CN111018901B - Zanamivir and ranamivir intermediate and synthesis method thereof - Google Patents
Zanamivir and ranamivir intermediate and synthesis method thereof Download PDFInfo
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- CN111018901B CN111018901B CN201910533416.2A CN201910533416A CN111018901B CN 111018901 B CN111018901 B CN 111018901B CN 201910533416 A CN201910533416 A CN 201910533416A CN 111018901 B CN111018901 B CN 111018901B
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- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 title abstract description 20
- 229960001028 zanamivir Drugs 0.000 title abstract description 20
- 238000001308 synthesis method Methods 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 225
- 150000001875 compounds Chemical class 0.000 claims abstract description 187
- 238000004519 manufacturing process Methods 0.000 claims abstract description 170
- 239000003054 catalyst Substances 0.000 claims abstract description 92
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 72
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims abstract description 62
- 229940127204 compound 29 Drugs 0.000 claims abstract description 60
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims abstract description 55
- 239000003446 ligand Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims description 410
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 223
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 213
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 187
- 239000002904 solvent Substances 0.000 claims description 163
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 92
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 75
- 239000002585 base Substances 0.000 claims description 70
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000003960 organic solvent Substances 0.000 claims description 56
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 48
- 239000003153 chemical reaction reagent Substances 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 46
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 37
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 33
- 229940125851 compound 27 Drugs 0.000 claims description 33
- 239000003513 alkali Substances 0.000 claims description 31
- 150000007529 inorganic bases Chemical class 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 150000007530 organic bases Chemical class 0.000 claims description 24
- 239000003586 protic polar solvent Substances 0.000 claims description 21
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 150000001879 copper Chemical class 0.000 claims description 11
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 10
- 239000012346 acetyl chloride Substances 0.000 claims description 10
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 5
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 239000004210 ether based solvent Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 229960003280 cupric chloride Drugs 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- PXTVBRBJKTZPND-UHFFFAOYSA-N phenol;pyrrolidine Chemical compound C1CCNC1.OC1=CC=CC=C1 PXTVBRBJKTZPND-UHFFFAOYSA-N 0.000 claims description 3
- 239000003223 protective agent Substances 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 3
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 285
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 90
- 229940125782 compound 2 Drugs 0.000 description 72
- 239000000243 solution Substances 0.000 description 71
- 238000004440 column chromatography Methods 0.000 description 70
- 239000011734 sodium Substances 0.000 description 70
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 64
- 230000015572 biosynthetic process Effects 0.000 description 62
- 238000003786 synthesis reaction Methods 0.000 description 62
- 229940126214 compound 3 Drugs 0.000 description 56
- 239000003208 petroleum Substances 0.000 description 51
- 238000005160 1H NMR spectroscopy Methods 0.000 description 44
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 44
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 43
- 229940125773 compound 10 Drugs 0.000 description 42
- 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 description 42
- 239000000706 filtrate Substances 0.000 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 37
- 239000002253 acid Substances 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- 238000007254 oxidation reaction Methods 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- 230000035484 reaction time Effects 0.000 description 34
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 33
- 229940126657 Compound 17 Drugs 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 33
- 239000007800 oxidant agent Substances 0.000 description 33
- 238000010998 test method Methods 0.000 description 33
- 238000004809 thin layer chromatography Methods 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 32
- 239000003638 chemical reducing agent Substances 0.000 description 32
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 29
- 150000008282 halocarbons Chemical group 0.000 description 29
- 238000002360 preparation method Methods 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 27
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 27
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- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 26
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- 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 description 25
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- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 25
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- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 3
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- 239000005909 Kieselgur Substances 0.000 description 3
- 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 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 3
- 150000002828 nitro derivatives Chemical class 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 3
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 3
- 229960003752 oseltamivir Drugs 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 108090000790 Enzymes Proteins 0.000 description 2
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- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 241000902900 cellular organisms Species 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012025 fluorinating agent Substances 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- JHTJPSCVBLCXEO-UHFFFAOYSA-N n-(triethylazaniumyl)sulfonylcarbamate Chemical compound CC[N+](CC)(CC)S(=O)(=O)NC([O-])=O JHTJPSCVBLCXEO-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000002911 sialidase inhibitor Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- DRZNAWCWULQRGP-UHFFFAOYSA-N sulfur trioxide;urea Chemical compound NC(N)=O.O=S(=O)=O DRZNAWCWULQRGP-UHFFFAOYSA-N 0.000 description 2
- CSOJECDGWHHWRS-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylcarbamothioyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C CSOJECDGWHHWRS-UHFFFAOYSA-N 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- LGVZIYROFKTBHM-UHFFFAOYSA-N (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl)methanesulfonic acid toluene Chemical compound C12(C(=O)CC(CC1)C2(C)C)CS(=O)(=O)O.C2(=CC=CC=C2)C LGVZIYROFKTBHM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DTJIBVSGNIAPCX-UHFFFAOYSA-N 2,2,2-trifluoroacetyl bromide Chemical compound FC(F)(F)C(Br)=O DTJIBVSGNIAPCX-UHFFFAOYSA-N 0.000 description 1
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical group C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- SKCAPDDCPPQINN-UHFFFAOYSA-N C(Cl)(Cl)Cl.C12(C(=O)CC(CC1)C2(C)C)CS(=O)(=O)O Chemical compound C(Cl)(Cl)Cl.C12(C(=O)CC(CC1)C2(C)C)CS(=O)(=O)O SKCAPDDCPPQINN-UHFFFAOYSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- 238000006842 Henry reaction Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- GGISZLOBBISXOZ-UHFFFAOYSA-N acetic acid;chloroform Chemical compound CC(O)=O.ClC(Cl)Cl GGISZLOBBISXOZ-UHFFFAOYSA-N 0.000 description 1
- XMGZWGBXVLJOKE-UHFFFAOYSA-N acetic acid;toluene Chemical compound CC(O)=O.CC1=CC=CC=C1 XMGZWGBXVLJOKE-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- OIJMIQIDIZASII-UHFFFAOYSA-N benzene;benzoic acid Chemical compound C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 OIJMIQIDIZASII-UHFFFAOYSA-N 0.000 description 1
- KJAFZRCNIJFECP-UHFFFAOYSA-N benzoic acid chlorobenzene Chemical compound ClC1=CC=CC=C1.C(C1=CC=CC=C1)(=O)O KJAFZRCNIJFECP-UHFFFAOYSA-N 0.000 description 1
- VYXHQRRLAQJDGH-UHFFFAOYSA-N benzoic acid;dichloromethane Chemical compound ClCCl.OC(=O)C1=CC=CC=C1 VYXHQRRLAQJDGH-UHFFFAOYSA-N 0.000 description 1
- RTLDOURIKMGJKF-UHFFFAOYSA-N benzoic acid;tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl.OC(=O)C1=CC=CC=C1 RTLDOURIKMGJKF-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- UCKORWKZRPKRQE-UHFFFAOYSA-N bromo(triethyl)silane Chemical compound CC[Si](Br)(CC)CC UCKORWKZRPKRQE-UHFFFAOYSA-N 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- DBPQHXPBQWYJQS-UHFFFAOYSA-N bromo-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)Br DBPQHXPBQWYJQS-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000010493 gram-scale synthesis Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 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
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- HBDVWUMXFHLGTC-UHFFFAOYSA-N pyrazole-1-carboxamide;hydrochloride Chemical compound Cl.NC(=O)N1C=CC=N1 HBDVWUMXFHLGTC-UHFFFAOYSA-N 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GDKYNMQBGVLYPS-UHFFFAOYSA-N tert-butyl 1-carbamimidoylpyrazole-3-carboxylate Chemical compound CC(C)(C)OC(=O)C=1C=CN(C(N)=N)N=1 GDKYNMQBGVLYPS-UHFFFAOYSA-N 0.000 description 1
- XUZZGCGXZLFIIH-UHFFFAOYSA-N tert-butyl 1-carbamoylpyrazole-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)C1=NN(C=C1)C(=O)N XUZZGCGXZLFIIH-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
- C07D317/36—Alkylene carbonates; Substituted alkylene carbonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a zanamivir and lanamivir intermediate and a synthesis method thereof. The invention provides a synthesis method of a compound 29, which comprises the following steps: compound 28 is reacted with compound 9 in the presence of a base, a catalyst and a catalyst ligand in an aprotic solvent to provide compound 29. The synthetic method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good industrial production prospect.
Description
Technical Field
The invention relates to intermediates of zanamivir and ranamivir and a synthesis method thereof.
Background
Zanamivir (Zanamivir) is the first neuraminidase inhibitor synthesized based on drug design, and it and Oseltamivir (Oseltamivir) are currently the few two drugs approved for the treatment of influenza a and b viruses on the market. It was discovered by the scientists at Biota in 1989 and was assigned to the gillanin smith corporation for clinical treatment in 1990. 1999 acquired FDA approval and marketed in the united states.
First synthesis of zanamivir was accomplished in 1994 at M.V. Itzstein, university of Monnash, Australia (Carbohydr. Res.,1994,259, 301-305). They start from N-acetylneuraminic acid, introduce the required nitrogen atom by ring opening of oxazoline ring by azide, and obtain zanamivir through several steps of conversion after azide hydrogenation.
This method only provides milligram quantities of product for clinical studies. The use of azides, reagents and intermediates presents a risk of explosion, which is hazardous for large-scale industrial production. In addition, the raw material N-acetylneuraminic acid is not easily available, which also limits the application of the method.
In 1995, Scheigetz et al, Merck, Canada, found the reaction to be poorly reproducible. They used the same starting materials and similar strategies, and optimized the synthesis process of zanamivir such that the yield and reproducibility were improved (org. Prep. Proc. Int.,1995,27, 637-644). DPPA is used to replace the explosive reagent such as lithium azide. Although they synthesized only milligram-grade product, they laid the foundation for the latter study.
In 1995, gram-scale synthesis of zanamivir was first reported by M.Chandler et al, Kulansu Schker, UK (J.chem.Soc., Perkin Trans.I,1995, 1173-1180). They also use N-acetylneuraminic acid as starting material, and 3 steps obtain the key oxazoline intermediate of the forebody very efficiently. Using TMSN3The product can be obtained after 5 steps of conversion after being used as a nitrogen source.
Although they obtained 1.28 grams of zanamivir, they all required multiple reactions prepared on a hundreds of gram scale, including 600 gram-scale azide substitution reactions, and multiple ion exchange resin desalting steps. The total yield of the 9-step reaction is 8.3%, and improvement is still needed in many places.
The former work was to structurally modify N-acetylneuraminic acid, and in 2004, professor Yaojun, Shanghai, China, also reported the synthesis of zanamivir (org. Lett.,2004,6, 2269-2272). Different from the predecessors, the synthesis method adopts cheap glucolactone as a raw material, adopts a key azide compound to introduce nitrogen atoms required in zanamivir through an aziridine ring-opening reaction, and can complete the synthesis of the azides through subsequent conversion after the azides are hydrogenated.
However, although its starting materials are very inexpensive, its 24-step reaction, an overall yield of 0.2%, makes the process very difficult to industrialize.
Professor m.shibasaki at the university of tokyo, japan, 2012,51,1644-1647, also reported the synthesis of zanamivir by their team (angew.chem.int.ed.,2012,51, 1644). They constructed two key chiral centers using asymmetric Henry reactions developed by their group and synthesized key oxazoline intermediates using novel 3, 3-sigma rearrangement reactions. As with professor Yao congratulatory, they also completed their synthesis in 24 steps with a total yield of 1.2%. Although the reaction is quite novel, the lengthy linear steps and low yields also make the process difficult to industrialize.
However, with the emergence of resistant strains, the development of some novel NA inhibitors has been accelerated. Laninamivir (Lanamivir) is a neuraminidase inhibitor developed by Biota Pharmaceuticals and Daiichi Sankyo, and is useful for treating influenza virus infections resistant to oseltamivir. The person taking Laninamivir recovered in an average of over 60 hours earlier than the person taking duffy. Laninamivir was approved in 2010 to be marketed in japan under the name Inavir. Its octanoate CS-8958 was also marketed in Japan in the same year.
In 2002, the synthesis of laninamivir was first completed by T.Honda et al, Daiichi Sankyo, Japan (US 6340702). They started from a sugar protected by benzyl, obtained an Aldol reaction precursor by a literature method, constructed a core skeleton by Aldol reaction enzyme, and transformed by 11 steps to obtain laninamivir.
In the same year, Daiichi Sankyo, Japan, T.Honda et al, have improved the synthesis of laninamivir (bioorg.Med.chem.Lett.,2002,12, 1921-1924). They start from the known cheaper pyranose compounds, obtain Aldol reaction precursors through several simple conversions, then construct their core skeleton through Aldol reaction enzyme, obtain laninamivir through 8 conversions.
The method has the advantage that N-acetylneuraminic acid which is used as a raw material is not easily available in a large quantity, so that the application of the method is limited.
In 2002, Daiichi Sankyo, Japan, Y.Kawaoka et al, reported improved synthesis of ranavir (bioorg.Med.chem.Lett.,2002,12, 1925-1928). They start from N-acetylneuraminic acid, first protect the two hydroxyl groups close to the terminal positions with acetonide and methylate the desired hydroxyl group, convert the hydroxyl group into an amine group and then convert in several steps to obtain the ranavir.
In 2008, the synthesis of ranamivir was perfected and a world patent was filed by y.nakamura et al of Daiichi Sankyo, japan (WO 2008/126943). They also use N-acetylneuraminic acid as starting material, and 3 steps obtain the key oxazoline intermediate of the forebody very efficiently. Using TMSN3The product can be obtained after 5 steps of conversion after being used as a nitrogen source.
It is expected that the development of a more efficient synthesis method for synthesizing important intermediates of zanamivir will lead to a more economical and simpler operation of the whole synthesis route.
Disclosure of Invention
The invention aims to overcome the defects of long synthetic route, low total yield, poor atom economy, dangerous operation, high production cost, unsuitability for industrial production and the like of the existing zanamivir, and provides an intermediate of zanamivir and lanamivir and a synthetic method thereof. The synthetic method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good industrial production prospect.
The present invention provides a method for preparing compound 2, which can be performed by method 1 or method 2,
the method 1 comprises the following steps: carrying out a protecting group removing reaction on the compound 3 to obtain a compound 2;
wherein R is hydrogen or methyl; r1Is Trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen;
R2and R5Each independently is methyl, ethyl or propyl; r4Is an amino protecting group, such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or p-toluenesulfonyl (Ts).
The method 2 comprises the following steps: performing hydrolysis reaction on the compound 35 to obtain a compound 2;
r is hydrogen or methyl.
Method 1 for preparing compound 2 can be carried out by a conventional method in the art for such deprotection reactions, and the following reaction methods and conditions are particularly preferred in the present invention: in an aprotic solvent, in the presence of an acid, carrying out a protecting group removing reaction on the compound 3 to obtain a compound 2;
in the method 1 for producing the compound 2, the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method 1 for producing the compound 2, the volume-to-mass ratio of the aprotic solvent to the compound 3 is preferably 0.1 to 5mL/mg, and more preferably 0.1 to 1 mL/mg.
In the method 1 for preparing the compound 2, the acid is preferably an inorganic acid and/or an organic acid; the inorganic acid is preferably hydrochloric acid; the organic acid is preferably trifluoroacetic acid; the hydrochloric acid can be a hydrochloric acid reagent which is conventional and commercially available in the field, and preferably the hydrochloric acid accounts for 10-37% by mass, wherein the mass percentage refers to the mass of the hydrogen chloride in the total mass of the hydrochloric acid reagent.
In the method 1 for producing the compound 2, the molar ratio of the compound 3 to the acid is preferably 1:1 to 1:100, and more preferably 1:30 to 1: 50.
In the process 1 for producing the compound 2, the temperature of the reaction for removing the protecting group is preferably 10 to 40 ℃ and more preferably 20 to 30 ℃.
In the method 1 for preparing the compound 2, the progress of the deprotection reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 20 hours, more preferably 8 to 10 hours, with the time when the compound 3 disappears being the end point of the reaction.
The method 1 for preparing the compound 2 further comprises the following step, in the method 1 for preparing the compound 2, when R is1When the compound is Trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), methoxymethyl (MOM) or methyl, the compound 3 can be prepared by the following method I; when R is1When the hydrogen is used, the compound 3 can be prepared by the following method II; when R is1When the compound is Trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen, the compound 3 can be prepared by the following method III;
the method comprises the following steps: carrying out oxidation reaction on a compound 4 and an oxidant in a protic solvent under an acidic condition to obtain a compound 3;
the second method comprises the following steps: carrying out reduction reaction on the compound 12 and a reducing agent in an aprotic solvent to obtain a compound 3;
the third method comprises the following steps: carrying out hydrolysis reaction on the compound 34 to obtain a compound 3;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 3 can adopt the conventional method of the oxidation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the first method for preparing the compound 3, the protic solvent is preferably an alcohol solvent and/or water; the alcohol solvent is preferably tert-butyl alcohol; when a mixed solvent of tert-butanol and water is used, the volume ratio of tert-butanol to water in the mixed solvent of tert-butanol and water is preferably 10:1 to 1:1, and more preferably 5:1 to 3: 1.
In the first process for producing the compound 3, the volume-to-mass ratio of the protic solvent to the compound 4 is preferably 20 to 300mL/g, and more preferably 120 to 300 mL/g.
In the first method for preparing the compound 3, the oxidizing agent is preferably chlorous acid; the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.
In the first process for producing the compound 3, the molar ratio of the compound 4 to the oxidizing agent is preferably 1:1 to 1:5, and more preferably 1:3 to 1: 4.
In the first method for preparing the compound 3, the acidic condition is preferably realized by adding a strong base and a weak acid salt, and the strong base and the weak acid salt are preferably sodium dihydrogen phosphate. When the strong base weak acid salt is used for realizing the acidic condition, the molar ratio of the strong base weak acid salt to the compound 4 is preferably 1: 1-20: 1, and more preferably 5: 1-10: 1.
In the first method for preparing the compound 3, the acidic condition is preferably pH 2-5.
In the first process for producing the compound 3, the temperature of the oxidation reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the first process for preparing compound 3, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 24 hours, more preferably 2 to 8 hours, with the disappearance of compound 4 as a reaction endpoint.
The process for preparing compound 3-1 is preferably carried out in the presence of a radical scavenger, preferably 2-methylbutene or phenol. The molar ratio of the radical scavenger to the compound 4 is preferably 0.5:1 to 3:1, and more preferably 1:1 to 2: 1.
The method 1 for preparing the compound 2 further comprises the following steps, and in the first method for preparing the compound 3, the compound 4 can be prepared by the following method: carrying out oxidation reaction on the compound 5 and an oxidant in an aprotic solvent to obtain the compound 4;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 4 can adopt the conventional method of such oxidation reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 4, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably 1, 4-dioxane.
In the method for producing compound 4, the volume-to-mass ratio of the aprotic solvent to compound 5 is preferably 20 to 300mL/g, and more preferably 150 to 300 mL/g.
In the method for preparing the compound 4, the oxidizing agent is preferably selenium dioxide.
In the method for preparing the compound 4, the molar ratio of the compound 5 to the oxidizing agent is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 3.
In the method for producing compound 4, the temperature of the oxidation reaction is preferably 30 to 100 ℃, more preferably 60 to 100 ℃, still more preferably 35 to 80 ℃, and most preferably 40 to 80 ℃.
In the process for preparing compound 4, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours, with the disappearance of compound 5 as a reaction end point.
The process for preparing compound 4 is preferably carried out under a blanket of an inert gas, preferably one or more of nitrogen, argon and helium.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 4, the compound 5 can be prepared by the following method: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on a compound 6 and an acetylation reagent to obtain a compound 5;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 5 can adopt the conventional method of nucleophilic substitution reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the method for preparing the compound 5, the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the organic base is preferably one or more of pyridine, piperidine and triethylamine.
In the method for preparing the compound 5, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.
In the method for preparing the compound 5, the molar ratio of the compound 6 to the base is preferably 1:3 to 1:6, and more preferably 1:4 to 1: 5.
In the method for preparing the compound 5, the acetylation reagent is an acetylation reagent with acetyl groups, which is commonly used in the nucleophilic substitution reaction, and preferably acetyl halide and/or acetic anhydride; the acetyl halide is preferably acetyl chloride or acetyl bromide.
In the method for preparing the compound 5, the molar ratio of the compound 6 to the acetylating agent is preferably 1:1 to 1:20, more preferably 1:1 to 1:3, and still more preferably 1:1 to 1: 1.1.
In the method for producing compound 5, the temperature of the nucleophilic substitution reaction is preferably 0 to 100 ℃, and more preferably 0 to 60 ℃.
In the method for preparing the compound 5, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 24h, more preferably 2h to 3h, with the disappearance of the compound 6 as a reaction endpoint.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 5, the compound 6 can be prepared by the following method: in an aprotic solvent, under the action of an acid and a reducing agent, carrying out reduction reaction on the compound 7 to obtain a compound 6;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
In the method for preparing the compound 6, the aprotic solvent is preferably an ester solvent; the ester solvent is preferably ethyl acetate.
In the method for producing compound 6, the volume-to-mass ratio of the aprotic solvent to compound 7 is preferably 20 to 200mL/g, and more preferably 90 to 120 mL/g.
In the process for preparing compound 6, the acid is preferably an organic acid; the organic acid is preferably glacial acetic acid.
In the method for producing the compound 6, the molar ratio of the acid to the compound 7 is preferably 10:1 to 100:1, and more preferably 60:1 to 100: 1.
In the method for preparing the compound 6, the reducing agent is preferably one or more of zinc, iron and aluminum.
In the method for producing the compound 6, the molar ratio of the reducing agent to the compound 7 is preferably 10:1 to 100:1, and more preferably 60:1 to 100: 1.
