triphenylphosphine and DEAD, at 0 DEG C
Stirring reaction 1 hour.After having reacted, in reactant liquor, add 1000ml ethyl acetate, use 1000ml
0.5M sodium hydroxide solution washs three times, and organic facies anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, slightly
Capo chromatography (petrol ether/ethyl acetate=40:1～20:1) purifies to obtain target compound 12 (22.65g, product
Rate 72%).
2) triphenylphosphine (39.4g, 150mmol) is dissolved in 500ml oxolane, is cooled to 0 DEG C, to
Wherein add diethyl azodiformate (DEAD) (20.9g, 120mmol), stir 1 hour at 0 DEG C
To suspension.The mixture of compound 10 (22.5g, 60mmol) and 11 (25.4g, 150mmol) is used
450ml oxolane dissolves, and is added thereto to the suspension of triphenylphosphine and DEAD, stirs at 0 DEG C at 0 DEG C
Mix reaction 3 hours.After having reacted, in reactant liquor, add 1000ml ethyl acetate, use 1000ml 0.5M
Sodium hydroxide solution washs three times, and organic facies anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, crude product post layer
Analysis (petrol ether/ethyl acetate=40:1～20:1) purifies to obtain target compound 12 (23.3g, productivity 74%).
Embodiment 11: the synthesis of compound 13
1) compound 12 (20g, 38mmol) is dissolved in 200ml anhydrous tetrahydro furan, adds the four of 1M
The tetrahydrofuran solution (114ml, 114mmol) of butyl ammonium fluoride, stirring reaction 12 hours under room temperature.Reaction
After end, adding 200ml shrend and go out reaction, with the extraction of 200ml ethyl acetate, organic facies 200ml is washed
Washing once, anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure obtains target compound 13 (9.87g, productivity 88%).
2) compound 12 (20g, 38mmol) is dissolved in 200ml anhydrous tetrahydro furan, adds the four of 1M
The tetrahydrofuran solution (76ml, 76mmol) of butyl ammonium fluoride, stirring reaction 12 hours under room temperature.Reaction knot
Shu Hou, adds 200ml shrend and goes out reaction, extract by 200ml ethyl acetate, organic facies 200ml water washing
Once, anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure obtains target compound 13 (9.65g, productivity 86%).
Embodiment 12: the synthesis of Entecavir
1) compound 13 (5g, 17mmol) is joined in 100ml 2M sodium hydroxide solution, by reactant liquor
It is heated to 70 DEG C, stirring reaction 4 hours.After reaction terminates, reactant liquor is cooled to 0 DEG C, uses 1M hydrochloric acid
Solution adjusts pH to 6.8, and stirs 2h at 0 DEG C, filters to obtain Entecavir (3.3g, productivity 71%).
2) compound 13 (5g, 17mmol) is joined in 100ml 2M sodium hydroxide solution, by reactant liquor
It is heated to 70 DEG C, stirring reaction 4 hours.After reaction terminates, reactant liquor is cooled to 0 DEG C, uses 1M hydrochloric acid
Solution adjusts pH to 6.8, and stirs 2h at 0 DEG C, filters to obtain Entecavir (3.4g, productivity 73%).