In the method for producing compound 6, the temperature of the reduction reaction is preferably 0 to 40 ℃, and more preferably 10 to 30 ℃.
In the process for preparing compound 6, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 20 hours, and more preferably 10 to 15 hours, with the disappearance of compound 7 as the reaction end point.
The process for preparing compound 6 preferably employs the following steps: and (3) adding a reducing agent and an acid into the solution formed by the compound 7 and the aprotic solvent in sequence to perform reduction reaction to obtain a compound 6.
The process for preparing compound 6 preferably comprises the following work-up steps: after the reaction is finished, adding alkali to adjust the pH value to about 7, extracting, concentrating and separating by column chromatography to obtain a compound 6. The alkali is preferably organic alkali, and the organic alkali is preferably ammonia water; the ammonia water can be a conventional commercial ammonia water reagent, the mass percentage concentration of the ammonia water reagent is preferably 5-50%, and more preferably 15-40%, and the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution. The solvent used for extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The method of column chromatography may be carried out by methods conventional in the art for such procedures.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 6, the compound 7 can be prepared by the following method: in an organic solvent and in the presence of alkali, carrying out dehydration reaction on the compound 8 and a dehydrating agent to obtain the compound 7;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 7 can adopt the conventional method of such dehydration reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 7, the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; further preferred are ether solvents and/or halogenated hydrocarbon solvents; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the aromatic hydrocarbon solvent is preferably toluene.
In the method for producing the compound 7, the volume-to-mass ratio of the organic solvent to the compound 8 is preferably 20 to 200mL/g, and more preferably 100 to 150 mL/g.
In the process for preparing compound 7, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.
In the method for preparing the compound 7, the molar ratio of the base to the compound 8 is preferably 100:1 to 1:1, and more preferably 50:1 to 1:1.
In the process for preparing compound 7, the dehydrating agent is preferably one or more of thionyl chloride, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N- (triethylammoniumsulfonylcarbamate, i.e., N- (triethylammoniumsulfonyl) carbamate, CAS: 29684-56-8).
In the method for preparing the compound 7, the molar ratio of the compound 8 to the dehydrating agent is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 3.
In the method for producing compound 7, the temperature of the dehydration reaction is preferably 0 to 40 ℃, and more preferably 10 to 30 ℃.
In the process for preparing the compound 7, the progress of the dehydration reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 5 hours, more preferably 1 to 3 hours, with the disappearance of the compound 8 as a reaction end point.
The process for preparing compound 7 is preferably carried out in the presence of a catalyst, preferably 4-Dimethylaminopyridine (DMAP). The molar ratio of the catalyst to the compound 8 is preferably 1:1 to 1:10, and more preferably 1:1 to 1: 5.
The process for preparing compound 7 preferably employs the following steps: and (2) sequentially adding a catalyst and a dehydrating agent into a solution formed by the compound 8, the alkali and the organic solvent, and performing dehydration reaction to obtain the compound 7.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 7, the compound 8 can be prepared by the following method: reacting a compound 10 with a compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain a compound 8;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 8 can adopt the conventional method of the reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the method for preparing the compound 8, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 8, the volume-to-mass ratio of the aprotic solvent to compound 9 is preferably 1 to 50mL/g, and more preferably 1 to 10 mL/g.
In the process for preparing compound 8, the base is preferably an inorganic base; the inorganic base is preferably one or more of cesium carbonate, sodium carbonate, potassium carbonate and potassium tert-butoxide.
In the method for preparing the compound 8, the molar ratio of the compound 9 to the base is preferably 1:1 to 10:1, and more preferably 1:1 to 3: 1.
In the method for preparing the compound 8, the catalyst is preferably inorganic copper salt and/or organic copper salt; the inorganic copper salt is a salt formed by the reaction of copper and inorganic acid; the organic copper salt refers to a salt formed by the reaction of copper and organic acid. The inorganic copper salt is preferably one or more of cupric chloride, cuprous bromide, cupric bromide and cuprous iodide, and further preferably cupric bromide and/or cupric chloride; the organic copper salt is preferably copper acetate.
In the method for preparing the compound 8, the molar ratio of the compound 9 to the catalyst is preferably 1:1 to 10:1, and more preferably 3:1 to 10: 1.
In the method for preparing the compound 8, the molar ratio of the compound 10 to the compound 9 is preferably 1:1 to 5:1, and more preferably 2:1 to 5: 1.
In the method for preparing the compound 8, the catalyst ligand is preferably a pyrrolidine-phenolic catalyst; said pyrrolidine-phenolic catalyst is preferably
In the method for preparing the compound 8, the molar ratio of the catalyst ligand to the compound 9 is preferably 1:10 to 3:10, and more preferably 2:10 to 3: 10.
In the method for producing the compound 8, the reaction temperature is preferably-20 ℃ to 40 ℃, and more preferably-20 ℃ to 30 ℃.
In the process for preparing the compound 8, the progress of the reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 24 to 96 hours, and more preferably 24 to 48 hours, with the disappearance of the compound 9 as a reaction end point.
In the process for preparing compound 8, the catalyst ligand
Can be synthesized according to the method reported in chem.eur.j.2012,18,12357.
In the method for preparing the compound 8, the compound 9 can be synthesized by the method reported in Tetrahedron: asymmetry.1998,9, 1359-1367.
The second method for preparing compound 3 can adopt the conventional method of the reduction reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the second method for preparing the compound 3, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the second process for producing the compound 3, the volume-to-mass ratio of the aprotic solvent to the compound 12 is preferably 10 to 500mL/g, more preferably 400 to 500 mL/g.
In the second method for preparing the compound 3, the reducing agent is preferably zinc borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride or lithium borohydride.
In the second process for producing the compound 3, the molar ratio of the compound 12 to the reducing agent is preferably 1:1 to 1:5, and more preferably 1:1 to 1: 3.
In the second process for producing the compound 3, the temperature of the reduction reaction is preferably-78 to 40 ℃, and more preferably 20 to 30 ℃.
In the second method for preparing compound 3, the progress of the reduction reaction can be monitored by conventional testing methods in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 12h, more preferably 4h to 10h, with the disappearance of compound 12 as the reaction endpoint.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method two for preparing the compound 3, the compound 12 can be prepared by adopting the following method: carrying out oxidation reaction on the compound 13 and an oxidant in a protic solvent under an acidic condition to obtain the compound 12;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 12 can be carried out by conventional methods in the art for such oxidation reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in the method for preparing the compound 12, the protic solvent is preferably an alcoholic solvent and/or water; the alcohol solvent is preferably tert-butyl alcohol; when a mixed solvent of tert-butanol and water is used, the volume ratio of tert-butanol to water in the mixed solvent of tert-butanol and water is preferably 10:1 to 1:1, and more preferably 5:1 to 3: 1.
In the method for producing compound 12, the volume-to-mass ratio of the protic solvent to compound 13 is preferably 20 to 300mL/g, and more preferably 200 to 300 mL/g.
In the process for preparing compound 12, the oxidizing agent is preferably chlorous acid; the chlorous acid is preferably obtained by reacting sodium chlorite with sodium dihydrogen phosphate.
In the method for preparing the compound 12, the molar ratio of the compound 13 to the oxidizing agent is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 3.
In the process for preparing compound 12, the acidic condition is preferably achieved by adding a strong base and a weak acid salt, and the strong base and the weak acid salt are preferably sodium dihydrogen phosphate. When the acidic condition is realized by using the strong base weak acid salt, the molar ratio of the strong base weak acid salt to the compound 13 is preferably 1: 1-20: 1, and more preferably 5: 1-10: 1.
In the method for preparing the compound 12, the acidic condition is preferably pH 2-5.
In the method for producing compound 12, the temperature of the oxidation reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 12, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 24 hours, more preferably 2 to 8 hours, with the disappearance of compound 13 as a reaction end point.
The process for preparing compound 12 is preferably carried out in the presence of a radical scavenger, preferably 2-methylbutene or phenol. The molar ratio of the radical scavenger to the compound 13 is preferably 0.5:1 to 3:1, and more preferably 1:1 to 2: 1.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 12, the compound 13 can be prepared by adopting the following method: carrying out oxidation reaction on the compound 14 and an oxidant in an aprotic solvent to obtain the compound 13;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 13 can be carried out by conventional methods in the art for such oxidation reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in the method for preparing the compound 13, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably 1, 4-dioxane.
In the method for producing compound 13, the volume-to-mass ratio of the aprotic solvent to compound 14 is preferably 20 to 300mL/g, and more preferably 150 to 300 mL/g.
In the method of preparing compound 13, the oxidizing agent is preferably selenium dioxide.
In the method for preparing the compound 13, the molar ratio of the compound 14 to the oxidizing agent is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 3.
In the method for producing compound 13, the temperature of the oxidation reaction is preferably 80 to 150 ℃, and more preferably 100 to 140 ℃.
In the process for preparing compound 13, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 5 hours, and more preferably 2 to 4 hours, with the time when compound 14 disappears being the reaction end point.
The process for preparing compound 13 is preferably carried out under a blanket of an inert gas, preferably one or more of nitrogen, argon and helium.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 13, the compound 14 can be prepared by the following method: carrying out oxidation reaction on the compound 15 to obtain the compound 14;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 14 can be carried out by a method conventional in the art for such oxidation, and Ley's oxidation is particularly preferred in the present invention; the Ley's oxidation reaction may be a conventional method in the art, and the following reaction method and conditions are particularly preferred in the present invention: compound 15 and an oxidant are subjected to a Leeb's oxidation reaction in an organic solvent in the presence of a catalyst to obtain compound 14.
In the method for preparing the compound 14, the organic solvent is preferably a halogenated hydrocarbon solvent and/or a nitrile solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the nitrile solvent is preferably acetonitrile; the organic solvent is preferably a mixed solvent of dichloromethane and acetonitrile; when a mixed solvent of dichloromethane and acetonitrile is adopted, the volume ratio of dichloromethane to acetonitrile in the mixed solvent of dichloromethane and acetonitrile is preferably 20: 1-1: 1, and more preferably 15: 1-10: 1.
In the method for producing compound 14, the volume-to-mass ratio of the organic solvent to compound 15 is preferably 20 to 200mL/g, and more preferably 150 to 200 mL/g.
In the process for preparing compound 14, the oxidizing agent is preferably N-Methylmorpholine oxide (CAS: 7529-22-8, England name 4-Methylmorpholine N-oxide).
In the method for preparing the compound 14, the molar ratio of the compound 15 to the oxidizing agent is preferably 1:1 to 1:5, and more preferably 1:1 to 1:2.
In the process for preparing compound 14, the catalyst is preferably ammonium tetra-n-propylperruthenate (TPAP).
In the method for preparing the compound 14, the molar ratio of the compound 15 to the catalyst is preferably 20:1 to 5:1, and more preferably 10:1 to 15: 1.
In the process for producing compound 14, the temperature of the Leeb oxidation reaction is preferably 10 to 40 ℃ and more preferably 20 to 30 ℃.
In the process for preparing compound 14, the progress of the Lee's oxidation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 5 to 20 hours, more preferably 8 to 12 hours, with the time when compound 15 disappears being generally the end point of the reaction.
The process for preparing compound 14 is preferably carried out in the presence of a molecular sieve; the molecular sieve is preferably
And (3) a molecular sieve. The mass molar ratio of the molecular sieve to the compound 15 is preferably 1 to 5g/mol, and more preferably 1 to 2 g/mol.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 14, the compound 15 can be prepared by adopting the following method: in a solvent, carrying out a reaction of removing a hydroxyl protecting group on the compound 16 and a fluorination reagent to obtain a compound 15;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above; r3For example, Trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS) or methoxymethyl (MOM) as a hydroxyl-protecting group.
The method for preparing compound 15 can be a conventional method for such a hydroxyl-protecting group-removing reaction in the art, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 15, the solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 15, the volume-to-mass ratio of the solvent to compound 15 is preferably 1 to 100mL/g, and more preferably 50 to 100 mL/g.
In the method for preparing the compound 15, the fluorinating agent is preferably tetrabutylammonium fluoride and/or potassium fluoride.
In the method for preparing the compound 15, the molar ratio of the compound 16 to the fluorinating agent is preferably 1:1 to 1:5, and more preferably 1:1 to 1:2.
In the process for producing compound 15, the reaction temperature for removing the hydroxyl protecting group is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 15, the progress of the reaction for removing the hydroxyl protecting group can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours, with the time when compound 16 disappears as a reaction end point.
The process 1 for preparing compound 2 further comprises the following steps, and in the process for preparing compound 15, the compound 16 can be prepared by the following steps: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the compound 17 and an acetylation reagent to obtain the compound 16;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above.
In the method for preparing the compound 16, the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the organic base is preferably one or more of pyridine, piperidine and triethylamine.
In the method for preparing the compound 16, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, piperidine and triethylamine.
In the method for preparing the compound 16, the molar ratio of the compound 17 to the base is preferably 1:1 to 1:5, and more preferably 1:1 to 1: 4.
In the method for preparing the compound 16, the acetylation reagent is an acetylation reagent with acetyl groups, which is commonly used in the nucleophilic substitution reaction, and preferably acetyl halide and/or acetic anhydride, and further preferably acetic anhydride; the acetyl halide is preferably acetyl chloride or acetyl bromide.
In the method for preparing the compound 16, the molar ratio of the compound 17 to the acetylation reagent is preferably 1: 1-1: 20; when the acetylating agent is an acetyl halide, the molar ratio of the compound 17 to the acetylating agent is preferably 1:1 to 1:3, more preferably 1:1 to 1: 1.5.
In the method for producing compound 16, the temperature of the nucleophilic substitution reaction is preferably 0 to 100 ℃, and more preferably 0 to 60 ℃.
In the method for preparing compound 16, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1h to 24h, more preferably 8h to 12h, with the disappearance of compound 17 as the reaction end point.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 16, the compound 17 can be prepared by the following method: in an aprotic solvent, under the action of an acid and a reducing agent, carrying out reduction reaction on the compound 18 to obtain a compound 17;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above.
In the process for preparing compound 17, the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for producing compound 17, the volume-to-mass ratio of the aprotic solvent to compound 18 is preferably 1 to 200mL/g, and more preferably 30 to 50 mL/g.
In the process for preparing compound 17, the acid is preferably an organic acid; the organic acid is preferably glacial acetic acid.
In the method for producing compound 17, the molar ratio of the acid to compound 18 is preferably 10:1 to 100:1, and more preferably 40:1 to 100: 1.
In the process for preparing compound 17, the reducing agent is preferably one or more of zinc, iron and aluminum.
In the method for producing the compound 17, the molar ratio of the reducing agent to the compound 18 is preferably 10:1 to 100:1, and more preferably 40:1 to 100: 1.
In the method for producing compound 17, the temperature of the reduction reaction is preferably 0 to 40 ℃, and more preferably 10 to 30 ℃.
In the process for preparing compound 17, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 20 hours, more preferably 12 to 18 hours, with the disappearance of compound 18 as a reaction end point.
The process for preparing compound 17 preferably employs the following steps: and (3) adding a reducing agent and an acid into the solution formed by the compound 18 and the aprotic solvent in sequence to perform reduction reaction to obtain the compound 17.
The process for preparing compound 17 preferably comprises the following work-up steps: after the reaction is finished, adding alkali to adjust the pH value to about 7, extracting, concentrating and separating by column chromatography to obtain the compound 17. The alkali is preferably organic alkali, and the organic alkali is preferably ammonia water; the ammonia water can be a conventional commercially available ammonia water reagent, the mass percentage concentration of the ammonia water reagent is preferably 5-50%, and more preferably 15-40%, and the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution. The solvent used for extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The method of column chromatography may be carried out by methods conventional in the art for such procedures.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 17, the compound 18 can be prepared by the following method: in an organic solvent and in the presence of alkali, carrying out dehydration reaction on the compound 19 and a dehydrating agent to obtain the compound 18;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 18 can be carried out by a conventional method in the art for such dehydration reaction, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 18, the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; further preferred are ether solvents and/or halogenated hydrocarbon solvents; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the aromatic hydrocarbon solvent is preferably toluene.
In the method for producing compound 18, the volume-to-mass ratio of the organic solvent to compound 19 is preferably 20 to 200mL/g, and more preferably 100 to 150 mL/g.
In the process for preparing compound 18, the dehydrating agent is preferably one or more of thionyl chloride, methanesulfonyl chloride and Burgess reagent (Burgess reagent means methyl N- (triethylammoniumsulfonylcarbamate, i.e., N- (triethylammoniumsulfonyl) carbamate, CAS: 29684-56-8).
In the method for producing the compound 18, the molar ratio of the compound 19 to the dehydrating agent is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 3.
In the process for preparing compound 18, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.
In the process for preparing compound 18, the molar ratio of said base to said compound 19 is preferably 1: 1-50: 1; for example, 1:1 to 10:1, and further for example, 3:1 to 6: 1.
In the method for producing compound 18, the temperature of the dehydration reaction is preferably 0 to 40 ℃, and more preferably 10 to 30 ℃.
In the process for preparing compound 18, the progress of the dehydration reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 20 hours, more preferably 8 to 15 hours, with the disappearance of compound 19 as a reaction end point.
The process for preparing compound 18 is preferably carried out in the presence of a catalyst, preferably 4-Dimethylaminopyridine (DMAP, CAS:1122-58-3, England name 4-dimethylamino pyridine). The molar ratio of the catalyst to the compound 19 is preferably 1:1 to 1:5, and more preferably 1:3 to 1: 4.
The process for preparing compound 18 preferably employs the following steps: and (2) sequentially adding 4-Dimethylaminopyridine (DMAP) and methanesulfonyl chloride into a solution formed by the compound 19, triethylamine and an organic solvent, and performing dehydration reaction to obtain the compound 18.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 18, the compound 19 can be prepared by the following method: reacting compound 10 with compound 20 in the presence of a basic substance in an aprotic solvent to obtain said compound 19;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 19 can adopt the conventional method of the reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the method for preparing the compound 19, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 19, the volume-to-mass ratio of the aprotic solvent to compound 10 is preferably 1 to 50mL/g, and more preferably 30 to 50 mL/g.
In the process for preparing compound 19, the basic substance can be an alkaline-developing substance (i.e., a substance having a pH greater than 7) as is conventional in the art; one or more of inorganic base, organic base, basic oxide, strong base and weak acid salt and ion exchange resin are preferred; the inorganic base is preferably sodium methoxide and/or potassium tert-butoxide; the organic base is preferably one or more of tetrabutylammonium hydroxide, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU, CAS:6674-22-2, England name 1,8-Diazabicyclo [5.4.0] undec-7-ene), Tetramethylguanidine (TMG, CAS: 80-70-6, England name Tetramethylguanidine) and Lithium diisopropylamide (LDA, CAS: 4111-54-0, England name Lithium diisopropyramide). The alkaline oxide is preferably alkaline aluminum trioxide; the strong base weak acid salt is preferably potassium acetate; the ion exchange resin is preferably Amberlite A-21.
In the method for producing the compound 19, the molar ratio of the basic substance to the compound 10 is preferably 1:1 to 1:10, and more preferably 1:1 to 1: 5.
In the method for producing compound 19, the reaction temperature is preferably 0 to 40 ℃, and more preferably 10 to 30 ℃.
In the process for preparing compound 19, the progress of the reaction can be monitored by a conventional test method in the art (such as TLC or HPLC), and the reaction time is generally 1 to 10 hours, more preferably 5 to 8 hours, with the disappearance of compound 20 as a reaction end point.
In the method for preparing the compound 8 or 19, the compound 10 can be synthesized by the method reported in the literature Angew.chem.int.Ed.,2010,49, 4656-one 4660, and the following reaction method and conditions can also be adopted:
the method 1 for preparing the compound 2 further comprises the following steps of carrying out Michael addition reaction on the compound 11 and acetone in an organic solvent in the presence of an additive and a catalyst to obtain the compound 10;
wherein R is4The definition of (A) is as described above.
The method for preparing compound 10 can be a conventional method in the art for such michael addition reaction, and the following reaction methods and conditions are particularly preferred in the present invention:
in the method for preparing the compound 10, the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent and a halogenated aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene and/or mesitylene; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane and/or carbon tetrachloride; the ether solvent is preferably diethyl ether and/or anisole; the alkane solvent is preferably n-hexane; the halogenated aromatic hydrocarbon solvent is preferably chlorobenzene and/or trifluorotoluene.
In the method for producing compound 10, the volume-to-mass ratio of the organic solvent to compound 11 is preferably 0.1 to 10mL/g, and more preferably 0.1 to 1 mL/g.
In the process for preparing compound 10, the additive is preferably an organic acid; the organic acid is preferably one or more of benzoic acid, acetic acid, p-dibenzoic acid, p-hydroxybenzoic acid, p-nitrobenzoic acid, (+) -camphorsulfonic acid and p-toluenesulfonic acid.
In the method for preparing the compound 10, the molar ratio of the additive to the compound 11 is preferably 0.1:1 to 1:1, and more preferably 0.1:1 to 0.5: 1.
In the method for producing the compound 10, the molar ratio of the acetone to the compound 11 is preferably 5:1 to 20:1, and more preferably 5:1 to 10: 1.
In the method for preparing the compound 10, the catalyst is preferably any one of the catalysts shown as the following formula, and is further preferably a Jacobsen catalyst;
in the method for producing the compound 10, the molar ratio of the catalyst to the compound 11 is preferably 0.01:1 to 0.1:1, and more preferably 0.01:1 to 0.05: 1.
In the process for producing compound 10, the temperature of the Michael addition reaction is preferably from 0 ℃ to 40 ℃, more preferably from 20 ℃ to 30 ℃.
In the process for preparing compound 10, the progress of the Michael addition reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1d to 5d, more preferably 3d to 4d, with the time when compound 11 disappears being the reaction end point.
In the method for preparing compound 10, the Jacobsen catalyst can be synthesized by the method reported in the document j.am.chem.soc.,2006,128, 7170-7171.
The process for preparing compound 10 preferably comprises the steps of: adding a catalyst, an additive and acetone in sequence into a solution of the compound 11 and an organic solvent, and carrying out Michael addition reaction to obtain the compound 10.
The method 1 for preparing the compound 2 further comprises the following step, and in the method for preparing the compound 19, the compound 20 can be synthesized by the method reported in the references bioorg.Med.chem.,2003,11, 827-841. The following reaction methods and conditions are particularly preferred in the present invention: carrying out oxidation reaction on the compound 21 and an oxidant in an aprotic solvent to obtain the compound 20;
wherein R is2、R3And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 20 can adopt the conventional method of the oxidation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the method for preparing the compound 20, the aprotic solvent is preferably an ether solvent and/or a halogenated hydrocarbon solvent; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for producing compound 20, the volume-to-mass ratio of the aprotic solvent to compound 21 is preferably 1 to 50mL/g, and more preferably 10 to 30 mL/g.
In the process for preparing compound 20, the oxidizing agent is preferably one or more of dess-martin oxidizer (CAS:87413-09-0, British name 1,1, 1-triacyloxy-1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one), pyridinium chlorochromate (PCC), and Pyridinium Dichromate (PDC).
In the method for preparing the compound 20, the molar ratio of the compound 21 to the oxidizing agent is preferably 1:1 to 1:5, and more preferably 1:1 to 1:2.
In the method for producing compound 20, the temperature of the oxidation reaction is preferably 0 to 40 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 20, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 10 hours, more preferably 1 to 3 hours, with the time when compound 21 disappears being generally used as the end point of the reaction.
The process for preparing compound 20 is preferably carried out in the presence of a base; the alkali is preferably inorganic alkali; the inorganic base is preferably one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate. The molar ratio of the compound 21 to the base is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 4.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 20, the compound 21 can be prepared by adopting the following method: in the presence of a catalyst, carrying out condensation reaction on a compound 22 and ketone to obtain a compound 21;
wherein R is2、R3And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 21 can adopt the conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the process for preparing compound 21, the catalyst is preferably montmorillonite; the montmorillonite is preferably conventional commercially available montmorillonite, and further preferably K-10 montmorillonite.
In the process for producing the compound 21, the mass molar ratio of the catalyst to the compound 22 is preferably 100g/mol to 1000g/mol, and more preferably 400g/mol to 600 g/mol.
In the process for preparing compound 21, the ketone is preferably acetone, butanone, 2-pentanone or 3-pentanone.
In the method for producing compound 21, the volume-to-mass ratio of the ketone to compound 22 is preferably 30 to 100mL/g, and more preferably 30 to 50 mL/g.
In the method for producing compound 21, the temperature of the condensation reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 21, the progress of the condensation reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 5 to 20 hours, more preferably 8 to 15 hours, with the disappearance of compound 22 as the reaction end point.
The process for preparing compound 21 is preferably carried out in the presence of a molecular sieve; the molecular sieve is preferably a conventional commercially available molecular sieve, and more preferably
And (3) a molecular sieve.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 21, the compound 22 is preferably prepared by adopting the following method: carrying out reduction reaction on the compound 23 and a reducing agent in an aprotic solvent to obtain the compound 22;
wherein R is3The definition of (A) is as described above.
In the method for preparing the compound 22, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 22, the volume-to-mass ratio of the aprotic solvent to compound 23 is preferably 1 to 50mL/g, and more preferably 1 to 10 mL/g.
In the method for preparing compound 22, the reducing agent is preferably one or more of lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride.
In the method for preparing the compound 22, the molar ratio of the reducing agent to the compound 23 is preferably 1:1 to 5:1, and more preferably 1:1 to 3: 1.
In the method for producing compound 22, the temperature of the reduction reaction is preferably 0 to 40 ℃, and more preferably 10 to 30 ℃.
In the process for preparing compound 22, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 20 hours, more preferably 10 to 15 hours, with the disappearance of compound 23 as a reaction end point.
The process for preparing compound 22 preferably employs the following steps: the solution of the compound 23 in the aprotic solvent is added dropwise to the solution of the aprotic solvent in the reducing agent to carry out a reduction reaction, thereby obtaining a compound 22.
The method 1 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 22, the compound 23 can be prepared by the following method: reacting D- (-) -diethyl tartrate 24 with a hydroxyl protecting group in an organic solvent in the presence of a base to obtain a compound 23;
wherein R is3The definition of (A) is as described above.
The method for preparing compound 23 can be carried out by conventional methods for nucleophilic substitution reactions of this type in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
in the process for preparing compound 23, the organic solvent is preferably an amide solvent; the amide solvent is preferably N, N-dimethylformamide.
In the method for producing compound 23, the volume-to-mass ratio of the organic solvent to compound 6 is preferably 1 to 50mL/g, and more preferably 1 to 10 mL/g.
In the process for preparing compound 23, the base is preferably an inorganic base; the inorganic base is preferably sodium hydride; the sodium hydride is preferably a conventional commercially available sodium hydride reagent; the mass percent of the sodium hydride reagent is preferably 20-95%, and more preferably 50-85%; the mass percentage refers to the mass percentage of sodium hydride in the total mass of the sodium hydride reagent.
In the process for preparing compound 23, the molar ratio of said base to said diethyl D- (-) -tartrate 24 is preferably 1:1.
In the method for preparing the compound 23, the hydroxyl protecting reagent is preferably one or more of tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane and chloromethyl methyl ether.
In the process for producing compound 23, the reaction temperature for the above-mentioned hydroxy-protecting group is preferably from 0 ℃ to 40 ℃, more preferably from 10 ℃ to 30 ℃.
In the process for preparing compound 23, the progress of the reaction of the protecting group of the upper hydroxyl group can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 24 hours, and more preferably 8 to 15 hours, with the end point being generally the time when the D- (-) -diethyl tartrate 24 disappears.
The process for preparing compound 23 preferably employs the following steps: and (2) dropwise adding a solution formed by D- (-) -diethyl tartrate 24 and an organic solvent into a solution formed by sodium hydride and the organic solvent, dropwise adding a solution formed by a hydroxyl protecting reagent and the organic solvent, and performing nucleophilic substitution reaction to obtain the compound 23.
In the present invention, the compound 11 can be referred to the literature, Zhu, s.; yu, s.; wang, y.; ma, d.angelw.chem., int.ed.2010,49,4656.
Method 2 for preparing compound 2 can be carried out by a conventional method in the art for such hydrolysis reaction, and the following reaction method and conditions are particularly preferred in the present invention: hydrolyzing the compound 35 with alkali in an aprotic solvent to obtain the compound 2;
in the method 2 for preparing the compound 2, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In Process 2 for producing Compound 2, the volume-to-mass ratio of the aprotic solvent to Compound 35 is preferably from 0.1mL/mg to 5mL/mg, more preferably from 0.1mL/mg to 1 mL/mg.
In method 2 for preparing compound 2, the base is preferably an inorganic base, and the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the sodium hydroxide, potassium hydroxide or lithium hydroxide may be a reagent conventionally commercially available in the art. The inorganic base may be in the form of an aqueous solution thereof, and when the inorganic base is in the form of an aqueous solution thereof, the molar concentration of the aqueous solution of the inorganic base is preferably 1mol/L to 10mol/L, more preferably 5mol/L to 10mol/L, and the molar concentration refers to the ratio of the number of moles of the inorganic base to the volume of the aqueous solution of the inorganic base.
In the method 2 for producing the compound 2, the molar ratio of the compound 35 to the base is preferably 1:1 to 1:100, and more preferably 1:40 to 1: 100.
In the method 2 for producing the compound 2, the temperature of the hydrolysis reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the method 2 for preparing the compound 2, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 20 hours, more preferably 1 to 5 hours, with the time when the compound 35 disappears being generally used as the reaction end point.
The method for preparing the compound 3 can adopt the conventional method of the reaction of the hydrolysis in the field, and the following reaction method and conditions are particularly preferred in the invention: hydrolyzing compound 34 with a base in an aprotic solvent to obtain compound 3;
in the third method for preparing the compound 3, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the third process for producing compound 3, the volume-to-mass ratio of the aprotic solvent to compound 34 is preferably 0.1 to 5mL/mg, more preferably 0.1 to 1 mL/mg.
In the third method for preparing the compound 3, the base is preferably an inorganic base, and the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the sodium hydroxide, potassium hydroxide or lithium hydroxide may be a reagent conventionally commercially available in the art. The inorganic base may be in the form of an aqueous solution thereof, and when the inorganic base is in the form of an aqueous solution thereof, the molar concentration of the aqueous solution of the inorganic base is preferably 1mol/L to 10mol/L, more preferably 5mol/L to 10mol/L, and the molar concentration refers to the ratio of the number of moles of the inorganic base to the volume of the aqueous solution of the inorganic base.
In the third process for preparing the compound 3, the molar ratio of the compound 34 to the base is preferably 1:1 to 1:100, and more preferably 1:40 to 1: 100.
In the third method for producing the compound 3, the temperature of the hydrolysis reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the third process for preparing compound 3, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 10 minutes to 20 hours, and more preferably 30 minutes to 10 hours, with the disappearance of compound 34 as a reaction endpoint.
In the present invention, said method 1 for preparing compound 2 further preferably comprises the steps of: hydrolyzing compound 34 with a base in an aprotic solvent to give compound 3, and then performing a deprotection reaction in the presence of an acid to give compound 2 without post-treatment.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method 2 for preparing the compound 2, the compound 35 can be prepared by adopting the following method: carrying out a protecting group removing reaction on the compound 34 to obtain a compound 35;
wherein, R, R1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 35 can be a conventional method for such deprotection reactions in the art, and the following reaction methods and conditions are particularly preferred in the present invention: the compound 35 can be obtained by subjecting the compound 34 to a deprotection reaction in an aprotic solvent in the presence of an acid.
In the method for preparing the compound 35, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 35, the volume-to-mass ratio of the aprotic solvent to compound 34 is preferably 0.1 to 5mL/mg, and more preferably 0.1 to 1 mL/mg.
In the process for preparing compound 35, the acid is preferably an inorganic acid; the inorganic acid is preferably hydrochloric acid; the hydrochloric acid can be a hydrochloric acid reagent which is conventional and commercially available in the field, and preferably the hydrochloric acid with the mass percentage of 1-10% is selected, wherein the mass percentage refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid reagent.
In the method for producing the compound 35, the molar ratio of the compound 34 to the acid is preferably 1:1 to 1:100, and more preferably 1:30 to 1: 50.
In the process for producing compound 35, the temperature of the reaction for removing a protecting group is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 35, the progress of the deprotection reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 20 hours, more preferably 1 to 8 hours, with the disappearance of compound 34 as a reaction end point.
Method 2 for preparing compound 2 preferably comprises the steps of: the compound 2 can be obtained by subjecting the compound 34 to a deprotection reaction in an aprotic solvent in the presence of an acid to obtain the compound 35, followed by hydrolysis reaction in the presence of a base without any post-treatment.
The method 1 or 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 35 or the method three for preparing the compound 3, the compound 34 can be prepared by adopting the following method: carrying out nucleophilic substitution reaction on the compound 33 and an acetylation reagent in a solvent in the presence of alkali to obtain a compound 34;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 34 can be carried out by conventional methods for nucleophilic substitution reactions of this type in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
in the method for preparing the compound 34, the solvent is preferably a halogenated hydrocarbon solvent and/or an organic base; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The organic base is preferably one or more of pyridine, diisopropylethylamine, piperidine and triethylamine.
In the method for preparing compound 34, the base is preferably an organic base, and the organic base is preferably one or more of pyridine, diisopropylethylamine, piperidine and triethylamine.
In the method for preparing the compound 34, the molar ratio of the compound 33 to the base is preferably 1:3 to 1:6, and more preferably 1:4 to 1: 5.
In the method for preparing the compound 34, the acetylation reagent is an acetylation reagent with acetyl groups, which is commonly used in the nucleophilic substitution reaction, and preferably acetyl halide and/or acetic anhydride; the acetyl halide is preferably acetyl chloride or acetyl bromide.
In the method for producing compound 34, the molar ratio of the acetylating agent to compound 33 is preferably 1:1 to 1:3, more preferably 1:1 to 1: 1.1.
In the method for producing compound 34, the temperature of the nucleophilic substitution reaction is preferably 0 to 100 ℃, and more preferably 0 to 30 ℃.
In the method for preparing compound 34, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 10min to 2h, more preferably 10min to 1h, with the time when compound 33 disappears being the end point of the reaction.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 34, the compound 33 can be prepared by adopting the following method: in an aprotic solvent, under the action of an acid and a reducing agent, carrying out reduction reaction on the compound 32 to obtain a compound 33;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
In the process for preparing compound 33, the aprotic solvent is preferably an ester solvent; the ester solvent is preferably ethyl acetate.
In the method for producing compound 33, the volume-to-mass ratio of the aprotic solvent to compound 32 is preferably 20 to 200mL/g, and more preferably 90 to 120 mL/g.
In the process for preparing compound 33, the acid is preferably an organic acid; the organic acid is preferably glacial acetic acid.
In the method for producing the compound 33, the molar ratio of the acid to the compound 32 is preferably 10:1 to 100:1, and more preferably 60:1 to 100: 1.
In the method for preparing the compound 33, the reducing agent is preferably one or more of zinc, iron and aluminum.
In the method for producing the compound 33, the molar ratio of the reducing agent to the compound 32 is preferably 10:1 to 100:1, and more preferably 60:1 to 100: 1.
In the method for producing compound 33, the temperature of the reduction reaction is preferably-10 ℃ to 40 ℃, and more preferably 0 ℃ to 30 ℃.
In the process for preparing compound 33, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 1 to 24 hours, and more preferably 4 to 10 hours, with the disappearance of compound 32 as the reaction end point.
The process for preparing compound 33 preferably employs the following steps: and (3) adding a reducing agent and an acid into the solution formed by the compound 32 and the aprotic solvent in sequence to perform reduction reaction to obtain the compound 33.
The process for preparing compound 33 preferably comprises the following work-up steps: after the reaction, filtration, extraction, concentration and column chromatography were carried out to obtain compound 33. The filtration is preferably carried out by means of kieselguhr. The extraction is preferably carried out by using an ester solvent, and the ester solvent is preferably ethyl acetate. The method of column chromatography may be carried out by methods conventional in the art for such procedures.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 33, the compound 32 can be prepared by the following method: in an organic solvent and in the presence of alkali, carrying out dehydration reaction on the compound 31 and a dehydrating agent to obtain the compound 32;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing the compound 32 can adopt the conventional method of such dehydration reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 32, the organic solvent is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; further preferred are ether solvents and/or halogenated hydrocarbon solvents; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane; the aromatic hydrocarbon solvent is preferably toluene.
In the method for producing compound 32, the volume-to-mass ratio of the organic solvent to compound 31 is preferably 1 to 200mL/g, and more preferably 20 to 100 mL/g.
In the process for preparing compound 32, the base is preferably an organic base; the organic base is preferably triethylamine and/or pyridine.
In the method for producing the compound 32, the molar ratio of the base to the compound 31 is preferably 10:1 to 1:1, and more preferably 8:1 to 5: 1.
In the process for producing the compound 32, the dehydrating agent is preferably thionyl chloride and/or methanesulfonyl chloride.
In the method for producing the compound 32, the molar ratio of the compound 31 to the dehydrating agent is preferably 1:1 to 1:5, and more preferably 1:2 to 1: 3.
In the method for producing compound 32, the temperature of the dehydration reaction is preferably-78 to 30 ℃ and more preferably-78 to 0 ℃.
In the process for preparing compound 32, the progress of the dehydration reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 0.1 to 5 hours, more preferably 0.5 to 2 hours, with the disappearance of compound 31 as a reaction end point.
The process for preparing compound 32 preferably comprises the steps of: adding a dehydrating agent into a solution formed by the compound 31, alkali and an organic solvent, and performing dehydration reaction to obtain the compound 32.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 32, the compound 31 can be prepared by adopting the following method: carrying out oxidation reaction on the compound 30 in an aprotic solvent in the presence of an oxidant to obtain a compound 31;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 31 can adopt the conventional method of such oxidation reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
in the process for preparing compound 31, the aprotic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for producing compound 31, the volume-to-mass ratio of the aprotic solvent to compound 30 is preferably 20 to 300mL/g, and more preferably 50 to 150 mL/g.
In the method for preparing compound 31, the oxidant is preferably dessimutan oxidant (CAS: 87413-09-0). The desmesartan oxidizer may be a commercially available reagent that is conventional in the art.
In the method for preparing the compound 31, the molar ratio of the compound 30 to the oxidizing agent is preferably 1:1 to 1:3, and more preferably 1:1 to 1:2.
In the method for producing the compound 31, the temperature of the oxidation reaction is preferably-30 ℃ to 30 ℃, and more preferably-20 ℃ to 30 ℃.
In the method for preparing the compound 31, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 10 hours, more preferably 1 to 5 hours, with the time when the compound 30 disappears being generally used as the reaction end point.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 31, the compound 30 can be prepared by adopting the following method: hydrolyzing the compound 29 in a protic solvent in the presence of a base to obtain the compound 30;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 30 can be a conventional method of such hydrolysis reaction in the art, and the following reaction method and conditions are particularly preferred in the present invention:
in the process for preparing compound 30, the protic solvent is preferably an alcoholic solvent; the alcohol solvent is preferably methanol.
In the method for producing compound 30, the volume-to-mass ratio of the protic solvent to compound 29 is preferably 20 to 300mL/g, and more preferably 30 to 100 mL/g.
In the process for preparing compound 30, the base is preferably potassium carbonate and/or sodium methoxide, and more preferably sodium methoxide.
In the method for preparing the compound 30, the molar ratio of the compound 29 to the base is preferably 3:1 to 1:1, and more preferably 2:1 to 1:1.
In the method for producing compound 30, the temperature of the hydrolysis reaction is preferably 0 to 50 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 30, the progress of the hydrolysis reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, or NMR), and the reaction time is preferably 1 hour to 1 day, more preferably 3 hours to 10 hours, with the disappearance of compound 29 as a reaction end point.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 30, the compound 29 can be prepared by adopting the following method: reacting compound 28 with compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain said compound 29;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above.
The method for preparing compound 29 can be carried out by conventional methods in the art for such reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in the method for preparing the compound 29, the aprotic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 29, the volume-to-mass ratio of the aprotic solvent to compound 9 is preferably 1 to 50mL/g, and more preferably 10 to 30 mL/g.
In the process for preparing compound 29, the base is preferably an inorganic base; the inorganic base is preferably cesium carbonate.
In the method for preparing the compound 29, the molar ratio of the compound 9 to the base is preferably 1:1 to 5:1, and more preferably 2:1 to 4: 1.
In the method for preparing the compound 29, the catalyst is preferably inorganic copper salt; the inorganic copper salt refers to a salt formed by the reaction of copper and inorganic acid. The inorganic cupric salt is preferably one or more of cupric chloride, cuprous bromide, cupric bromide and cuprous iodide, and is further preferably cupric bromide.
In the method for preparing the compound 29, the molar ratio of the compound 28 to the catalyst is preferably 1:1 to 10:1, and more preferably 2:1 to 10: 1.
In the method for preparing the compound 29, the molar ratio of the compound 28 to the compound 9 is preferably 1:1 to 1:5, and more preferably 1:1 to 1:2.
In the method for preparing the compound 29, the catalyst ligand is preferably a pyrrolidine-phenolic catalyst; the pyrrolidine-phenol catalystPreference is given to
In the method for preparing the compound 29, the molar ratio of the catalyst ligand to the compound 28 is preferably 1:10 to 3:10, and more preferably 1:5 to 3: 10.
In the process for producing compound 29, the reaction temperature is preferably-20 ℃ to 40 ℃, and more preferably-20 ℃ to 30 ℃.
In the process for preparing compound 29, the progress of the reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 24 to 96 hours, more preferably 24 to 48 hours, with the disappearance of compound 28 as a reaction end point.
In the process for preparing compound 29, the catalyst ligand
Can be synthesized according to the method reported in chem.eur.j.2012,18,12357.
In the method for preparing the compound 29, the compound 9 can be synthesized by the method reported in Tetrahedron: asymmetry.1998,9, 1359-1367.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 29, the compound 28 can be prepared by adopting the following method: in an organic solvent, in the presence of a base and a catalyst, reacting the compound 27 with a hydroxyl protecting group on a hydroxyl protecting reagent to obtain the compound 28;
wherein R is4The definition of (A) is as described above.
The method for preparing compound 28 can be a conventional method for such a reaction of a hydroxyl protecting group in the art, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 28, the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the method for producing compound 28, the volume-to-mass ratio of the organic solvent to compound 27 is preferably 1 to 100mL/g, and more preferably 10 to 50 mL/g.
In the process for preparing compound 28, the base is preferably an organic base; the organic solvent is preferably triethylamine.
In the method for preparing the compound 28, the molar ratio of the base to the compound 27 is preferably 1:1 to 3: 1.
In the process for preparing compound 28, the catalyst is preferably 4-dimethylaminopyridine.
In the method for producing the compound 28, the molar ratio of the catalyst to the compound 27 is preferably 0.01:1 to 0.5:1, and more preferably 0.05:1 to 0.2: 1.
In the process for preparing compound 28, the hydroxyl protecting agent is preferably acetic anhydride, acetyl chloride, acetyl bromide, trifluoroacetyl chloride, trifluoroacetyl bromide, trimethylchlorosilane, trimethylbromosilane, t-butyldimethylchlorosilane, t-butyldimethylbromosilane, triethylchlorosilane, triethylbromosilane, benzylchloride or benzylbromide, and more preferably acetic anhydride.