Claims (6)
1. an entecavir compound prepared synthetic method, it is characterised in that the method is with (S)-3-hydroxyl adipic acid two
Methyl ester (compound 1) is initiation materialComprise the following steps:
1) compound 1 protects to obtain compound 2 through hydroxyl TBS；
2) compound 2 generates compound 3 through Dieckmann condensation reaction；
3) compound 3 protects into ketal through ketone, generates compound 4；
4) compound 4 is reduced into hydroxyl through ester group, generates compound 5；
5) compound 5 is through hydroxyl protection, generates compound 6；
6) compound 6 deprotection generates compound 7；
7) compound 7 becomes silyl enol ether through ketone, generates compound 8；
8) compound 8 metachloroperbenzoic acid aoxidizes to obtain compound 9；
9) compound 9 is through wittig reacting generating compound 10；
10) compound 10 and compound 11 mix, through Mitsunobu reacting generating compound 12；
11) compound 12 desiliconization protection group generates compound 13；
12) compound 13 hydrolyzed under basic conditions generates Entecavir；
The most entecavir compound prepared synthetic method, it is characterised in that comprise the steps:
1) compound 1 is generated compound 2 with TBSCl in the presence of organic solvent, acid binding agent；
2) by step 1) in gained compound 2 in a solvent, alkaline matter be catalyzed under cyclization；Locate after through
Manage to obtain compound 3；
3) in the presence of organic solvent and catalyst, by step 2) in gained compound 3 anti-with ethylene glycol
Compound 4 should be prepared；
4) by step 3) in gained compound 4 be dissolved in anhydrous tetrahydro furan, at sodium borohydride and lithium chloride
The lower reaction of effect, post-treated compound 5；
5) by step 4) gained compound 5 generates chemical combination with TBSCl in the presence of organic solvent, acid binding agent
Thing 6；
6) by step 5) gained compound 6 is dissolved in methanol, and add hydrochloric acid and carry out ketal deprotection reaction,
Post-treated compound 7；
7) by step 6) gained compound 7 in organic solvent, anti-in the presence of organic base and TMSOTf
Compound 8 should be prepared；
8) by step 7) gained compound 8 through metachloroperbenzoic acid oxidation reaction, post-treated chemical combination
Thing 9；
9) by step 8) gained compound 9 in a solvent, and Witting reagent effect, post-treated must change
Compound 10；
10) by step 9) gained compound 10 is at triphenylphosphine, diethyl azodiformate or azo diformazan
React with compound 11 in the presence of acid diisopropyl ester, post-treated compound 12；
11) by step 10) gained compound 12 in a solvent, add tetrabutyl ammonium fluoride carry out desiliconization protection
Base reacts, and reaction terminates, post-treated compound 13；
12) by step 11) gained compound 13 joins in alkaline solution, and reactant liquor is heated to 70 DEG C,
Stirring reaction, after reaction terminates, post-treated Entecavir.
The most entecavir compound prepared synthetic method, it is characterised in that specifically comprise the following steps that
1) compound 1 is dissolved in organic solvent, is sequentially added into acid binding agent, TBSCl, stirring reaction under room temperature
3-5 hour, adding shrend and go out, separatory, organic phase washed with water, anhydrous sodium sulfate is dried, and filters, decompression
Concentrate, obtain compound 2；Described organic solvent is selected from dichloromethane, dimethylformamide, chloroform, tetrahydrochysene furan
One or more in muttering；Described acid binding agent is imidazoles or pyridine；
2) by step 1) in gained compound 2 be dissolved in solvent, add alkaline matter, be heated to reflux 2-5 hour,
Question response terminates, concentrating under reduced pressure；Residue adds 0.5M hydrochloric acid solution, extracts with dichloromethane, organic facies
Being washed twice with water, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, and crude product purifies to change through silica gel column chromatography
Compound 3；Described solvent is methanol, ethanol, the tert-butyl alcohol, oxolane, dimethylformamide；Described alkalescence
Material is sodium alkoxide or potassium alcoholate, Sodamide., sodium hydride, hydrofining or calcium hydride；
3) by step 2) in gained compound 3 be dissolved in organic solvent, add ethylene glycol and catalyst, add
Hot reflux divides water, reacts 4-10 hour, after not having moisture to produce, stops heating, is cooled to room temperature, adds
Saturated sodium bicarbonate solution stirs 10 minutes, separatory, organic phase washed with water twice, and anhydrous sodium sulfate is dried,
Filtering, concentrating under reduced pressure obtains compound 4；Described catalyst is p-methyl benzenesulfonic acid, pyridine hydrochloride or pyridinium tribromide