In the process for producing compound 28, the reaction temperature for the hydroxy-protecting group is preferably 0 to 40 ℃, more preferably 10 to 30 ℃.
In the method for preparing compound 28, the progress of the reaction of the protecting group of the upper hydroxyl group can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and generally, the reaction time is preferably 1 minute to 1 hour, more preferably 10 minutes to 30 minutes, when compound 27 disappears as the end point of the reaction.
The process for preparing compound 28 preferably employs the following steps: adding a catalyst into a solution formed by the compound 27 and an organic solvent, and dropwise adding alkali and a hydroxyl protecting reagent to perform a reaction of a hydroxyl protecting group to obtain the compound 28.
The process for preparing compound 28 further preferably employs the following steps: adding a catalyst into a solution formed by the compound 27 and an organic solvent, and then dripping alkali and a hydroxyl protecting reagent in sequence to perform a reaction of a hydroxyl protecting group to obtain the compound 28.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 28, the compound 27 can be prepared by adopting the following method: carrying out reduction reaction on the compound 26 and a reducing agent in a protic solvent to obtain the compound 27;
wherein R is4The definition of (A) is as described above.
The method for preparing compound 27 can adopt the conventional method of such reduction reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
in the process for preparing compound 27, the protic solvent is preferably an alcoholic solvent; the alcohol solvent is preferably methanol.
In the method for producing compound 27, the volume-to-mass ratio of the protic solvent to compound 26 is preferably 1 to 100mL/g, and more preferably 20 to 40 mL/g.
In the method for preparing compound 27, the reducing agent is preferably an alkali metal borohydride, which refers to an alkali metal and BH4 -The salt formed is preferably one or more of sodium borohydride, potassium borohydride and lithium borohydride, which are conventional commercially available reagents.
In the method for producing the compound 27, the molar ratio of the reducing agent to the compound 26 is preferably 0.4:1 to 10:1, and more preferably 0.4:1 to 1:1.
In the method for producing compound 27, the temperature of the reduction reaction is preferably 0 to 40 ℃, and more preferably 20 to 30 ℃.
In the process for preparing compound 27, the progress of the reduction reaction can be monitored by a conventional test method in the art (such as TLC, NMR or HPLC), and the reaction time is preferably 10 minutes to 1 hour, more preferably 10 minutes to 30 minutes, with the time when compound 26 disappears being the reaction end point.
The process for preparing compound 27 preferably comprises the steps of: adding sodium borohydride into a solution of the compound 26 and a protic solvent, and carrying out a reduction reaction to obtain the compound 27.
The method 2 for preparing the compound 2 further comprises the following steps, and in the method for preparing the compound 27, the compound 26 can be prepared by adopting the following method: carrying out Michael addition reaction on the compound 11 and methyl pyruvate in an organic solvent in the presence of a catalyst to obtain a compound 26;
wherein R is4The definition of (A) is as described above.
The method for preparing compound 26 can be a conventional method in the art for such michael addition reaction, and the following reaction method and conditions are particularly preferred in the present invention:
in the method for preparing the compound 26, the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alkane solvent and a halogenated aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably toluene and/or mesitylene; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane and/or trichloromethane; the ether solvent is preferably diethyl ether and/or anisole; the alkane solvent is preferably n-hexane.
In the method for producing compound 26, the volume-to-mass ratio of the organic solvent to compound 11 is preferably 1 to 100mL/g, and more preferably 1 to 10 mL/g.
In the method for producing compound 26, the molar ratio of methyl pyruvate to compound 11 is preferably 1:1 to 1:10, and more preferably 1:3 to 1: 10.
In the method for preparing the compound 26, the catalyst is preferably any one of the catalysts shown as the following formula, and is further preferably a Jacobsen catalyst:
in the method for producing the compound 26, the molar ratio of the catalyst to the compound 11 is preferably 0.01:1 to 0.2:1, and more preferably 0.03:1 to 0.1: 1.
In the process for producing compound 26, the temperature of the Michael addition reaction is preferably from-10 ℃ to 40 ℃, more preferably from 0 ℃ to 30 ℃, and still more preferably from 20 ℃ to 30 ℃.
In the process for preparing compound 26, the progress of the Michael addition reaction can be monitored by a conventional test method in the art (e.g., TLC, NMR or HPLC), and the reaction time is preferably 12 hours to 5 days, more preferably 12 hours to 48 hours, with the time when the methyl pyruvate ester of the compound disappears being the end point of the reaction.
In the method for preparing compound 26, the Jacobsen catalyst can be synthesized as reported in the document j.am.chem.soc.,2006,128, 7170-7171.
The process for preparing compound 26 preferably comprises the steps of: adding a catalyst and methyl pyruvate into a solution of the compound 11 and an organic solvent in sequence to carry out a Michael addition reaction to obtain the compound 26.
Compound 2 described in the present invention is preferably prepared by any of the following routes:
route one:
and a second route:
and a third route:
route four
Compound 20 is preferably prepared using the following route:
compound 10 was prepared using the following route:
in the present invention, compound 1 can also be prepared after compound 2 is prepared, which comprises the following steps: in a solvent, carrying out nucleophilic substitution reaction on a compound 2 and a guanidine reagent to obtain a compound 1;
wherein R is methyl or hydrogen; compound 1 is Zanamivir (Zanamivir) when R is hydrogen; compound 1 is ranavir (laninavir) when R is methyl.
The method for preparing the compound 1 can be synthesized by the method reported in J.chem.Soc., Perkin Trans.I,1995,1173-1180, and the conventional method of nucleophilic substitution reaction of this type in the art can be adopted, and the following reaction method and conditions are particularly preferred in the present invention:
in the process for preparing compound 1, the solvent is preferably water.
In the method for producing the compound 1, the volume-to-mass ratio of the solvent to the compound 2 is preferably 1 to 100mL/g, and more preferably 60 to 90 mL/g.
In the process for preparing compound 1, the guanidine reagent is preferably thiourea trioxide, N '-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (N, N' -bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamide, CAS: 152120-54-2), 1H-pyrazole-1-carboxamidine hydrochloride (1H-pyrazole-1-carboxamide hydrochloride, CAS: 4023-02-3) or N, N '-Di-tert-butoxycarbonylthiourea (N, N' -Di-Boc-thiourea, CAS: 145013-05-04)
In the method for preparing the compound 1, the molar ratio of the compound 2 to the guanidine reagent is preferably 1:1 to 1:30, and more preferably 1:10 to 1: 15.
In the method for producing compound 1, the temperature of the nucleophilic substitution reaction is preferably 10 to 40 ℃, and more preferably 20 to 30 ℃.
In the method for preparing the compound 1, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 18h to 36h, and more preferably 30h to 36h, with the disappearance of the compound 2 as a reaction endpoint.
The process for preparing compound 1 is preferably carried out in the presence of a base.
When the process for preparing compound 1 is carried out in the presence of a base, said base is preferably an inorganic base; the inorganic base is preferably potassium carbonate and/or sodium carbonate; the molar ratio of the inorganic base to the compound 2 is preferably 1:1 to 3:1, and more preferably 1:1 to 2: 1.
The process for preparing compound 1 preferably employs the following steps: and sequentially adding alkali and a guanidine reagent in batches into a solution formed by the compound 2 and a solvent to perform nucleophilic substitution reaction to obtain the compound 1.
After preparing ranamivir, when R in the compound 1 is methyl, the octanoate CS-8958 of the ranamivir can be prepared by the method of a patent (WO 2008/126943).
The invention also provides compoundsProcess for the synthesis of compound 3, when R is1When the compound is Trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), methoxymethyl (MOM) or methyl, the compound 3 can be prepared by the following method I; when R is1When the hydrogen is used, the compound 3 can be prepared by the following method II; when R is1When the compound is Trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), methoxymethyl (MOM), methyl or hydrogen, the compound 3 can be prepared by the following method III;
the method comprises the following steps: carrying out oxidation reaction on a compound 4 and an oxidant in a protic solvent under an acidic condition to obtain a compound 3;
the second method comprises the following steps: in an aprotic solvent, carrying out reduction reaction on the compound 12 and a reducing agent to obtain a compound 3;
the third method comprises the following steps: carrying out hydrolysis reaction on the compound 34 to obtain a compound 3;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of Compound 3.
The invention also provides a synthesis method of the compound 4, which comprises the following steps: in an aprotic solvent, carrying out an oxidation reaction on a compound 5 and an oxidant to obtain a compound 4;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of Compound 4.
The invention also provides a synthesis method of the compound 5, which comprises the following steps: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on a compound 6 and an acetylation reagent to obtain a compound 5;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of Compound 5.
The invention also provides a synthesis method of the compound 6, which comprises the following steps: in an aprotic solvent, under the action of an acid and a reducing agent, carrying out reduction reaction on the compound 7 to obtain a compound 6;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of Compound 6.
The invention also provides a synthesis method of the compound 7, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 8 and a dehydrating agent to obtain a compound 7;
wherein R is1、R2、R4And R5Are all defined asAs described above; the reaction conditions were the same as those described above for the preparation of Compound 7.
The invention also provides a synthesis method of the compound 8, which comprises the following steps: reacting a compound 10 with a compound 9 in an aprotic solvent in the presence of an alkali, a catalyst and a catalyst ligand to obtain a compound 8;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as described above for the preparation of Compound 8.
The invention also provides a method for synthesizing the compound 10, which comprises the following steps: in an organic solvent, in the presence of an additive and a catalyst, carrying out Michael addition reaction on a compound 11 and acetone to obtain a compound 10;
wherein R is4The definitions of (A) and (B) are as described above; each reaction condition was as described above for the method of preparing compound 10.
The invention also provides a method for synthesizing the compound 12, which comprises the following steps: carrying out oxidation reaction on the compound 13 and an oxidant in an aprotic solvent under an acidic condition to obtain a compound 12;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above; each reaction condition was as described above for the method of preparing compound 12.
The invention also provides a method for synthesizing the compound 13, which comprises the following steps: carrying out oxidation reaction on the compound 14 and an oxidant in an aprotic solvent to obtain a compound 13;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of compound 13.
The invention also provides a method for synthesizing the compound 14, which comprises the following steps: carrying out oxidation reaction on the compound 15 to obtain a compound 14;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above; each reaction condition was as described above for the method of preparing compound 14.
The invention also provides a method for synthesizing the compound 15, which comprises the following steps: in a solvent, carrying out a reaction of removing a hydroxyl protecting group on the compound 16 and a fluorination reagent to obtain a compound 15;
wherein R is2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of Compound 15.
The invention also provides a method for synthesizing the compound 16, which comprises the following steps: in a solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on a compound 17 and an acetylation reagent to obtain a compound 16;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above; each reaction condition was as described above for the method of preparing compound 16.
The invention also provides a method for synthesizing compound 17, which comprises the following steps: carrying out reduction reaction on the compound 18 in an aprotic solvent under the action of an acid and a reducing agent to obtain a compound 17;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of Compound 17.
The invention also provides a method for synthesizing the compound 18, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out dehydration reaction on the compound 19 and a dehydrating agent to obtain a compound 18;
wherein R is2、R3、R4And R5The definitions of (A) and (B) are as described above; each reaction condition was as described for the method for preparing compound 18.
The invention also provides a method for synthesizing the compound 21, which comprises the following steps: in the presence of a catalyst, carrying out condensation reaction on the compound 22 and ketone to obtain a compound 21;
wherein R is2、R3And R5The definitions of (A) and (B) are as described above; each reaction condition was as described for the method for preparing compound 21.
The present invention also provides a method for the synthesis of compound 22, comprising the steps of: in an aprotic solvent, carrying out a reduction reaction on the compound 23 and a reducing agent to obtain a compound 22;
R3the definition of (a) is as described above; each reaction condition was as described above for the method of preparing compound 22.
The invention also provides a method for synthesizing the compound 23, which comprises the following steps: in an organic solvent and in the presence of alkali, carrying out a reaction of protecting groups on a hydroxyl group of D- (-) -diethyl tartrate 24 and a hydroxyl protecting reagent to obtain a compound 23;
R3the definition of (a) is as described above; each reaction condition was as described for the method for preparing compound 23.
The present invention also provides a process for the preparation of compound 35, comprising the steps of: carrying out a protecting group removing reaction on the compound 34 to obtain a compound 35;
R、R1、R2、R4and R5The definitions of (A) and (B) are as described above; each reaction condition was as described for the method for preparing compound 35.
The present invention also provides a process for the preparation of compound 34, comprising the steps of: carrying out nucleophilic substitution reaction on the compound 33 and an acetylation reagent in a solvent in the presence of alkali to obtain a compound 34;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; each reaction condition is as described above for the method of preparing compound 34.
The present invention also provides a process for the preparation of compound 33, comprising the steps of: carrying out reduction reaction on the compound 32 in an aprotic solvent under the action of an acid and a reducing agent to obtain a compound 33;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those described above for the preparation of compound 33.
The present invention also provides a process for the preparation of compound 32, comprising the steps of: in an organic solvent and in the presence of alkali, carrying out dehydration reaction on the compound 31 and a dehydrating agent to obtain the compound 32;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; each reaction condition is as described above for the method of preparing compound 32.
The present invention also provides a process for the preparation of compound 31, comprising the steps of: carrying out oxidation reaction on the compound 30 in an aprotic solvent in the presence of an oxidant to obtain a compound 31;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; the reaction conditions were the same as those in the above-mentioned preparation of Compound 31The method is described.
The present invention also provides a process for the preparation of compound 30, comprising the steps of: hydrolyzing the compound 29 in a protic solvent in the presence of a base to obtain the compound 30;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; each reaction condition was as described above for the method for preparing the compound 30.
The present invention also provides a process for the preparation of compound 29, comprising the steps of: reacting compound 28 with compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain said compound 29;
wherein R is1、R2、R4And R5The definitions of (A) and (B) are as described above; each reaction condition was as described for the method for preparing the compound 29 described above.
The present invention also provides a process for the preparation of compound 28, comprising the steps of: in an organic solvent, in the presence of a base and a catalyst, reacting the compound 27 with a hydroxyl protecting group on a hydroxyl protecting reagent to obtain the compound 28;
wherein R is4As defined above; each reaction condition was as described above for the preparation of compound 28.
The present invention also provides a process for the preparation of compound 27, comprising the steps of: carrying out reduction reaction on the compound 26 and a reducing agent in a protic solvent to obtain the compound 27;
wherein R is4Is tert-butyloxycarbonyl; the reaction conditions were the same as those described above for the preparation of compound 27.
The present invention also provides a process for the preparation of compound 26, comprising the steps of: carrying out Michael addition reaction on the compound 11 and methyl pyruvate in an organic solvent in the presence of a catalyst to obtain a compound 26;
wherein R is4The definition of (a) is as described above; each reaction condition is as described above for the method of preparing compound 26.
The present invention also provides compounds 3, 4, 5, 6, 7, 8, 10,12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 having the formula:
wherein R is1Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen; r2And R5Each independently is methyl, ethyl or propyl; r4Is an amino protecting group; the amino protecting group is tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; r3Is a hydroxyl protecting group, and the hydroxyl protecting group is trimethyl siliconA tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triisopropylsilyl group or a methoxymethyl group.
Preferably, R1Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen, R2And R5Each independently is methyl, R4Is tert-butyloxycarbonyl; or R3Is hydrogen, R2And R5Each independently is methyl, R4Is tert-butyloxycarbonyl.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the invention, the room temperature refers to the ambient temperature and is-20 ℃ to 40 ℃.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the synthetic method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, short steps, high total yield, low production cost, good product purity, high chiral purity and good industrial production prospect.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
"dr" in the present invention is an abbreviation for the diapereoisomer ratio in English, indicating the ratio of diastereomers; when the product is a pair of diastereomers, the two data before and after "&" indicate the chemical shift values of the hydrogen or carbon at the same position in the two isomers.
EXAMPLE 1 Synthesis of Compound 10
Nitro Compound 11 (R)4Is tert-butyloxycarbonyl) (38.72g,205.76mmol) was dissolved in dry toluene (13mL), and after adding Jacobsen catalyst (4.01g,10.27mmol) and benzoic acid (5.02g,41.11mmol) in this order, acetone (152.3mL,2056mmol), the reaction was carried out at room temperature for 4 d. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 10 (R) is obtained4Tert-butyloxycarbonyl) (42.6g, 84%, 84% ee). Recrystallizing the product with petroleum ether/ethyl acetate (20: 1) to obtain a compound 10 (R)4T-butyloxycarbonyl) (37.1g, 73% yield, 93% ee). [ alpha ] to]D 20＝+1.83°(c 1.0,CHCl3)；1HNMR(400MHz,CDCl3):δ5.28(d,J＝5.6Hz,1H),4.72(dd,J＝12.4,5.6Hz,1H),4.55(dd,J＝12.4,5.2Hz,1H),4.48(m,1H),2.17(s,3H),1.41(s,9H)；13CNMR(100MHz,CDCl3):δ216.17,154.87,80.47,76.94,45.28,44.08,30.38,28.25；ESI-MS(m/z):269([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c10H18N2NaO5([M+Na]+) 269.11052, Experimental value: 269.11079.
nitro Compound 11 (R)4T-butyloxycarbonyl) (170mg,0.90mmol) was dissolved in anhydrous toluene (30uL), and Jacobsen catalyst (3.5mg,0.009mmol) and benzoic acid (1.1mg,0.009mmol) were added in this order, followed by addition of acetone (670uL,9.034mmol), followed by reaction at room temperature for 4 d. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 10 (R) is obtained4tert-Butoxycarbonyl) (205mg, 92% yield, 70% ee). [ alpha ] to]D 20＝+0.75°(c 1.0,CHCl3)；1HNMR(400MHz,CDCl3):δ5.28(d,J＝5.6Hz,1H),4.72(dd,J＝12.4,5.6Hz,1H),4.55(dd,J＝12.4,5.2Hz,1H),4.48(m,1H),2.17(s,3H),1.41(s,9H)；13CNMR(100MHz,CDCl3):δ216.17,154.87,80.47,76.94,45.28,44.08,30.38,28.25；ESI-MS(m/z):269([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c10H18N2NaO5([M+Na]+) 269.11052, Experimental value: 269.11079.
the preparation of compound 10 is catalyzed by different catalysts, and the reaction conditions are optimized as shown in table 1; the preparation of compound 10 under the catalysis of catalyst 12(Cat.12) and under different organic solvent conditions, the reaction conditions were optimized as shown in Table 2; preparation of compound 10 under catalysis of catalyst 12(cat.12) and under different additive conditions, the reaction conditions were optimized as shown in table 3; . Cat.1, Cat.2 and Cat.3 are commercially available products. Cat.4 can be referred to: j.am.chem.soc.2012,134, 20197; the reported methods were synthesized. Cat.5 can be found in references: angew.chem.int.ed.2012,51,8838; the reported methods were synthesized. Cat.6 can be found in: chem.commun.2012,48,5193; the reported methods were synthesized. Cat.7 can be found in: org.lett.2007,9,599; the reported methods were synthesized. Cat.8 can be referred to: j.am.chem.soc.2006,128, 9624; the reported methods were synthesized. Cat.9 can be referred to: eur.j.org.chem.2010, 1849; the reported methods were synthesized. Cat.10 can be found in: tetrahedron.lett.2010,51, 209; the reported methods were synthesized. Cat.11 can be found in: org.lett.2010,12,1756; the reported methods were synthesized. Cat.12 can be found in: j.am.chem.soc.2006,128, 7170; the reported methods were synthesized; cat.13 can be found in: adv.synth.cat.2012, 354, 740; the reported methods were synthesized.
TABLE 1 Compound 10 Synthesis catalyst screening
Yield calculated from Recovered Starting materials
TABLE 2 Compound 10 Synthesis organic solvent Screen (Cat.12)
| Experiment number | Additive agent | Organic solvent | Temperature of | Time | Yield (%) | ee(％) |
| 1 | Benzoic acid | Benzene and its derivatives | At room temperature | 4d | 78 | 83 |
| 2 | Benzoic acid | Mesitylene | At room temperature | 4d | 84 | 84 |
| 3 | Benzoic acid | Chlorobenzene | At room temperature | 4d | 71 | 84 |
| 4 | Benzoic acid | Trifluorotoluene | At room temperature | 4d | 69 | 84 |
| 5 | Benzoic acid | Phenylmethyl ether | At room temperature | 4d | 77 | 84 |
| 6 | Benzoic acid | N-hexane | At room temperature | 4d | 81 | 78 |
| 7 | Benzoic acid | Ether (A) | At room temperature | 4d | 81 | 82 |
| 8 | Benzoic acid | Methylene dichloride | At room temperature | 4d | 71 | 83 |
| 9 | Benzoic acid | Carbon tetrachloride | At room temperature | 4d | 47 | 83 |
TABLE 3 Compound 10 Synthesis additive screening (Cat.12)
| Experiment number | Additive agent | Organic solvent | Temperature of | Time | Yield (%) | ee(％) |
| 1 | Acetic acid | Toluene | At room temperature | 4 days | 92 | 75 |
| 2 | P-dibenzoic acid | Toluene | At room temperature | 4 days | 84 | 73 |
| 3 | P-hydroxybenzoic acid | Toluene | At room temperature | 4 days | 89 | 79 |
| 4 | P-nitrobenzoic acid | Toluene | At room temperature | 4 days | 87 | 79 |
| 5 | (+) -Camphorsulfonic acid | Toluene | At room temperature | 4 days | 77 | 84 |
| 6 | P-toluenesulfonic acid | Toluene | At room temperature | 4 days | 64 | 84 |
The structure of the catalyst is as follows:
the structure of the Jacobsen catalyst (cat.12) is shown below:
EXAMPLE 2 Compound 8 (R)1Is methoxymethyl, R2And R5Each independently being methyl) synthesis
Compound 9 (R)1Is methoxymethyl, R2And R5Methyl independently of each other) (32.00g,121.82mmol) was dissolved in anhydrous tetrahydrofuran (60mL) for further use. Weighing Compound 10 (R)4T-butyloxycarbonyl) (90.00g,365.50mmol), copper bromide (8.16g,36.55mmol), cesium carbonate (18.00g,54.82mmol), catalyst ligand
(15.60g,36.55mmol) was placed in an egg-shaped flask, anhydrous tetrahydrofuran (1500mL) was added and stirred at room temperature for 4h to yield a small amount of white solid, then Compound 9 (R) was added at 0 deg.C1Is methoxymethyl, R2And R5Each independently is methyl) tetrahydrofuran solution, continuously reacting for 36 hours at 0 ℃, quenching the reaction by saturated ammonium chloride solution, extracting by ethyl acetate, directly performing column chromatography after the solvent is rotated, and obtaining a compound 8 (R) by petroleum ether/ethyl acetate being 4:11Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (56.50g, 80% yield), the catalyst ligand was recovered
(12.10g, yield 78%) with Compound 10 (R)4tert-Butoxycarbonyl) (62.50g, yield 69%).1HNMR(400MHz,CDCl3):δ4.45～4.80(m,7H),4.17～4.22(m,1H),4.00～4.05(m,2H),3.67(m,1H),3.40(m,3H),2.17～2.23(m,1H),1.75～1.85(m,1H),1.50(m,3H),1.42(m,9H),1.39(m,3H)1.33(m,3H)；13C NMR(100MHz,CDCl3):δ155.23,109.60,98.36,96.26,82.74,81.50,76.82,73.19,67.19,65.36,56.09,48.75,38.30,28.13,27.57,25.97,25.23；ESI-MS(m/z):473.3([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c19H34N2NaO10([M+Na]+) 473.21057, Experimental value: 473.21034.
the conditions for the synthesis of compound 8 and the equivalent thereof are shown in tables 4 and 5, and the reaction substrate equivalent thereof is shown in table 6.
TABLE 4 screening of Synthesis catalyst types for Compound 8
a(the ratio of the molar amount of the catalyst to the molar amount of the compound 9 was 0.2)
TABLE 5 screening of Compound 8 Synthesis catalyst equivalents
TABLE 6 screening of reaction substrate equivalents for Compound 8 Synthesis 10
EXAMPLE 3 Compound 7 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 8 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (20g,44.40mmol) was dissolved in anhydrous dichloromethane (3.0L), pyridine (71.5mL,888.00mmol) and thionyl chloride (6.5mL,88.80mmol) were added sequentially at 0 deg.C, reacted for 2h at 0 deg.C, quenched with 18mL of water, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and obtaining a compound 7 (R) by petroleum ether/ethyl acetate (8: 1)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (13.44g, yield 70%) (dr ═ 8: 1). [ alpha ] to]D 20＝+27.95°(c0.75,CHCl3)；1H NMR(Pyridine-d5400MHz) (major isomers): δ 8.24(d, J ═ 8.0Hz,1H),5.14(t, J ═ 7.6Hz,1H),5.04(t, J ═ 9.6,1H),4.69(br,1H),4.62(d, J ═ 10.8Hz,1H),4.65(dd, J ═ 6.4,2.4Hz,2H),4.58(d, J ═ 6.4Hz,1H),4.51(d, J ═ 6.4Hz,1H),4.43(s,1H),4.26(q, J ═ 5.6,1H),4.02(dd, J ═ 8.4,6.0Hz,1H),3.94(dd, J, 8.4,6.4, 3.3H), 3.79(d, 3.19H), 3.79 (H), 3.19H, 3.5H, 1H), 3.9H (s, 1H);13CNMR(100MHz,Pyridine-d5) Delta 156.85,153.21,109.42,99.08,98.91,85.11,79.64,76.84,76.61,76.39,66.91,56.53,51.20,28.84,27.21,25.84, 19.34; ESI-MS (M/z) 455.4([ M + Na ]]+) (ii) a ESI-HRMS (m/z) calculated value: c19H32N2NaO9([M+Na]+) 455.20000, Experimental value: 455.20090.
compound 8 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (100mg,0.22mmol) was dissolved in anhydrous tetrahydrofuran (15mL), triethylamine (92. mu.L, 0.66mmol), DMAP (6mg,0.04mmol) and methanesulfonyl chloride (49. mu.L, 0.22mmol) were sequentially added, and reacted at room temperature for 8 hours,triethylamine (61. mu.L, 0.44mmol), DMAP (4mg,0.03mmol) and methanesulfonyl chloride (28. mu.L, 0.13mmol) were added and the reaction was continued for 4 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and obtaining a compound 7 (R) by petroleum ether/ethyl acetate (8: 1)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (56mg, 58% yield).
Compound 8 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Was t-butyloxycarbonyl) (100mg,0.22mmol) was dissolved in dry toluene (15mL) and Burgess reagent (Burgess reagent means methyl N- (triethyllammonium sulfonyl) carbamate, CAS:29684-56-8) (79mg,0.33mmol) was added and reacted at room temperature for 8 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and obtaining a compound 7 (R) by petroleum ether/ethyl acetate (8: 1)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (41mg, yield 43%).
EXAMPLE 4 Compound 6 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 7 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (10g,23.12mmol) was dissolved in ethyl acetate (1.10L), cooled to 0 deg.C and zinc powder (151g,2312.00mmol) and glacial acetic acid (133mL,2312.00mmol) were added in sequence and the reaction was continued at this temperature overnight. Filtering to remove excessive zinc powder, adding excessive ammonia water into the filtrate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 6(R is petroleum ether/ethyl acetate 2: 1)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (7.91g, yield 85%). [ alpha ] to]D 20＝-15.58°(c 1.0,CHCl3)；1H NMR(CDCl3,400MHz):δ4.96(d,J＝6.8Hz,1H),4.74(d,J＝6.8Hz,1H),4.42(br,1H),4.39(s,1H),4.30(br,1H),4.24(m,1H),4.00～4.30(m,3H),3.67(d,J＝10.0Hz,1H),2.85(t,J＝9.6Hz,1H),1.71(s,3H),1.45(s,9H),1.39(s,3H),1.35(s,3H)；13C NMR(100MHz,CDCl3):δ156.45,152.96,108.00,98.77,98.13,80.37,79.67,77.78,75.02,65.40,56.24,51.80,51.04,28.39,26.40,25.43,19.21；ESI-MS(m/z):403.4([M+H]+) (ii) a ESI-HRMS (m/z) calculated value: c19H35N2O7([M+H]+) 403.24388, Experimental value: 403.24551.
compound 7 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1g,2.31mmol) was dissolved in ethyl acetate (110mL), cooled to 0 deg.C and iron powder (12.95g,231.20mmol) was added in sequence with glacial acetic acid (13.3mL,231.20mmol) and the reaction was continued overnight at this temperature. Filtering to remove excessive iron powder, adding excessive ammonia water into the filtrate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 6(R is petroleum ether/ethyl acetate 2: 1)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (510mg, yield 55%).
Compound 7 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1g,2.31mmol) was dissolved in ethyl acetate (110mL), cooled to 0 deg.C and aluminum powder (6.24g,231.20mmol) was added followed by glacial acetic acid (13.3mL,231.20mmol) and the reaction continued at this temperature overnight. Filtering to remove excessive aluminum powder, adding excessive ammonia water into the filtrate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 6(R is petroleum ether/ethyl acetate 2: 1)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (316mg, yield 34%).
EXAMPLE 5 Compound 5 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 6 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (10g,24.85mmol) was dissolved in dichloromethane (1L), cooled to 0 deg.C and triethylamine (14.0mL,99.40mmol) and acetyl chloride (1.77mL,25.10mmol) were added in sequence and reacted at 0 deg.C for 2 h. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 5 (R) is obtained1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (9.94g, yield 90%). [ alpha ] to]D 20＝+11.14°(c 1.1,CHCl3)；1H NMR(CD3CN,400MHz):δ6.40(d,J＝8.4Hz,1H),5.29(d,J＝6.8Hz,1H),4.63～4.68(m,2H),4.45(s,1H),4.18～4.25(m,3H),4.08(dd,J＝8.8,6.0Hz,1H),4.04(dd,J＝8.8,6.0Hz,1H),3.86(t,J＝9.6Hz,1H),3.80(dd,J＝6.0,1.2Hz,1H),3.35(s,3H),1.88(s,3H),1.73(br,3H),1.42(s,9H),1.39(s,3H),1.33(s,3H)；13C NMR(100MHz,CD3CN):δ170.17,155.64,151.44,107.97,98.17,97.46,78.13,76.13,76.00,75.24,65.79,55.17,49.94,48.19,27.35,25.71,24.21,22.21,18.08；ESI-MS(m/z):467.5([M+Na]+),483.6([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c21H36N2NaO8([M+Na]+) 467.23639, Experimental value: 467.23778.
compound 6 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1g,2.49mmol) was dissolved in pyridine (120mL), acetic anhydride (5mL) was added, and the temperature was raised to 60 ℃ for reaction for 12 hours. Column chromatography was performed directly after solvent rotation to obtain compound 5(0.91g, 82% yield) with petroleum ether/ethyl acetate ratio of 4: 1.
Compound 6 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1g,2.49mmol) was dissolved in piperidine (120mL), acetic anhydride (5mL) was added, and the reaction was allowed to warm to 60 ℃ for 12 h. Column chromatography was performed directly after solvent rotation to obtain compound 5(0.82g, 74% yield) with petroleum ether/ethyl acetate 4: 1.
EXAMPLE 6 Compound 4 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 5 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (1.0g,2.25mmol) was dissolved in anhydrous 1, 4-dioxane (300mL) and selenium dioxide (500mg,4.50mmol) was added. Argon gas is introduced into the solution for 5min to remove oxygen in the solution, and the reaction is carried out for 2h at 70 ℃ under the protection of argon gas. Filtering with a funnel filled with diatomaceous earth, concentrating the filtrate, performing column chromatography, and collecting the filtrate with petroleum ether/ethyl acetate ratio of 1:1 to obtain compound 4 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (515mg, yield 50%). [ alpha ] to]D 20＝+54.55°(c 0.9,CHCl3)；1H NMR(400MHz,CDCl3):δ9.17(s,1H),6.08(d,J＝6.8Hz,1H),5.72(d,J＝2.5Hz,1H),5.14(d,J＝7.2Hz,1H),4.65～4.75(m,3H),4.28～4.38(m,2H),4.07～4.19(m,3H),3.83(d,J＝5.5Hz,1H),3.35(s,3H),1.98(s,3H),1.43(m,9H),1.39(s,3H),1.34(s,3H)；13C NMR(100MHz,CDCl3):δ185.28,170.98,156.00,151.70,118.87,108.82,98.98,80.32,77.08,75.35,66.49,56.24,49.48,48.53,29.67,28.27,26.67,25.16,23.40；ESI-MS(m/z):481.5([M+Na]+),513.6([M+MeOH+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c21H34N2NaO9([M+Na]+) 481.21565, Experimental value: 481.21434.
compound 5 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (1.0g,2.25mmol) was dissolved in anhydrous 1, 4-dioxane (300mL) and selenium dioxide (500mg,4.50mmol) was added. Argon gas is introduced into the solution for 5min to remove oxygen in the solution, and the reaction is carried out for 2h at 100 ℃ under the protection of argon gas. Filtering with a funnel filled with diatomaceous earth, concentrating the filtrate, performing column chromatography, and collecting the filtrate with petroleum ether/ethyl acetate ratio of 1:1 to obtain compound 4 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (309mg, 30% yield).
EXAMPLE 7 Compound 3 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 4 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (1.0g,2.18mmol) was dissolved in tert-butanol (120mL) and water (40mL), 2-methylbutene (40mL) was added followed by sodium dihydrogen phosphate (2.10mg,17.44mmol), and finally sodium chlorite (789mg,8.72mmol) was added. The reaction was carried out at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and collecting the filtrate with dichloromethane/methanol ratio of 8:1 to obtain compound 3 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (827mg, yield 80%). [ alpha ] to]D 20＝+10.12°(c 0.43MeOH)；1H NMR(CD3OD,500MHz):δ5.71(d,J＝2.0Hz,1H),4.73(d,J＝6.5Hz,1H),4.68(d,J＝7.0,1H),4.37～4.46(m,2H),4.29(d,J＝8.4Hz,1H),4.20(dd,J＝6.4,4.8Hz,1H),4.07(dd,J＝7.2,4.8Hz,1H),3.99(t,J＝8.0Hz,1H),3.86(d,J＝5.5Hz,1H),3.38(s,3H),1.97(s,3H),1.44(s,9H),1.40(s,3H),1.34(s,3H)；13C NMR(125MHz,DMSO-d6):δ169.91,162.77,156.09,134.05,128.27,108.20,98.21,78.21,76.94,76.07,75.39,65.91,56.12,50.02,47.71,28.65,26.94,25.64,23.31；ESI-MS(m/z):473.4([M-H]+) ESI-HRMS (m/z): calculated: c21H33N2O10([M-H]+) 473.21407, Experimental value: 473.21467.
EXAMPLE 8 Synthesis of Compound 2(R is hydrogen)
Compound 3 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (100mg,0.211mmol) was dissolved in dichloromethane (100mL), and trifluoroacetic acid (10mL) was added to react at room temperature for 8 h. The system was concentrated to give the trifluoroacetate salt of compound 2(R is hydrogen) (85mg, yield 90%). [ alpha ] to]D 20＝+20.13°(c 0.01,DMSO)；1HNMR(D2O,500MHz):δ5.85(d,J＝2.5Hz,1H),4.35(d,J＝11.0Hz,1H),4.26(dd,J＝10.5,9.5Hz,1H),4.10(dd,J＝9.5,2.5Hz,1H),3.88(ddd,J＝9.0,5.5,3.0Hz,1H),3.76(dd,J＝12.0,3.0Hz,1H),3.57(dd,J＝12.0,5.5Hz,1H),3.46(dd,J＝9.0,1Hz,1H),3.30(s,1H),1.98(s,1H)；13C NMR(125MHz,D2O):δ174.55,164.72,146.71,104.12,77.23,75.73,69.52,62.27,60.32,50.44,45.43,22.13；ESI-MS(m/z):289.2([M-H]+) ESI-HRMS (m/z): calculated: c11H17N2O7([M-H]+) 289.10412, Experimental value: 289.10520.
EXAMPLE 10 Compound 23 (R)3Is tert-butyldimethylsilyl group) synthesis
24g of NaH (24g,0.4mmol, 60% by mass, the mass percentage being the mass of sodium hydride in the total mass of the sodium hydride reagent) was weighed into a 2L three-necked flask, 600mL of N, N-dimethylformamide (DMF, CAS:68-12-2) was added, the mixture was cooled to 0 ℃ and 82.5g of D- (-) -diethyl tartrate 24(82.5g, 0.4mmol) was dissolvedTo the suspension was slowly added dropwise in 200mL of N, N-dimethylformamide (DMF, CAS:68-12-2), and the reaction was completed for about half an hour, whereby the system became clear. TBSCl (tert-butyldimethylsilyl chloride) (60.3g, 0.4mmol) was added to the above solution, and the reaction was allowed to warm to room temperature overnight. Adding saturated NH4Quenching with Cl solution, extracting with ethyl acetate for 3 times, washing with saturated salt solution, drying with anhydrous sodium sulfate, spin-drying, and performing column chromatography to obtain compound 23 (R15: 1)3Tert-butyldimethylsilyl group) (128.2g, yield 80%). [ alpha ] to]D 20＝-29.17°(c 1.0,CHCl3)；1HNMR(400MHz,CDCl3):δ4.50(d,J＝1.6Hz,1H),4.45(dd,J＝10.0,1.6Hz,1H),4.00～4.24(m,4H),3.04(d,J＝10.0Hz,1H),1.20(q,J＝6.8Hz,6H),0.77(s,9H),0.01(s,3H),-1.0(s,3H)；13CNMR(100MHz,CDCl3):δ171.30,170.36,73.59,73.16,61.77,61.34,25.41,18.08,14.05,13.96，-4.84，-5.92；ESI-MS(m/z):343([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c14H28NaO6Si([M+Na]+) 343.1546, Experimental value: 343.15474.
EXAMPLE 11 Compound 22 (R)3Is tert-butyldimethylsilyl group) synthesis
Weighing LiBH4(13.72g, 0.63mmol) in a three-necked flask, 630mL of anhydrous tetrahydrofuran was added, cooled to 0 deg.C, and Compound 23 (R)3Tert-butyldimethylsilyl) (96.13g, 0.3mmol) was dissolved in 200mL, and the solution was slowly added thereto, and the mixture was naturally warmed to room temperature and reacted overnight. Adding saturated NH4After quenching with Cl solution, it was extracted 3 times with ethyl acetate, washed once with saturated brine and dried over anhydrous sodium sulfate. Spin-drying the solvent and column chromatography with dichloromethane/methanol 15:1 to afford compound 22 (R)3Tert-butyldimethylsilyl group) (63.8g, yield 90%). [ alpha ] to]D 20＝-3.68°(c 1.0,CHCl3)；1HNMR(400MHz,CD3CN):δ3.62(m,1H),3.44～3.50(m,2H),3.38～3.41(m,3H),2.77(t,J＝6.0Hz,1H),2.73(t,J＝5.6Hz,1H),2.68(d,J＝6.8Hz,1H),0.81(s,9H),0.01(s,3H),0.00(s,3H)；13CNMR(100MHz,CDCl3):δ72.21,72.10,63.33,62.49,25.73,17.93,-4.62,-5.02.ESI-MS(m/z):259([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c10H24NaO4Si([M+Na]+) 259.13361, Experimental value: 259.13304.
EXAMPLE 12 Compound 21 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl) are disclosed
Become into
Weighing Compound 22 (R)3Is tert-butyl dimethyl silicon base) (31g, 0.131mol) is put into an egg-shaped bottle, and 78.6g of montmorillonite K-10, 31g are added in turn
Molecular sieves and 1500mL of acetone were reacted at room temperature overnight. Filtering with a layer of diatomaceous earth, washing the residue with ethyl acetate for 2 times, and spin-drying the solvent to obtain crude compound 21 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently methyl) (36g, 100% yield). [ alpha ] to]D 20＝+13.65°(c 1.0,CHCl3)；1HNMR(400MHz,CDCl3):δ4.19(q,J＝6.8Hz,1H),3.98(dd,J＝8.0,6.8Hz,1H),3.83(dd,J＝8.4,6.8Hz,1H),3.81(t,J＝5.6Hz,1H),3.63～3.67(m,1H),3.50～3.56(m,1H),2.18(t,J＝6.4Hz,1H),1.42(s,3H),1.34(s,3H),0.89(s,9H),0.10(s,6H)；13CNMR(100MHz,CDCl3):δ109.17,77.12,72.85,65.30,63.64,26.28,25.81,25.11,18.09,-4.68,-4.78.ESI-MS(m/z):299([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c13H28NaO4Si([M+Na]+) 299.16491, Experimental value: 299.16474.
EXAMPLE 13 Compound 20 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently being methyl) synthesis
Weighing Compound 21 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Methyl (45g, 0.163mmol) is added into an egg-shaped bottle, 800mL of anhydrous tetrahydrofuran is added, then the mixture is cooled to 0 ℃, sodium bicarbonate (49.3g, 0.587mmol) is added, then Des-Martin oxidant (CAS:87413-09-0, the name of England is 1,1, 1-triacyloxy-1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one) (82.96g, 0.196mmol) is added, the mixture is naturally raised to room temperature, after the reaction is finished for about 2 hours, a TLC point plate tracks the end of the reaction, silica gel is filled and washed by dichloromethane, filter residue is concentrated and then directly subjected to column chromatography, and petroleum ether/ethyl acetate ═ 20:1 is obtained, and then the compound 20 (R: 20) is obtained (R: 1)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently methyl) (41.15g, 92% yield). [ alpha ] to]D 20＝-22.59°(c 1.0,CHCl3)；1HNMR(400MHz,CDCl3):δ9.68(d,J＝1.2Hz,1H),4.31(m,1H),4.06(dd,J＝8.4,6.8Hz,1H),4.04(dd,J＝4.8,1.2Hz,1H),3.93(dd,J＝8.4,6.0Hz,1H),1.41(s,3H),1.33(s,3H),0.91(s,9H),0.10(s,3H),0.08(s,3H)；13CNMR(100MHz,CDCl3):δ201.88,109.42,77.45,76.11,64.79,25.72,25.38,24.81,17.93,-5.06,-5.40.ESI-MS(m/z):297([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c13H26NaO4Si([M+Na]+) 297.14926, Experimental value: 297.1500.
weighing Compound 21 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Methyl) (45g, 0.163mmol) in an egg-shaped flask, cooling to 0 deg.C after addition of 800mL of anhydrous methylene chloride, adding sodium bicarbonate (49.3g, 0.587mmol), adding dess-Martin oxidant (CAS:87413-09-0, England name 1,1, 1-triacyloxy-1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one) (82.96g, 0.196mmol), naturally raising to room temperature after completion of the reaction for about 2 hours, following the completion of the reaction on a TLC plate, suction filtering the pad silica gel and applying the bis (benzidoxol) -3(1H) -one)Washing the filter residue with chloromethane, concentrating, and performing column chromatography to obtain compound 20 (R) with petroleum ether/ethyl acetate ratio of 20:13Is tert-butyl dimethylsilyl radical, R2And R5Each independently methyl) (42.94g, 96% yield).