Change hydrogen salt；Described organic solvent is toluene, benzene, dichloromethane, chloroform or oxolane；
4) sodium borohydride and lithium chloride are joined in anhydrous tetrahydro furan, under nitrogen protection stirring 30 minutes,
Stopping stirring allowing solid deposit, and the round bottom that the supernatant is added dropwise to the anhydrous tetrahydro furan equipped with compound 4 burns
In Ping, it is stirred at room temperature until reactionless thing, adds shrend and go out reaction, reactant liquor concentrating under reduced pressure removal oxolane,
Residue from dichloromethane extracts, organic phase washed with water twice, merges, and is dried, and filters, concentrating under reduced pressure,
Crude product purifies to obtain compound 5 through silica gel column chromatography；
5) by step 4) gained compound 5 is dissolved in organic solvent, is sequentially added into acid binding agent, TBSCl, room temperature
Lower stirring reaction 3-5 hour, adds shrend and goes out, separatory, organic phase washed with water, and anhydrous sodium sulfate is dried,
Filter, concentrating under reduced pressure, obtain compound 6；Described organic solvent is selected from dichloromethane, dimethylformamide, chlorine
One or more in imitative, oxolane；Described acid binding agent is imidazoles or pyridine；
6) by step 5) gained compound 6 is dissolved in methanol, adds 3N hydrochloric acid, under room temperature at 50 DEG C
Stirring reaction 2-4 hour, until reactionless thing, is cooled to room temperature, adjusts pH extremely with saturated sodium bicarbonate solution
Neutrality, extracts with dichloromethane, and organic facies is dried through anhydrous sodium sulfate, filters, and concentrating under reduced pressure, crude product is through silicon
Plastic column chromatography purifies to obtain compound 7；
7) by step 6) compound 7 is dissolved in organic solvent, is cooled to 0 DEG C, drips organic base the most wherein
And TMSOTf, stir the mixture 1 hour of gained at 5 DEG C；After having reacted, add shrend and go out reaction, divide
From organic facies, washing with water, be dried through anhydrous sodium sulfate, filter, concentrating under reduced pressure obtains target compound 8；Institute
The organic base stated is one or more of pyridine, triethylamine, imidazoles or DBU；Described organic solvent is dichloro
Methane；
8) by step 7) gained compound 8 is dissolved in dichloromethane, is cooled to-25 DEG C, is sequentially added into phosphoric acid
Disodium hydrogen and the metachloroperbenzoic acid of 70%, at-25 DEG C, stirring reaction 2-4 hour, adds sodium sulfite
Solution and sodium bisulfate, reactant liquor is heated to room temperature, stirs 1-2 hour, and after having reacted, separation has
Machine phase, is washed twice with water, and is dried through anhydrous sodium sulfate, filters, and concentrating under reduced pressure, crude product is through silica gel column chromatography
Purify to obtain compound 9；
9) step 9) being prepared as of described Witting reagent: under nitrogen protection, by triphenylmethylphosphonium bromide
Join in solvent, be cooled at 0 DEG C, add base catalyst, finish, be warmed to room temperature reaction, thus
Prepare Witting reagent, described solvent be dichloromethane, oxolane, toluene, ether one or more,
Described base catalyst is Feldalat NM, Sodium ethylate, potassium tert-butoxide or n-BuLi；Described post processing is: cancellation,
Concentrating under reduced pressure, ethyl acetate extracts, and washing organic facies, anhydrous sodium sulfate are dried, filter, concentrating under reduced pressure, slightly
Product purify to obtain compound 10 through silica gel column chromatography；
10) step 10) described reaction is to carry out in solvents tetrahydrofurane, add at 0 DEG C triphenylphosphine and
The suspension of DEAD, stirring reaction 1-5 hour at 0 DEG C, described post processing is: after having reacted, to
In reactant liquor add ethyl acetate, with 0.5M sodium hydroxide solution wash, anhydrous sodium sulfate be dried organic facies,
Filtration, concentrating under reduced pressure, crude product purifies to obtain compound 12 through silica gel column chromatography；
11) step 11) described reaction is to carry out in solvents tetrahydrofurane, stirring reaction 12 hours under room temperature,
Described post processing is: after reaction terminates, cancellation, and ethyl acetate extracts, water washing organic facies, anhydrous sodium sulfate
It is dried, filtration, concentrating under reduced pressure；
12) step 12) described in alkaline solution be 2M sodium hydroxide solution, the described stirring response time
Being 4 hours, described post processing is: after reaction terminates, reactant liquor is cooled to 0 DEG C, uses 1M hydrochloric acid solution
Adjust pH to 6.8, and at 0 DEG C, stir 2h, filter to obtain Entecavir.