EXAMPLE 15 Compound 19 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 10 (R)4t-Butoxycarbonyl) (17.93g,72.9mmol) was dissolved in anhydrous tetrahydrofuran (600mL), and sodium methoxide (790mg,14.6mmol) was added thereto and the mixture was stirred at room temperature for 30 min. Adding 20 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Methyl) (20.01g,72.9mmol) in 300mL tetrahydrofuran and reacted at room temperature for 8 h. Directly performing column chromatography after solvent rotation, recovering raw material 10 (R) with petroleum ether/ethyl acetate ratio of 4:14tert-Butoxycarbonyl) (3.5g, yield 19%) to give compound 19 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (29.3g, 96% yield after recovery of Starting material (brsm: basic on Recovered Starting Materials).1HNMR(400MHz,CDCl3):δ5.12(m,1H),4.83(m,1H),4.27(m,1H),4.08(m,1H),4.00(m,1H),3.93(m,1H),3.72(m,1H),3.61(m,1H),2.73～2.89(m,1H),1.85～2.05(m,1H),1.30～1.44(m,18H),0.87(m,9H),0.08(m,6H)；13CNMR(100MHz,CDCl3):δ154.91,109.14,95.75,84.63,81.68,80.24,73.92,71.40,65.81,48.84,40.50,28.71,26.60,26.23,25.20,18.31,-4.63；ESI-MS(m/z):543([M+Na]+),559([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c23H44N2NaO9Si([M+Na]+) 534.2719, Experimental value: 534.27083.
example 15 was repeated, except that sodium methoxide was replaced by the following base, Compound 19 (R) in the presence of a different base3Is tert-butylDimethylsilyl radical, R2And R5Each independently is methyl, R4T-butoxycarbonyl) as shown in table 7.
TABLE 7 Synthesis of Compound 19 in the Presence of various bases
EXAMPLE 16 Compound 18 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 19 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (130mg,0.25mmol) was dissolved in anhydrous tetrahydrofuran (15mL), triethylamine (174. mu.L, 0.75mmol), 4-Dimethylaminopyridine (DMAP) (7mg,0.05mmol) and methanesulfonyl chloride (56. mu.L, 0.25mmol) were added sequentially and reacted at room temperature for 8h, further triethylamine (90. mu.L, 0.63mmol), 4-Dimethylaminopyridine (DMAP) (4mg,0.03mmol) and methanesulfonyl chloride (28. mu.L, 0.13mmol) were added and the reaction was continued for 4 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 18 (R) with petroleum ether/ethyl acetate ratio of 8:13Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (89mg, yield 71%). [ alpha ] to]D 20＝+9.13°(c 1.0,CHCl3)；1H NMR(CDCl3,400MHz):δ4.89(br,1H),4.35(m,2H),4.56～4.70(m,2H),4.50(s,1H),4.20(d,J＝7.2Hz,1H),4.03(dd,J＝8.0,6.8Hz,1H),3.95(dd,J＝8.4,5.2Hz,1H),4.50(s,1H),3.81(m,3H),3.66(t,J＝8.0Hz,1H),1.76(s,3H),1.42(s,9H),1.40(s,3H),1.30(s,3H),0.90(s,9H),0.12(s,3H),0.08(s,3H)；13CNMR(100MHz,CDCl3):δ154.89,152.88,109.41,96.64,83.12,80.48,77.23,65.83,49.28,26.20,26.63,25.88,25.23,19.15,18.35,-4.51,-4.80；ESI-MS(m/z):503([M+H]+),525([M+Na]+),541([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c23H42N2NaO8Si([M+Na]+) 525.2619, Experimental value: 525.26027.
compound 19 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (28.6g,54.9mmol) was dissolved in anhydrous dichloromethane (1.1L), cooled to 0 deg.C, pyridine (221mL,2746.4mmol) was added and stirred for 30 min. Thionyl chloride (20mL,274.6mmol) was added at this temperature and allowed to spontaneously warm to room temperature for reaction for 2 h. A small amount of sodium hydroxide solid was added to quench the reaction and filtered through celite. Concentrating, and performing column chromatography to obtain compound 18 (R) with petroleum ether/ethyl acetate ratio of 10:13Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (22.4g, yield 81%).
Compound 19 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Was t-butyloxycarbonyl) (130mg,0.25mmol) was dissolved in dry toluene (15mL) and Burgess reagent (Burgess reagent means methyl N- (triethyllammonium sulfonyl) carbamate, CAS:29684-56-8) (91mg,0.38mmol) was added and reacted at room temperature for 8 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 18 (R) with petroleum ether/ethyl acetate ratio of 8:13Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (53mg, yield 43%).
EXAMPLE 17 Compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 18 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1.22g,2.43mmol) was dissolved in dichloromethane (50mL), and zinc powder (6.35g,97.10mmol) and glacial acetic acid (5.55mL,97.10mmol) were added in order to react at room temperature for 18 h. Filtering to remove excessive zinc powder, concentrating the filtrate, performing column chromatography, and collecting the filtrate with petroleum ether/ethyl acetate ratio of 2:1 to obtain compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (1.00g, yield 87%). [ alpha ] to]D 20＝+11.96°(c 1.0,CHCl3)；1H NMR(CDCl3,400MHz):δ4.50(d,J＝7.6Hz,1H),4.35(m,2H),4.07(m,2H),3.94(d,J＝8.0Hz,1H),3.65(t,J＝8.0Hz,1H),3.40(d,J＝8.4Hz,1H),2.93(t,J＝8.8Hz,1H),1.68(s,3H),1.45(s,9H),1.40(s,3H),1.33(s,3H),0.91(s,9H),0.12(s,3H),0.09(s,3H)；13CNMR(100MHz,CDCl3):δ156.41,152.60,109.05,97.39,81.21,79.49,78.24,77.93,66.21,51.39,28.36,26.67,25.92,25.50,19.25,18.36,-4.55,-4.74；ESI-MS(m/z):473([M+H]+) (ii) a ESI-HRMS (m/z) calculated value: c23H45N2O6Si([M+H]+) 473.3056, Experimental value: 473.30414.
compound 18 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1.22g,2.43mmol) was dissolved in dichloromethane (50mL), and zinc powder (159.8m g,2.43mmol) and glacial acetic acid (148uL,2.43mmol) were added in order to react at room temperature for 24 h. Filtering to remove excessive zinc powder, concentrating the filtrate, performing column chromatography, and collecting the filtrate with petroleum ether/ethyl acetate ratio of 2:1 to obtain compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (0.52g, yield 45%).
Compound 18 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1.22g,2.43mmol) was dissolved in dichloromethane (50mL) and iron powder (117.2m g,2.09mmol) was added followed by iceAcetic acid (148uL,2.43mmol) was reacted at room temperature for 24 h. Filtering to remove excessive iron powder, concentrating the filtrate, performing column chromatography, and collecting the filtrate with petroleum ether/ethyl acetate ratio of 2:1 to obtain compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (0.64g, yield 55%).
Compound 18 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1.22g,2.43mmol) was dissolved in dichloromethane (50mL), and aluminum powder (27.2mg,1.01mmol) and glacial acetic acid (148uL,2.43mmol) were added in order to react at room temperature for 24 h. Filtering to remove excessive iron powder, concentrating the filtrate, performing column chromatography, and collecting the filtrate with petroleum ether/ethyl acetate ratio of 2:1 to obtain compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (0.64g, yield 55%).
EXAMPLE 18 Compound 16 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1.24g,2.62mmol) was dissolved in pyridine (120mL), acetic anhydride (5mL) was added, and the reaction was allowed to warm to 60 ℃ for 12 h. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 16 (R) is obtained3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (1.20g, yield 89%) [ alpha. ]]D 20＝+4.4°(c 1.0,CHCl3)；1H NMR(CDCl3,400MHz):δ6.06(d,J＝7.6Hz,1H),5.35(d,J＝8.0Hz,1H),4.47(d,J＝1.6Hz,1H),4.04～4.21(m,3H),3.91～3.99(m,3H),3.72(t,J＝8.0Hz,1H),1.96(s,3H),1.73(s,3H),1.42(s,12H),1.36(s,3H),0.90(s,9H),0.10(s,3H),0.09(s,3H)；13CNMR(100MHz,CDCl3):δ170.45,156.24,152.34,108.85,96.62,79.76,79.42,78.03,75.16,65.86,49.43,49.14,28.34,26.69,25.97,25.80,23.38,19.43,18.30,-4.479；ESI-MS(m/z):537([M+Na]+),553([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c25H46N2NaO7Si([M+Na]+) 537.2976, Experimental value: 537.29665.
compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1.24g,2.62mmol) was dissolved in pyridine (120mL), and acetic anhydride (5mL) was added and reacted at 25 ℃ for 12 hours. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 16 (R) is obtained3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (0.43g, yield 32%).
Compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1.24g,2.62mmol) was dissolved in piperidine (120mL), acetic anhydride (5mL) was added, and the reaction was allowed to warm to 60 ℃ for 12 h. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 16 (R) is obtained3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (0.74g, yield 74%).
Compound 17 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1.24g,2.62mmol) was dissolved in dichloromethane (120mL), triethylamine (1.82mL,13.10mmol) and acetyl chloride (0.28mL,3.92mmol) were added, and the temperature was raised to 25 ℃ for 12 h. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 16 (R) is obtained3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (0.84g, yield 64%).
EXAMPLE 19 Compound 15 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 16 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1.20g,2.33mmol) was dissolved in anhydrous tetrahydrofuran (100mL), and a solution of tetrabutylammonium fluoride (1M/L) in tetrahydrofuran (3.5mL) was added and reacted at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 15 (R) with petroleum ether/ethyl acetate ratio of 4:13Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (813mg, yield 87%). [ alpha ] to]D 20＝+15.96°(c 1.0,CHCl3)；1H NMR(CD3OD,400MHz):δ6.32(br,1H),5.08(br,1H),4.49(s,1H),4.00～4.21(m,3H),3.82(m,1H),3.75(t,J＝8.0Hz,1H),3.68(m,1H),3.46(br,1H),1.94(s,3H),1.70(s,3H),1.38(s,12H),1.33(s,3H)；13CNMR(100MHz,CD3OD):δ173.43,158.06,153.18,110.18,98.10,80.23,79.41,77.76,72.20,67.41,50.64,28.84,26.77,26.00,22.92,19.80；ESI-MS(m/z):423([M+Na]+),439([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c19H32N2NaO7([M+Na]+) 423.2106, Experimental value: 423.21017.
compound 16 (R)3Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1.20g,2.33mmol) was dissolved in anhydrous tetrahydrofuran (100mL), and potassium fluoride (1.35g,2.66mmol) was added and reacted at room temperature for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain compound 15 (R) with petroleum ether/ethyl acetate ratio of 4:13Is tert-butyl dimethylsilyl radical, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (387mg, yield 41%).
EXAMPLE 20 Compound 14 (R)2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 15 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (400mg,1.00mmol) was dissolved in anhydrous dichloromethane (60mL) and acetonitrile (6mL) and added
Molecular sieves (200mg) and N-methylmorpholine oxide (203mg,1.50mmol) were stirred for 3min, ammonium tetra-N-propylperruthenate (TPAP) (35mg,0.10mmol) was added and the reaction was allowed to proceed at room temperature for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and collecting petroleum ether/ethyl acetate 1:1 to obtain compound 14 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (238mg, yield 64%). [ alpha ] to]D 20＝-11.84°(c 1.0,CHCl3)；1H NMR(CDCl3,400MHz):δ5.92(d,J＝6.4Hz,1H),4.79(t,J＝6.8Hz,1H),4.67(d,J＝4.8Hz,1H),4.99(d,J＝3.2Hz,1H),4.45(br,2H),4.28(t,J＝8.4Hz,1H),4.28(t,J＝8.4Hz,1H),4.08(dd,J＝8.4,6.8Hz,1H),4.05(br,1H),1.94(s,3H),1.84(s,3H),1.49(s,3H),1.39(s,12H),1.38(s,3H)；13CNMR(100MHz,CDCl3):δ202.86,170.23,155.58,153.60,112.13,95.29,80.19,78.32,66.17,49.59,47.10,29.67,28.25,25.62,25.22,23.10,19.62；ESI-MS(m/z):399([M+H]+),421([M+Na]+),437([M+K]+) ESI-HRMS (m/z) calculated value: c19H30N2NaO7([M+Na]+) 421.1962, Experimental value: 421.19452.
compound 15 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (400mg,1.00mmol) was dissolved in anhydrous dichloromethane (60 m)L), Dess-Martin oxidant (CAS:87413-09-0, British name 1,1, 1-triacyloxy-1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one) (636mg,1.5mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and collecting petroleum ether/ethyl acetate 1:1 to obtain compound 14 (R)2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (130mg, yield 35%).
EXAMPLE 21 Compound 13 (R)2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 14 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (160mg,0.40mmol) was dissolved in anhydrous 1, 4-dioxane (30mL) and selenium dioxide (90mg,0.80mmol) was added. Argon gas is introduced into the solution for 5min to remove oxygen in the solution, and the reaction is carried out for 4h at 130 ℃ under the protection of argon gas. Concentrating the system, performing column chromatography directly, and obtaining a compound 13 (R) by petroleum ether/ethyl acetate 1:12And R5Each independently is methyl, R4tert-Butoxycarbonyl) (74mg, yield 45%). [ alpha ] to]D 20＝+32.93°(c 1.0,CHCl3)；1H NMR(CDCl3,400MHz):δ9.24(d,J＝7.6Hz,1H),6.10(d,J＝8.4Hz,1H),5.82(d,J＝4.0Hz,1H),4.79～4.94(m,3H),4.63(m,1H),4.43(br,1H),4.27(t,J＝8.4Hz,1H),4.07(dd,J＝8.4,6.4Hz,1H),1.96(s,3H),1.49(s,3H),1.42(s,9H),1.38(s,3H)；13CNMR(100MHz,CDCl3):δ203.01,185.39,170.51,155.50,151.34,118.43,111.28,80.60,79.42,78.58,65.93,48.84,47.33,28.24,25.62,24.99,22.96；ESI-MS(m/z):413([M+H]+),435([M+Na]+),467([M+MeOH+Na]+),483([M+MeOH+K]+) (ii) a ESI-HRMS (m/z) calculated value: c19H28N2NaO8([M+Na]+) 435.1738, Experimental value: 435.1754.
compound 14 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (160mg,0.40mmol) was dissolved in anhydrous 1, 4-dioxane (30mL) and selenium dioxide (90mg,0.80mmol) was added. Argon gas is introduced into the solution for 5min to remove oxygen in the solution, and the reaction is carried out for 4h at 100 ℃ under the protection of argon gas. Concentrating the system, performing column chromatography directly, and obtaining a compound 13 (R) by petroleum ether/ethyl acetate 1:12And R5Each independently is methyl, R4tert-Butoxycarbonyl) (102mg, yield 62%).
EXAMPLE 22 Compound 12 (R)2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 13 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (74mg,0.18mmol) was dissolved in tert-butanol (15mL) and water (5mL), 2-methylbutene (0.3mL) was added followed by sodium dihydrogen phosphate (223mg,1.43mmol), and finally sodium chlorite (65mg,0.72 mmol). The reaction was carried out at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and collecting petroleum ether/ethyl acetate 1:1 to obtain compound 12 (R)2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (48mg, yield 63%). [ alpha ] to]D 20＝+24.52°(c 1.0,Acetone)；1H NMR(Acetone-d6,400MHz):δ7.18(d,J＝7.6Hz,1H),5.75(br,1H),4.78(dd,J＝7.6,6.8Hz,1H),4.76(d,J＝7.6Hz,1H),4.35(q,J＝7.2Hz,1H),4.23(m,1H),4.18(t,J＝8.4Hz,1H),3.99(dd,J＝8.4,6.4Hz,1H),1.76(s,3H),1.29(s,12H),1.22(s,3H)；13CNMR(Acetone-d6,100MHz):δ201.72,169.06,161.70,154.92,143.77,110.01,109.05,79.30,78.27,77.56,65.27,47.75,46.80,27.13,24.60,24.29,21.52；ESI-MS(m/z):427([M-H]-) ESI-HRMS (m/z): calculated: c19H28N2NaO9([M+Na]+) 451.1687, Experimental value: 451.1670. example 23 Compounds3(R1Is hydrogen, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 12 (R)2And R5Each independently is methyl, R4T-butyloxycarbonyl) (12mg,0.028mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and a solution of zinc borohydride in tetrahydrofuran (0.5M) (100uL) was added and reacted at room temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and collecting petroleum ether/ethyl acetate 1:1 to obtain compound 3 (R)1Is hydrogen, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (9mg, 75%).
Compound 12 (R)2And R5Each independently is methyl, R4T-butyloxycarbonyl) (12mg,0.028mmol) was dissolved in anhydrous tetrahydrofuran (5mL), placed in a-78 ℃ cold bath, added slowly dropwise to a prepared solution of lithium aluminum hydride (0.21mmol) in tetrahydrofuran, and the reaction was continued at that temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography (dichloromethane/methanol/water 100: 20:1) to obtain compound 3 (R)1Is hydrogen, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (9.6mg, yield 80%).
[α]D 20＝+22.56°(c 0.03,CHCl3)；1H NMR(CD3OD,400MHz):δ5.58(s,1H),4.32(d,J＝10.0Hz,1H),4.24(m,1H),4.01～4.05(m,2H),3.86～3.94(m,2H),3.44(d,J＝8.4Hz,1H),1.87(s,3H),1.33(s,9H),1.26(s,3H),1.22(s,3H)；13CNMR(100MHz,CD3OD):δ174.14,169.50,157.74,148.50,110.52,106.26,81.15,75.72,74.18,69.17,66.64,49.11,48.32,27.56,25.88,24.20,22.03；ESI-MS(m/z):429([M-H]+) ESI-HRMS (m/z): calculated: c19H30N2NaO9([M+Na]+) 453.1844, Experimental value: 453.1843.
synthesis of Compound 3 under different reducing agent conditions
Example 23 was repeated, except that the following reducing agents were used instead of zinc borohydride, and the experimental results are shown in table 8 below:
TABLE 8 Synthesis of Compound 3 with different reducing Agents
| Reducing agent | NaBH4 | KBH4 | LiBH4 | Mg(BH4)2 |
| Time | 4h | 4h | 4h | 4h |
| Yield (%) | 52 | 45 | 32 | 63 |
EXAMPLE 24 Synthesis of Compound 2(R is hydrogen)
Compound 3 (R)1Is hydrogen, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (9mg,0.007mmol) was dissolved in dichloromethane (1.5mL), and trifluoroacetic acid (0.1mL) was added to react at room temperature for 8 h. Water (10uL) was added and the reaction was allowed to proceed at room temperature for 1 h. The system was concentrated to give the trifluoroacetate salt of compound 2(R is hydrogen) (10mg, yield 90%). [ alpha ] to]D 20+20.13 ° (c0.01, DMSO). Adding sodium hydroxide solution to adjust pH to alkalescence to obtain compound 2(R is hydrogen).1HNMR(D2O,400MHz):δ5.71(d,J＝2.4Hz,1H),4.38(m,2H),4.20(d,J＝8.0Hz,1H),3.99(ddd,J＝9.6,6.0,2.4Hz,1H),3.93(dd,J＝12.0,2.4Hz,1H),3.71(d,J＝9.6Hz,1H),3.69(dd,J＝11.6,6.0Hz,1H),2.12(s,3H)；13CNMR(100MHz,D2O):δ174.9,168.8,150.2,101.8,75.2,69.8,68.0,62.2,50.1,46.8,22.2；ESI-MS(m/z):291([M+H]+),313([M+Na]+),329([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c11H18N2NaO7([M+Na]+) 313.1006, Experimental value: 313.1012.
EXAMPLE 25 Synthesis of Zanamivir
Compound 2(R is hydrogen) (19mg,0.056mmol) is dissolved in water (1.5mL) and potassium carbonate (4.5mg,0.056mmol) and sulfur trioxide urea (4.1mg,0.056mmol) are added sequentially every 0.5h for a total of 12 additions. The reaction was carried out at room temperature for 36 h. After concentration and filtration, the filtrate was separated by HPLC to give the product (10mg, yield 50%).1H NMR(D2O,500MHz):δ5.65(d,J＝2.5Hz,1H),4.47(dd,J＝9.5,2.5Hz,1H),4.40(dd,J＝10,1.5Hz,1H),4.25(t,J＝10.0Hz,1H),3.97(ddd,J＝9.5,6.5,3.0Hz,1H),3.91(dd,J＝11.5,2.5Hz,1H),3.70(dd,J＝9.0Hz,1H),3.67(dd,J＝12.0,6.5Hz,1H),2.06(s,3H)；ESI-MS(m/z):333.3([M+H]+) Calculating a value: c12H21N4NaO7([M+Na]+) 333.14048, Experimental value: 333.14077.
EXAMPLE 26 Compound 8 (R)1Is methyl) synthesis
Compound 9 (R)1Is methyl, R2And R5Methyl each independently) (7.00g,40.19mmol) was dissolved in anhydrous tetrahydrofuran (20mL) for use. Weighing Compound 10 (R)4T-butyloxycarbonyl) (49.20g,199.79mmol), copper bromide (2.68g,12.00mmol), cesium carbonate (5.86g,12.00mmol), catalyst ligand
(5.13g,12.00mmol) was placed in an egg-shaped flask, anhydrous tetrahydrofuran (500mL) was added and stirred at room temperature for 4h to yield a small amount of white solid, and then Compound 10 (R) was added at 0 deg.C4T-butyloxycarbonyl) tetrahydrofuran solution, reacting at 0 deg.C for 36 hr, quenching with saturated ammonium chloride solution, extracting with ethyl acetate, performing column chromatography, and collecting petroleum ether/ethyl acetate 4:1 to obtain compound 8 (R)1Is methyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (14.12g, 78%) and the catalyst ligand recovered
(4.10g, 80%) with Compound 10 (R)4tert-Butoxycarbonyl) (41.50g, 84% yield).1HNMR(400MHz,CDCl3):δ4.55～4.80(m,4H),3.94～4.18(m,4H),3.41～3.55(m,3H),3.37(br,1H),2.65～2.80(m,1H),2.17～2.24(m,1H),1.48(m,3H),1.35～1.46(m,12H),1.33(m,3H)；13C NMR(100MHz,CDCl3):δ155.04,108.16,96.03,86.00,80.23,78.29,77.09,70.70,65.14,61.75,48.17,40.33,28.53,28.07,26.36,25.20；ESI-MS(m/z):443.4([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c18H32N2NaO9([M+Na]+) 443.2000, Experimental value: 443.19987.
the catalyst species screening in the synthesis of compound 8 is shown in table 9, and the catalyst equivalent screening is shown in table 10; the equivalent screening for compound 10 is shown in table 11.
TABLE 9 screening of Synthesis catalyst types for Compound 8
(the molar percentage of the catalyst was 20%)
TABLE 10 screening of Compound 8 Synthesis catalyst equivalents
TABLE 11 screening of equivalents of Compound 10 in the Synthesis of Compound 8
EXAMPLE 27 Compound 7 (R)1Is methyl) synthesis
Compound 8 (R)1Is methyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (11.57g,27.53mmol) was dissolved in anhydrous dichloromethane (1.5L), pyridine (110.82mL,1376.50mmol) and thionyl chloride (10mL,137.65mmol) were added sequentially at 0 deg.C, reacted for 2h at 0 deg.C, quenched with 15mL of water, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and obtaining a compound 7 (R) by petroleum ether/ethyl acetate (8: 1)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (8.36g, yield 76%) (d: r is 8: 1). [ alpha ] to]D 20＝+31.20°(c 0.2,CHCl3)；1H NMR(Pyridine-d5,400MHz):δ8.52(d,J＝8.4Hz,1H),5.45(dd,J＝9.6,8.0Hz,1H),5.31(t,J＝9.6,1H),4.75(d,J＝10.0Hz,1H),4.70(s,1H),4.48(m,1H),4.20(dd,J＝6.4,2.4Hz,1H),3.74(d,J＝3.6,1H),3.50(s,3H),1.69(s,3H),1.50(s,9H),1.48(s,3H),1.41(s,3H)；13CNMR(100MHz,Pyridine-d5):δ156.85,153.24,109.04,98.89,85.74,79.66,79.08,77.23,77.16,66.43,61.79,51.00,28.83,27.18,25.80,19.27；ESI-MS(m/z):425.5([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c18H30N2NaO8([M+Na]425.1894, experimental value: 425.1900.
compound 8 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (100mg,0.24mmol) was dissolved in anhydrous tetrahydrofuran (15mL), triethylamine (100. mu.L, 0.72mmol), DMAP (7mg,0.04mmol) and methanesulfonyl chloride (53. mu.L, 0.24mmol) were added sequentially and reacted at room temperature for 8h, and triethylamine (66. mu.L, 0.48mmol), DMAP (4mg,0.03mmol) and methanesulfonyl chloride (31. mu.L, 0.14mmol) were added and the reaction was continued for 4 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and obtaining a compound 7 (R) by petroleum ether/ethyl acetate (8: 1)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (44mg, yield 46%).
Compound 8 (R)1Is methyl, R2And R5Each independently is methyl, R4Was t-butyloxycarbonyl) (100mg,0.24mmol) was dissolved in dry toluene (15mL) and Burgess reagent (Burgess reagent means methyl N- (triethyllammonium sulfonyl) carbamate, CAS:29684-56-8) (86mg,0.36mmol) was added and reacted at room temperature for 8 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, performing column chromatography, and obtaining a compound 7 (R) by petroleum ether/ethyl acetate (8: 1)1Is methyl, R2And R5Each independently is methyl，R4tert-Butoxycarbonyl) (41mg, yield 43%).
EXAMPLE 28 Compound 6 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 7 (R)1Is methyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (8.36g,20.773mmol) was dissolved in ethyl acetate (1L), cooled to 0 deg.C and then reacted at room temperature for 18h with zinc powder (135.80g,2077.30mmol) and glacial acetic acid (118.80mL,2077.30mmol) in that order. Filtering to remove excessive zinc powder, concentrating the filtrate, performing column chromatography, and collecting the extract with petroleum ether/ethyl acetate ratio of 2:1 to obtain compound 6 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (5.91g, yield 76%). [ alpha ] to]D 20＝+29.63°(c 2.0,CHCl3)；1H NMR(CDCl3,400MHz):δ4.47(d,J＝8.8Hz,1H),4.31(s,1H),4.21～4.26(m,2H),3.95～4.05(m,4H),3.70(d,J＝10.0Hz,1H),2.81(t,J＝9.6Hz,1H),1.67(s,3H),1.42(s,9H),1.41(s,3H),1.33(s,3H)；13C NMR(100MHz,CDCl3):δ156.53,153.15,108.15,97.72,80.17,79.64,77.87,77.23,65.70,61.42,52.75,51.44,28.37,26.52,25.29,19.24；ESI-MS(m/z):373.3([M+H]+) (ii) a ESI-HRMS (m/z) calculated value: c18H33N2O6([M+H]373.2335, experimental value: 373.2333.
compound 7 (R)1Is methyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1g,2.48mmol) was dissolved in ethyl acetate (110mL), cooled to 0 deg.C and iron powder (13.88g,247.71mmol) was added followed by glacial acetic acid (14.2mL,248mmol) and the reaction was continued overnight at this temperature. Filtering to remove excessive iron powder, adding excessive ammonia water into the filtrate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 6 with petroleum ether/ethyl acetate ratio of 2:1(R1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (622mg, yield 65%).
Compound 7 (R)1Is methyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1g,2.48mmol) was dissolved in ethyl acetate (110mL), cooled to 0 deg.C and aluminum powder (6.70g,248mmol) was added followed by glacial acetic acid (14.2mL,248mmol) and the reaction was continued overnight at this temperature. Filtering to remove excessive aluminum powder, adding excessive ammonia water into the filtrate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 6(R is petroleum ether/ethyl acetate 2: 1)1Is methyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (412mg, yield 43%).
EXAMPLE 29 Compound 5 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 6 (R)1Is methyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (5.91g,15.87mmol) was dissolved in dichloromethane (1L), cooled to 0 deg.C and then triethylamine (8.82mL,62.83mmol) and acetyl chloride (1.11mL,15.87mmol) were added in sequence and reacted at 0 deg.C for 2 h. After solvent rotation, column chromatography is carried out directly, petroleum ether/ethyl acetate is 4:1, and the compound 5 (R) is obtained1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (5.81g, yield 88%). [ alpha ] to]D 20＝-1.43°(c 1.0,CHCl3)；1H NMR(CD3CN,400MHz):δ6.55(d,J＝7.6Hz,1H),5.32(d,J＝8.4Hz,1H),4.42(s,J＝1.6Hz,1H),4.20(m,2H),4.02～4.07(m,2H),3.93～3.99(m,2H),3.61(d,J＝4.0Hz,1H),3.43(s,3H),1.90(s,3H),1.70(s,3H),1.42(s,9H),1.40(s,3H),1.32(s,3H)；13C NMR(100MHz,CD3CN):δ171.06,156.88,152.75,108.71,98.75,79.34,78.91,77.98,77.91,66.29,61.63,51.17,49.33,28.56,26.77,25.51,23.39,19.24；ESI-MS(m/z):437.4([M+Na]+),453.5([M+K]+) (ii) a ESI-HRMS (m/z) calculated value: c20H34N2NaO7([M+Na]+) 437.2269, Experimental value: 437.2264.
compound 6 (R)1Is methyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (1g,2.67mmol) was dissolved in pyridine (120mL), acetic anhydride (5mL) was added, and the reaction was allowed to warm to 60 ℃ for 12 h. Column chromatography was performed directly after solvent rotation to obtain compound 5(0.88g, 74% yield) with petroleum ether/ethyl acetate 4: 1.
Compound 6 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (1g,2.67mmol) was dissolved in piperidine (120mL), acetic anhydride (5mL) was added, and the reaction was allowed to warm to 60 ℃ for 12 h. Column chromatography was performed directly after solvent rotation to obtain compound 5(1.02g, 86% yield) with petroleum ether/ethyl acetate 4: 1.
EXAMPLE 30 Compound 4 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 5 (R)1Is methyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (5.81g,14.02mmol) was dissolved in anhydrous 1, 4-dioxane (1L) and selenium dioxide (3.11g,28.04mmol) was added. Argon gas is introduced into the solution for 5min to remove oxygen in the solution, and the reaction is carried out for 2h at 75 ℃ under the protection of argon gas. Concentrating the system, performing column chromatography directly, and obtaining a compound 4 (R) by petroleum ether/ethyl acetate (1: 1)1Is methyl, R2And R5Each independently is methyl, R4T-butyloxycarbonyl) (3.12g, yield 52%). [ alpha ] to]D 20＝+48.01°(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3):δ9.15(s,1H),6.09(d,J＝9.6Hz,1H),5.68(d,J＝2.0Hz,1H),5.15(d,J＝9.2Hz,1H),4.56(td,J＝9.6,2.0Hz,1H),4.27～4.37(m,2H),4.19(dd,J＝8.8,6.0Hz,1H),4.13(d,J＝10.4Hz,1H),4.02(dd,J＝8.8,6.0Hz,1H),3.60(d,J＝4.4Hz,1H),3.49(s,3H),2.01(s,3H),1.43(m,12H),1.34(s,3H)；13C NMR(100MHz,CDCl3):δ185.16,170.66,156.34,151.89,118.76,108.43,80.28,78.12,78.04,65.93,61.47,50.13,48.02,28.32,26.56,25.26,23.31；ESI-MS(m/z):451.4([M+Na]+),467.4([M+K]+),483.3([M+MeOH+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c20H32N2NaO8([M+Na]+) 451.2051, Experimental value: 451.20509.
compound 5 (R)1Is methyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (5.81g,14.02mmol) was dissolved in anhydrous 1, 4-dioxane (1L) and selenium dioxide (3.11g,28.04mmol) was added. Argon gas is introduced into the solution for 5min to remove oxygen in the solution, and the reaction is carried out for 2h at 100 ℃ under the protection of argon gas. Concentrating the system, performing column chromatography directly, and obtaining a compound 4 (R) by petroleum ether/ethyl acetate (1: 1)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (1.32g, yield 22%).
EXAMPLE 31 Compound 3 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 4 (R)1Is methyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (2.33g,5.44mmol) was dissolved in tert-butanol (180mL) and water (60mL), 2-methylbutene (20mL) was added followed by sodium dihydrogen phosphate (5.25g,43.76mmol), and finally sodium chlorite (1.98g,21.89mmol) was added. The reaction was carried out at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate, and performing column chromatography to obtain petroleum ether/ethyl acetate (1: 1)Compound 3 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (2.13g, yield 95%). [ alpha ] to]D 20＝+42.60°(c 0.25,DMSO)；1H NMR(CD3OD,500MHz):δ5.57(d,J＝2.5Hz,1H),4.35～4.45(m,2H),4.23(dd,J＝9.0,6.0Hz,1H),4.16(d,J＝9.5Hz,1H),4.06(t,J＝9.5Hz,1H),4.04(dd,J＝9.0,7.5Hz,1H),3.67(d,J＝2.5Hz,1H),3.49(s,3H),1.98(s,3H),1.44(s,9H),1.41(s,3H),1.34(s,3H)；13C NMR(125MHz,DMSO-d6):δ169.57,163.57,156.11,145.00,111.10,107.72,78.31,77.93,77.65,77.48,65.35,61.26,49.46,47.50,28.63,26.81,25.80,23.29.ESI-MS(m/z):443.7([M-H]-) ESI-HRMS (m/z): calculated: c20H32N2NaO9([M+Na]+) 467.2000, Experimental value: 467.2004.
EXAMPLE 32 Synthesis of Compound 2(R is methyl)
Compound 3 (R)1Is methyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (100mg,0.225mmol) was dissolved in dichloromethane (20mL), and trifluoroacetic acid (2mL) was added and reacted at room temperature for 2 h. Water (0.1mL) was added and the reaction was carried out at room temperature for 1 h. The system was concentrated to give compound 2(R is methyl) as a trifluoroacetate salt (129mg, yield 100%). [ alpha ] to]D 20＝+0.33°(c 1.3,MeOH)；1H NMR(D2O,500MHz):δ5.85(d,J＝2.5Hz,1H),4.35(d,J＝11.0Hz,1H),4.26(dd,J＝10.5,9.5Hz,1H),4.10(dd,J＝9.5,2.5Hz,1H),3.88(ddd,J＝9.0,5.5,3.0Hz,1H),3.76(dd,J＝12.0,3.0Hz,1H),3.57(dd,J＝12.0,5.5Hz,1H),3.46(dd,J＝9.0,1Hz,1H),3.30(s,1H),1.98(s,3H)；13C NMR(125MHz,D2O):δ174.55,164.72,146.71,104.12,77.23,75.73,69.52,62.27,60.32,50.44,45.43,22.13；ESI-MS(m/z):305.2([M+H]+) ESI-HRMS (m/z): calculated: c12H21N2O7([M+H]+) 305.1343, Experimental value: 305.1342.
EXAMPLE 33 Compound 26 (R)4Tert-butoxycarbonyl) synthesis
Nitro Compound 11 (R)4T-butyloxycarbonyl) (165.41g,879mmol) was dissolved in chloroform (1500mL), and after adding Jacobsen catalyst (11.45g,29.31mmol) and methyl pyruvate (26.9mL,293mmol), the reaction was carried out at room temperature for 24 hours. Washing the reaction system with saturated sodium bicarbonate solution for 2 times, washing with saturated sodium chloride solution for one time, performing column chromatography after solvent rotation is finished, and obtaining pale yellow solid 26(R is petroleum ether/ethyl acetate 4: 1)4Tert-butyloxycarbonyl) (63.25g, 74% yield, 81% ee). The product was recrystallized from tetrahydrofuran/hexane 1:2 to yield 26 (R) as a white solid4tert-Butoxycarbonyl) (51g, 81% yield, 94% ee)
[α]D 20＝-0.8480°(c 1.0,CHCl3)
1H NMR(400MHz,CDCl3)δ5.15(s,1H),4.85～4.68(m,1H),4.68～4.52(m,2H),3.90(s,3H),3.40～3.20(m,2H),1.43(s,9H)；
13CNMR(126MHz,CDCl3):δ190.92,160.43,154.85,80.86,76.90,53.46,45.12,41.05,28.31(3C)；
ESI-MS(m/z):313.4([M+Na]+),345.3([M+MeOH+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c12H22N2NaO8([M+Na+MeOH]+) 345.1268, Experimental value: 345.1271.
the preparation of compound 26 is catalyzed by different catalysts, and the reaction conditions are optimized as shown in table 1; the preparation of compound 26 under the catalysis of catalyst 12(Cat.12) and under different organic solvent conditions, the reaction conditions were optimized as shown in Table 2; preparation of compound 26 under catalysis of catalyst 12(cat.12) and under different additive conditions, the reaction conditions were optimized as shown in table 3; . Cat.1, Cat.2 and Cat.3 are commercially available products. Cat.4 can be referred to: j.am.chem.soc.2012,134, 20197; the reported methods were synthesized. Cat.5 can be found in references: angew.chem.int.ed.2012,51,8838; the reported methods were synthesized. Cat.6 can be found in: chem.commun.2012,48,5193; the reported methods were synthesized. Cat.7 can be found in: org.lett.2007,9,599; the reported methods were synthesized. Cat.8 can be referred to: j.am.chem.soc.2006,128, 9624; the reported methods were synthesized. Cat.9 can be referred to: eur.j.org.chem.2010, 1849; the reported methods were synthesized. Cat.10 can be found in: tetrahedron.lett.2010,51, 209; the reported methods were synthesized. Cat.11 can be found in: org.lett.2010,12,1756; the reported methods were synthesized. Cat.12 can be found in: j.am.chem.soc.2006,128, 7170; the reported methods were synthesized; cat.13 can be found in: adv.synth.cat.2012, 354, 740; the reported methods were synthesized.
TABLE 1 Compound 26 Synthesis catalyst screening
Yield calculated from Recovered Starting materials
TABLE 2 Synthesis of Compound 26 organic solvent Screen (Cat.12)
TABLE 3 Compound 26 Synthesis additive Screen (Cat.12)
| Experiment number | Additive agent | Organic solvent | Temperature of | Time | Yield (%) | ee(％) |
| 1 | Acetic acid | Chloroform | At room temperature | 2d | 58 | 75 |
| 2 | P-dibenzoic acid | Chloroform | At room temperature | 2d | 24 | 73 |
| 3 | P-hydroxybenzoic acid | Chloroform | At room temperature | 2d | 56 | 79 |
| 4 | P-nitrobenzoic acid | Chloroform | At room temperature | 2d | 47 | 79 |
| 5 | (+) -Camphorsulfonic acid | Chloroform | At room temperature | 2d | 67 | 64 |
| 6 | P-toluenesulfonic acid | Chloroform | At room temperature | 2d | 34 | 68 |
| 7 | - | Chloroform | At room temperature | 2d | 74 | 81 |
The structure of the catalyst is as follows:
the structure of the Jacobsen catalyst (cat.12) is shown below:
EXAMPLE 34 Compound 27 (R)4Tert-butoxycarbonyl) synthesis
Compound 26(5g,17.2mmol) was dissolved in methanol (200mL) and NaBH was added4(260mg,6.87mmol), reacting at room temperature for 10min, adding saturated ammonium chloride, quenching, removing methanol, dissolving in water, extracting with ethyl acetate twice, drying with anhydrous sodium sulfate, and performing spin-drying column chromatography to obtain white solid 27 (R)4Tert-butoxycarbonyl) (4.95g, yield 98%).
1H NMR(500MHz,CDCl3) (pair of diastereomers in a ratio of 1:1) delta 5.28(d, J ═ 7.3Hz,1H)&5.03(d,J＝6.7Hz,1H),4.73～4.51(m,4H),4.48～4.37(m,2H),4.31(dd,J＝13.3,8.0Hz,2H),3.80(s,3H)&3.79(s,3H)3.09(br,2H),2.24～2.04(m,3H),1.91～1.78(m,1H),1.44(s,18H)；
13C NMR(126MHz,CDCl3) (a pair of diastereomers in a ratio of 1:1) delta 174.59&174.38,155.54&155.05,80.53&80.41,78.09,67.53,52.80&52.73,46.57&45.84,36.05&35.34,28.27(3C)&28.24(3C)；
ESI-MS(m/z):315.2([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c11H20N2NaO7([M+Na]+) 315.1163, Experimental value: 315.1166.
compound 26(2.9g,17.2mmol) is dissolved in tetrahydrofuran (100mL) and ZnCl is added2(1.36g,10mmol), stirring at 78 ℃ for 0.5h, adding a tetrahydrofuran solution of lithium tri-sec-butylborohydride (1.0mol/L,11mL), continuing to react at 78 ℃ for 10min, and adding saturated NH4Quenching Cl solution, heating to room temperature, adding a small amount of 1mol/L hydrochloric acid, diluting with water, extracting with ethyl acetate twice, drying with anhydrous sodium sulfate, filtering, concentrating, and performing spin-drying column chromatographyWhite solid 27 (R) is obtained4Tert-butoxycarbonyl) (2.9g, yield 99%, dr ═ 1: 2.7).
1H NMR(500MHz,CDCl3)δ5.28(d,J＝7.3Hz,1H)&5.03(d,J＝6.7Hz,1H),4.73～4.51(m,4H),4.48～4.37(m,2H),4.31(dd,J＝13.3,8.0Hz,2H),3.80(s,3H)&3.79(s,3H)3.09(br,2H),2.24～2.04(m,3H),1.91～1.78(m,1H),1.44(s,18H)；
13C NMR(126MHz,CDCl3)δ174.59&174.38,155.54&155.05,80.53&80.41,78.09,67.53,52.80&52.73,46.57&45.84,36.05&35.34,28.27&28.24；
ESI-MS(m/z):315.2([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c11H20N2NaO7([M+Na]+) 315.1163, Experimental value: 315.1166.
EXAMPLE 35 Compound 28 (R)4Tert-butoxycarbonyl) synthesis
Compound 27 (R)4t-Butoxycarbonyl) (1.8g,6.16mmol) was dissolved in anhydrous tetrahydrofuran (40mL), 4-dimethylaminopyridine (75mg,0.62mmol) was added, acetic anhydride (0.7mL,7.39mmol) was added, triethylamine (2.6mL,18.18mmol) was added, the reaction was carried out at room temperature for 10min, and a colorless oily liquid 28(2.02g, yield 99%) was obtained by spin-column chromatography.
1H NMR(400MHz,CDCl3) (pair of diastereomers at a ratio of 1:1) δ 5.17(t, J ═ 5.5Hz,1H),5.08(dd, J ═ 10.7,2.7Hz,1H),5.06 to 4.96(m,2H),4.68(dd, J ═ 13.1,5.1Hz,1H),4.61 to 4.50(m,3H),4.39 to 4.19(m,2H),3.76(s,3H)&3.74(s,3H)2.29(m,1H),2.15(s,3H)&2.14(s,3H),2.05(m,1H),1.42(s,9H)&1.41(s,9H)；
13C NMR(126MHz,CDCl3) (a pair of diastereomers in a ratio of 1:1) delta 170.26&170.15,170.10&169.71,154.96&154.74,80.78&80.68,78.29&77.59,69.17&68.66,52.84&52.78,46.26&45.69,33.22&32.84,28.36(3C)&28.30(3C),20.70&20.63；
ESI-MS(m/z):357.3([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c13H22N2NaO8([M+Na]+) 357.1268, Experimental value: 357.1273.
compound 27 (R)4t-Butoxycarbonyl) (117mg,0.4mmol) was dissolved in anhydrous dichloromethane (5mL), triethylamine (0.223mL,1.6mmol) was added, acetyl chloride (0.057mL,0.8mmol) was added, the reaction was carried out at room temperature for 24h, and column chromatography was performed to give colorless oily liquid 28(54mg, yield 40%).