The most entecavir compound prepared synthetic method, it is characterised in that:
Step 1) in compound 1 be 1:1.1-1.3:1.0-1.2 with acid binding agent, the mol ratio of TBSCl；
Step 2) in the mol ratio of compound 2 and alkaline matter be 1:1-3；
Step 3) in compound 3 be 1:2-4:0.05-0.10 with ethylene glycol, the mol ratio of catalyst；
Step 4) in compound 4 be 1:1.1-1.2:1.1-1.2 with sodium borohydride, the mol ratio of lithium chloride；
Step 5) in compound 5 be 1:1.1-1.3:1.1-1.2 with acid binding agent, the mol ratio of TBSCl；
Step 7) in compound 7 be 1:3-5:1-2 with organic base, the mol ratio of TMSOTf；
Step 10) in compound 10 and compound 11, triphenylphosphine, diethyl azodiformate or azo
The mol ratio of dioctyl phthalate diisopropyl ester is 1:1.5-2.5:1.5-2.5:1.5-2.5；
Step 11) in the mol ratio of compound 12 and tetrabutyl ammonium fluoride be 1:1.5-3.
The most entecavir compound prepared synthetic method, it is characterised in that:
Step 8) in compound 8 be 1:4-6:2-3 with disodium hydrogen phosphate, the mol ratio of metachloroperbenzoic acid；
Step 9) in the mol ratio of compound 9 and triphenylmethylphosphonium bromide, base catalyst be
1:1.4-1.6:1.4-1.6。
The most entecavir compound prepared synthetic method, it is characterised in that institute in course of reaction
The eluting solvent stating silica gel column chromatography use is petrol ether/ethyl acetate:
Step 2) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1；
Step 4) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=60:1-40:1；
Step 6) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=90:1-70:1；
Step 8) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=50:1-10:1；
Step 9) eluting solvent of silica gel column chromatography is petrol ether/ethyl acetate=50:1-10:1.
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| CN106749382B (en) * | 2016-11-12 | 2019-01-15 | 嘉兴敏实机械有限公司 | The preparation method of entecavir midbodies |
| CN106749256B (en) * | 2016-11-12 | 2018-10-12 | 吴友伟 | A kind of synthesis technology of entecavir midbodies |
| CN106554365B (en) * | 2016-11-12 | 2019-01-08 | 嘉兴敏实机械有限公司 | A kind of preparation process and its application of entecavir midbodies |
| CN106565769B (en) * | 2016-11-12 | 2018-12-04 | 北京汇康博源医药科技有限公司 | The synthesis technology of entecavir midbodies |
| CN109705063B (en) * | 2017-10-26 | 2021-01-01 | 广州市朗启医药科技有限责任公司 | Entecavir intermediate and synthetic method thereof, and synthetic method of entecavir |
| CN109134222B (en) * | 2018-09-14 | 2022-01-21 | 上海博栋化学科技有限公司 | Preparation method of 2-hydroxy isopropyl substituted acetophenone |
| CN108976231B (en) * | 2018-10-26 | 2019-12-24 | 东莞理工学院 | Method for synthesizing entecavir as hepatitis B treating medicine |
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| CN101148450A (en) * | 2007-11-02 | 2008-03-26 | 严红芳 | Preparation method of nucleoside compound |
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| WO2015051900A1 (en) * | 2013-10-08 | 2015-04-16 | Pharmathen S.A. | Process for the preparation of entecavir through novel intermediates |
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