EXAMPLE 36 Compound 29 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) is used
Become into
Copper bromide (254mg,1.14mmol), cesium carbonate (555mg,1.70mmol), and catalyst ligand were weighed out
(486mg,1.14mmol) was placed in an egg-shaped flask, anhydrous tetrahydrofuran (50mL) was added and stirred at room temperature for 2h to produce a small amount of white solid, which was then placed in a circulating cooling bath at 0 ℃ and a solution of 28(1.9g,5.68mmol) in anhydrous tetrahydrofuran (25mL) was added followed by a solution of 9(1.19g,6.83mmol) in anhydrous tetrahydrofuran and the reaction was continued at 0 ℃ for 48 h. Quenching reaction with saturated ammonium chloride solution, extracting with ethyl acetate, performing column chromatography to obtain compound 29 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (1.92g, yield 66%).
1H NMR(500MHz,CDCl3)δ5.20(t,J＝5.3Hz,1H),5.12(dd,J＝11.3,2.8Hz,1H),4.99(d,J＝10.3Hz,1H),4.87～4.81(m,4H),4.57(d,J＝5.4Hz,1H),4.54～4.47(m,1H),4.47～4.40(m,1H),4.25～4.19(m,2H),4.13～4.05(m,4H),4.01～3.95(m,2H),3.75(s,3H)&3.74(s,3H),3.53(s,3H)&3.52(s,3H),3.29(m,2H),2.21～2.15(m,1H),2.14(s,3H)&2.12(s,3H),2.07～1.99(m,2H),1.90(m,1H),1.47(s,9H)&1.46(s,9H),1.40(s,3H)&1.39(s,3H),1.33(s,3H)&1.32(s,3H)；
13C NMR(126MHz,CDCl3)δ170.14,170.04,169.79,169.44,157.35&157.14,108.49&108.36,90.07&89.99,82.06,82.04,79.44&79.40,77.02,69.92,69.64,68.71,68.35,66.09&66.06,61.50&61.42,52.81&52.77,46.04&46.03,33.36,28.37,28.27,28.21,26.62,25.38&25.36,20.70&20.51；
ESI-MS(m/z):531.6([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c21H36N2NaO12([M+Na]+) 531.2160, Experimental value: 531.2162.
EXAMPLE 37 Compound 30 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Dissolving compound 29(155mg,0.305mmol) in anhydrous methanol (5mL), adding sodium methoxide (16mg,0.305mmol), reacting at room temperature for 4h, adding saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 30 (R)1Is methyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (70mg, yield 50%) and Compound 29 (R)1Is methyl, R2And R5Each independently is methyl, R4T-butoxycarbonyl) 35 mg.
1H NMR(500MHz,CDCl3)δ4.85(dd,J＝9.8,2.6Hz,1H),4.79(d,J＝10.2Hz,1H),4.71(d,J＝4.9Hz,1H),4.65–4.57(m,1H),4.33(dd,J＝9.2,4.5Hz,1H),4.22(td,J＝6.4,4.7Hz,1H),4.11–4.05(m,2H),3.99(dd,J＝8.5,6.8Hz,1H),3.80(s,3H),3.51(s,3H),3.29(d,J＝4.5Hz,1H),3.13(d,J＝4.0Hz,1H),2.19–2.14(m,1H),1.89(ddd,J＝14.7,10.5,4.5Hz,1H),1.47(d,J＝4.7Hz,9H),1.39(s,3H),1.33(s,3H)；
13C NMR(126MHz,CDCl3)δ174.59&174.41,157.13&155.08,109.17&109.05,108.42&108.28,90.39&89.81,81.65,80.55&80.44,79.51&79.43,78.09,69.67,69.60,67.54,52.79&52.73,45.82,45.36,36.04,35.34,28.26&28.18,26.48&26.38,25.21&25.14.
ESI-MS(m/z):489.5([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c19H34N2NaO11([M+Na]+) 489.2055, Experimental value: 489.2058.
dissolving compound 29(1.2g, 2.36mmol) in anhydrous tetrahydrofuran (120mL), adding cesium carbonate (7.69g,23.6mmol), adding 30% hydrogen peroxide (12mL), stirring at room temperature for 6 hours, adding saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound 30(824mg, yield 75%) (R)1Is methyl, R2And R5Each independently is methyl, R4Is tert-butyloxycarbonyl)
EXAMPLE 38 Compound 31 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 30 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (500mg,1.07mmol) was dissolved in anhydrous dichloromethane (25mL), dess-Martin oxidant (500mg,1.18mmol) was added at-20 deg.C, reaction was carried out for 4h at-20 deg.C, saturated NaHCO was added3Quenching the solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 31 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4tert-Butoxycarbonyl) (433mg, yield 86%).
1H NMR(500MHz,CDCl3)δ4.87-4.83(m,1H),4.74-4.72(m,1H),4.65-4.63(m,2H),4.43(br,1H),4.14-4.11(m,1H),3.96-3.88(m,2H),3.82(s,3H),3.53(s,3H),3.47(s,1H),2.22-2.21(m,2H),1.42(s,9H),1.39(s,3H),1.32(s,3H)；
13C NMR(126MHz,CHCl3)δ169.11,154.65,125.64,108.60,94.43,85.49,80.79,78.34,76.61,71.47,62.05,53.93,30.46,28.29(3C),26.65,25.40.
ESI-MS(m/z):487.5([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c19H32N2NaO11([M+Na]+) 487.1898, Experimental value: 487.1896.
EXAMPLE 39 Compound 32 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 31 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (392mg,0.84mmol) was dissolved in anhydrous dichloromethane (8mL), pyridine (0.55mL,6.85mmol) was added at-10 deg.C, thionyl chloride (1.4mL,1.96mmol) was added, reaction was continued at-10 deg.C for 2h, quenched with water, washed once with a small amount of 1mol/L hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and column chromatographed to give compound 32 (R32)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (200mg, yield 53%).
[α]D 20＝+39.6880°(c 1.0,CHCl3)
1H NMR(500MHz,CD3CN)δ5.88(d,J＝2.2Hz,1H),5.74(s,1H),5.05–4.96(m,1H),4.93(t,J＝9.7Hz,1H),4.56(d,J＝9.6Hz,1H),4.29–4.23(m,1H),4.14(dd,J＝8.8,6.3Hz,1H),3.96(dd,J＝8.8,6.5Hz,1H),3.76(d,J＝2.8Hz,3H),3.47(s,3H),3.43(dd,J＝4.8,1.6Hz,1H),1.39(s,9H),1.36(s,3H),1.30(s,3H).
13C NMR(126MHz,CD3CN)δ162.20,156.02,145.04,111.60,109.15,83.66,80.78,78.78,77.85,76.89,66.33,61.99,53.11,50.47,28.34(3C),26.74,25.45；
ESI-MS(m/z):469.5([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c19H30N2NaO10([M+Na]+) 469.1793, Experimental value: 469.1797.
compound 31 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (20mg,0.043mmol) was dissolved in anhydrous dichloromethane (1mL), triethylamine (30. mu.L, 0.21mmol) was added, methanesulfonyl chloride (12. mu.L, 0.17mmol) was added, the reaction was continued at-10 ℃ for 2h, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and column chromatography was carried out to give compound 32 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (5mg, yield 26%).
EXAMPLE 40 Compound 33 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 32 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4t-Butoxycarbonyl) (38mg,0.085mmol) was dissolved in 2mL of anhydrous ethyl acetate, zinc powder (556mg,8.5mmol) was added, glacial acetic acid (487. mu.L, 8.5mmol) was added, the reaction was allowed to proceed overnight at room temperature, filtered through celite, washed with ethyl acetate, and concentrated column chromatography gave compound 33(28mg, yield 81%) (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Is tert-butoxycarbonyl).
[α]D 20＝+32.8100°(c 1.0,CHCl3)
1H NMR(500MHz,CDCl3)δ5.82(d,J＝2.5Hz,1H),4.53(d,J＝8.6Hz,1H),4.33–4.25(m,2H),4.21(dd,J＝8.8,6.3Hz,1H),4.07(dd,J＝8.7,7.2Hz,2H),3.83(dd,J＝10.1,1.3Hz,1H),3.75(s,3H),3.63(s,3H),2.96(t,J＝9.7Hz,1H),1.55(br,2H),1.46(s,9H),1.45(s,3H),1.37(s,3H).
13C NMR(126MHz,CDCl3)δ162.44,156.41,145.16,110.82,108.27,81.48,77.69,77.56,65.69,61.60,52.35,52.23,50.53,29.82,28.47(3C),26.61,25.44.
ESI-MS(m/z):417.5([M+H]+)；439.5([M+Na]+) (ii) a ESI-HRMS (m/z) calculated value: c19H33N2O8([M+H]+) 417.2235, Experimental value: 417.2231.
EXAMPLE 41 Compound 34 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) synthesis
Compound 33 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (27mg,0.064mmol) was dissolved in anhydrous dichloromethane (3mL), placed in an ice-water bath, triethylamine (38. mu.L, 0.26mmol) was added, acetyl chloride (5. mu.L, 0.077mmol) was added, reaction was carried out in an ice-water bath for 30min, and spin-dry column chromatography gave compound 34 (R)1Is methoxymethyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (27mg, 91% yield);
[α]D 20＝+17.5969°(c0.65,CHCl3)
1H NMR(500MHz,CDCl3)δ5.99(br,1H),5.84(d,J＝1.8Hz,1H),4.99(br,1H),4.47–4.45(m,1H),4.31-4.24(m,2H),4.18(dd,J＝8.7,6.2Hz,1H),4.08-4.04(m,2H),3.75(s,3H),3.66(d,J＝3.3Hz,1H),3.52(s,3H),1.99(s,3H),1.43(s,3H),1.42(s,9H),1.35(s,3H).
13C NMR(126MHz,CDCl3)δ170.63,162.14,156.44,144.81,110.18,108.44,80.34,78.61,77.83,65.87,61.81,52.45,49.99,48.38,29.83,28.43(3C),26.65,25.51,23.50.
ESI-MS(m/z):481.6([M+Na]+) ESI-HRMS (m/z): calculated: c21H34N2NaO9([M+Na]+) 481.2157, Experimental value: 481.2157
EXAMPLE 42 Compound 2 (R)1Is methyl) synthesis
Reacting compound 34 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butyloxycarbonyl) (20mg,0.044mmol) is dissolved in 1mL tetrahydrofuran, sodium hydroxide solution (3mol/L,0.44mL) is added, reaction is carried out at room temperature overnight to obtain intermediate compound 3, hydrochloric acid (3mol/L,0.9mL) is added into the system without post-treatment, reaction is continued for 0.5h, and the system is concentrated to obtain compound 2 (R)1Methyl) (13mg, yield 97.2%).
[α]D 20＝+0.33°(c 1.3,MeOH)
1H NMR(500MHz,D2O)δ6.09(d,J＝2.2Hz,1H),4.61(d,J＝10.7Hz,1H),4.49(t,J＝10.0Hz,1H),4.39(dd,J＝9.5,2.2Hz,1H),4.14-4.11(m,1H),4.00(dd,J＝12.0,2.8Hz,1H),3.81(dd,J＝12.0,5.7Hz,1H),3.71(d,J＝8.3Hz,1H),3.54(s,3H),2.23(s,3H).
13C NMR(126MHz,D2O)δ174.46,163.98,145.90,104.75,77.16,75.72,69.52,62.21,60.22,50.26,45.35,22.03.
ESI-MS(m/z):305.2([M+H]+) ESI-HRMS (m/z): calculated: c12H20N2NaO7([M+Na]+) 327.1163, Experimental value: 327.1160.
reacting compound 34 (R)1Is methyl, R2And R5Each independently is methyl, R4Tert-butoxycarbonyl) (20mg,0.044mmol) is dissolved in 1mL tetrahydrofuran, hydrochloric acid (3mol/L,0.44mL) is added, the mixture reacts for 1h at room temperature to obtain an intermediate 35, sodium hydroxide solution (3mol/L,0.9mL) is added into the system without post-treatment, the reaction is continued for 8h, 3mol/L hydrochloric acid is added to adjust the pH value to 2-3, and the system is concentrated to obtain a compound 2 (R)1Methyl) (13.2mg, yield 98.7%).
Data for Compound 35
[α]D 20＝+1.3240°(c 0.5,MeOH)
1H NMR(500MHz,D2O)δ6.01(d,J＝2.3Hz,1H),4.48(d,J＝10.7Hz,1H),4.38(t,J＝10.1Hz,1H),4.23(dd,J＝9.4,2.4Hz,1H),3.98(m,1H),3.88(dd,J＝12.0,2.5Hz,1H),3.82(s,3H),3.69(dd,J＝12.0,5.4Hz,1H),3.58(d,J＝8.5Hz,1H),3.41(s,3H),2.09(s,3H).
13C NMR(126MHz,D2O)δ174.53,163.07,145.81,104.71,77.17,75.88,69.57,62.22,60.34,53.10,50.33,45.35,22.14.
ESI-MS(m/z):319.4([M+H]+)；341.3([M+Na]+).
EXAMPLE 43 Synthesis of Laninamivir
Compound 2(R is methyl) (19mg,0.056mmol) is dissolved in water (1.5mL) and potassium carbonate (4.5mg,0.056mmol) and sulfur trioxide urea (4.1mg,0.056mmol) are added sequentially every 0.5h for a total of 12 additions. The reaction was carried out at room temperature for 36 h. After concentration and filtration, the filtrate was separated by HPLC to give the product (10mg, yield 50%). [ alpha ] to]D 20＝+8.44°(c0.5,H2O)；1H NMR(D2O,500MHz):δ5.52(d,J＝2.5Hz,1H),4.30(dd,J＝10.0,2.0Hz,2H),4.10(t,J＝9.5Hz,1H),3.88(ddd,J＝8.5,5.5,3.0Hz,1H),3.78(dd,J＝12.0,3.0Hz,1H),3.57(dd,J＝12.0,5.5Hz,1H),3.45(dd,J＝8.5,1.5Hz,1H),3.31(s,3H),1.94(s,3H)；13C NMR(125MHz,D2O):δ174.20,168.97,157.03,149.22,104.13,77.72,75.76,69.61,62.42,60.37,51.65,48.97,47.76,22.13；ESI-MS(m/z):347.8([M+H]+) ESI-HRMS (m/z): calculated: c13H23N4O7([M+H]+) 347.15613, Experimental value: 347.1565.
the trifluoroacetate salt of compound 2(R is methyl) (1.35g,3.23mmol) was dissolved in N, N-dimethylformamide (DMF, CAS:68-12-2) (40mL), and N, N-Diisopropylethylamine DIPEA (CAS:7087-68-5, N-Diisopropylethylamine) (1.7mL,9.70mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (1.42g,9.70mmol) were added every 1 day for a total of 3 times. And reacting at room temperature for 5 d. After addition of water, the mixture was washed with ethyl acetate 3 times, dichloromethane three times, and recrystallized 3 times from methanol/ethyl acetate at a ratio of 1: 8. The product was obtained (1.12g, yield 100%).
Laninavir octanoate CS-8958 can be synthesized by esterification of Laninavir with a reference to the patent (WO 2008/126943).
Claims (11)
1. A method of synthesizing compound 29, comprising the steps of: reacting compound 28 with compound 9 in an aprotic solvent in the presence of a base, a catalyst and a catalyst ligand to obtain compound 29;
wherein R is1Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen; r2And R5Each independently is methyl, ethyl or propyl; r4Is an amino protecting group which is tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.
2. The method according to claim 1, wherein in the method for preparing compound 29, the aprotic solvent is an ether solvent;
and/or, in the method for preparing the compound 29, the volume-to-mass ratio of the aprotic solvent to the compound 9 is 1mL/g to 50 mL/g;
and/or, in the method of making compound 29, the base is an inorganic base;
and/or, in the method for preparing the compound 29, the molar ratio of the compound 9 to the base is 1: 1-5: 1;
and/or, in the method for preparing compound 29, the catalyst is inorganic copper salt;
and/or in the method for preparing the compound 29, the molar ratio of the compound 28 to the catalyst is 1: 1-10: 1;
and/or in the method for preparing the compound 29, the molar ratio of the catalyst ligand to the compound 28 is 1: 10-3: 10;
and/or, in the method for preparing the compound 29, the molar ratio of the compound 28 to the compound 9 is 1: 1-1: 5;
and/or, in the method for preparing the compound 29, the reaction temperature is-20 ℃ to 40 ℃.
3. The method according to claim 2, wherein in the method for preparing compound 29, the aprotic solvent is an ether-based solvent, and the ether-based solvent is tetrahydrofuran;
and/or, in the method for preparing the compound 29, the volume-to-mass ratio of the aprotic solvent to the compound 9 is 10mL/g to 30 mL/g;
and/or, in the method of making compound 29, the base is an inorganic base, the inorganic base is cesium carbonate;
and/or, in the method for preparing the compound 29, the molar ratio of the compound 9 to the base is 2: 1-4: 1;
and/or, in the method for preparing the compound 29, the catalyst is inorganic copper salt, and the inorganic copper salt is one or more of cupric chloride, cuprous bromide, cupric bromide and cuprous iodide;
and/or in the method for preparing the compound 29, the molar ratio of the compound 28 to the catalyst is 2: 1-10: 1;
and/or, in the method for preparing the compound 29, the catalyst ligand is a pyrrolidine-phenol catalyst ligand, and the pyrrolidine-phenol catalyst ligand is
And/or in the method for preparing the compound 29, the molar ratio of the catalyst ligand to the compound 28 is 1: 5-3: 10;
and/or, in the method for preparing the compound 29, the molar ratio of the compound 28 to the compound 9 is 1: 1-1: 2;
and/or, in the method for preparing the compound 29, the reaction temperature is-20 ℃ to 30 ℃.
4. A method for synthesizing compound 28, comprising the steps of: in an organic solvent, in the presence of a base and a catalyst, reacting the compound 27 with a hydroxyl protecting group on a hydroxyl protecting reagent to obtain a compound 28;
R4is an amino protecting group which is tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.
5. The method according to claim 4, wherein in the method for preparing the compound 28, the organic solvent is an ether solvent;
and/or, in the method for preparing the compound 28, the volume-to-mass ratio of the organic solvent to the compound 27 is 1mL/g to 100 mL/g;
and/or, in the method of making compound 28, the base is an organic base;
and/or, in the method for preparing the compound 28, the molar ratio of the base to the compound 27 is 1: 1-3: 1;
and/or, in the method of making compound 28, the catalyst is 4-dimethylaminopyridine;
and/or, in the method for preparing the compound 28, the molar ratio of the catalyst to the compound 27 is 0.01: 1-0.5: 1;
and/or, in the method of making compound 28, the hydroxyl protecting agent is acetic anhydride, acetyl chloride, or acetyl bromide;
and/or, in the method for preparing compound 28, the temperature of the reaction of the hydroxyl protecting group is 0-40 ℃;
and/or, in a method of making compound 28, employing the steps of: adding a catalyst into a solution formed by the compound 27 and an organic solvent, and dropwise adding alkali and a hydroxyl protecting reagent to perform a reaction of a hydroxyl protecting group to obtain the compound 28.
6. The method according to claim 5, wherein in the method for preparing compound 28, the organic solvent is an ether solvent, and the ether solvent is tetrahydrofuran;
and/or, in the method for preparing the compound 28, the volume-to-mass ratio of the organic solvent to the compound 27 is 10mL/g to 50 mL/g;
and/or, in the method for preparing compound 28, the base is an organic base, and the organic base is triethylamine;
and/or, in the method for preparing the compound 28, the molar ratio of the catalyst to the compound 27 is 0.05: 1-0.2: 1;
and/or, in the method of making compound 28, the hydroxyl protecting reagent is acetic anhydride;
and/or, in the method for preparing compound 28, the temperature of the reaction of the hydroxyl protecting group is 10-30 ℃.
7. A method of synthesizing compound 30, comprising the steps of: hydrolyzing compound 29 in a protic solvent in the presence of a base to obtain compound 30;
wherein R is1Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen; r2And R5Each independently is methyl, ethyl or propyl; r4Is an amino protecting group which is tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.
8. The method according to claim 7, wherein in the method for preparing compound 30, compound 29 is prepared according to the method for synthesizing compound 29 according to any one of claims 1 to 3;
and/or, in the method for preparing compound 30, the protic solvent is an alcohol solvent;
and/or, in the method for preparing the compound 30, the volume-to-mass ratio of the protic solvent to the compound 29 is 20mL/g to 300 mL/g;
and/or, in the method for preparing compound 30, the base is potassium carbonate and/or sodium methoxide;
and/or, in the method for preparing the compound 30, the molar ratio of the compound 29 to the base is 3: 1-1: 1;
and/or, in the method for preparing the compound 30, the temperature of the hydrolysis reaction is 0-50 ℃.
9. The method of claim 8, wherein in the method of preparing compound 30, the protic solvent is an alcoholic solvent, and the alcoholic solvent is methanol;
and/or, in the method for preparing the compound 30, the volume-to-mass ratio of the protic solvent to the compound 29 is 30mL/g to 100 mL/g;
and/or, in the method for preparing compound 30, the base is sodium methoxide;
and/or, in the method for preparing the compound 30, the molar ratio of the compound 29 to the base is 2: 1-1: 1;
and/or, in the method for preparing the compound 30, the temperature of the hydrolysis reaction is 20-30 ℃.
10. A compound 28, 29 or 30 having the formula:
wherein R is1Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen; r2And R5Each independently is methyl, ethyl or propyl; r4Is an amino protecting group; the amino protecting group is tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl.
11. The compound 28, 29 or 30 of claim 10, wherein R is1Is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, methyl or hydrogen, R2And R5Each independently is methyl, R4Is tert-butyloxycarbonyl.
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