CN102964267A - Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application - Google Patents
Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application Download PDFInfo
- Publication number
- CN102964267A CN102964267A CN201110257557XA CN201110257557A CN102964267A CN 102964267 A CN102964267 A CN 102964267A CN 201110257557X A CN201110257557X A CN 201110257557XA CN 201110257557 A CN201110257557 A CN 201110257557A CN 102964267 A CN102964267 A CN 102964267A
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- CN
- China
- Prior art keywords
- acetamido
- methyl butyl
- tetrahydrobenzene
- phosphonic acids
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Cyclohexene compound Chemical class 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 241000712461 unidentified influenza virus Species 0.000 title claims abstract description 20
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 102000005348 Neuraminidase Human genes 0.000 title claims description 32
- 108010006232 Neuraminidase Proteins 0.000 title claims description 32
- 230000005764 inhibitory process Effects 0.000 title claims description 9
- 230000000694 effects Effects 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 34
- 206010022000 influenza Diseases 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 81
- 235000002639 sodium chloride Nutrition 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 41
- 229950004288 tosilate Drugs 0.000 claims description 36
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 30
- 150000003009 phosphonic acids Chemical class 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 26
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 22
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 125000005499 phosphonyl group Chemical group 0.000 claims description 14
- 241000700605 Viruses Species 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000005815 base catalysis Methods 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000006073 displacement reaction Methods 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 claims description 10
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 10
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 10
- 150000003863 ammonium salts Chemical class 0.000 claims description 10
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 10
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 10
- 239000001103 potassium chloride Substances 0.000 claims description 10
- 235000011164 potassium chloride Nutrition 0.000 claims description 10
- 159000000000 sodium salts Chemical class 0.000 claims description 10
- 241000713196 Influenza B virus Species 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000003053 piperidines Chemical class 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- 241000712431 Influenza A virus Species 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 150000001414 amino alcohols Chemical class 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 238000006859 Swern oxidation reaction Methods 0.000 claims description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 5
- 238000007259 addition reaction Methods 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 5
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- 150000003008 phosphonic acid esters Chemical class 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- SXYKEYGJJVQNKT-IXDOHACOSA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCN(CC)[C@@H]1CC(=CC[C@@H]1[C@H](CC(C)C)NC(=O)C)C(=O)O SXYKEYGJJVQNKT-IXDOHACOSA-N 0.000 claims description 4
- AJXNEYPDRZIWNY-UPJWGTAASA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-aminocyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@@H]1CC=C(C[C@H]1N)C(=O)O)NC(=O)C AJXNEYPDRZIWNY-UPJWGTAASA-N 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 claims description 4
- LQWJHHIKGNXXPC-KKUMJFAQSA-N ethyl (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-aminocyclohexene-1-carboxylate Chemical compound CCOC(=O)C1=CC[C@@H]([C@H](C1)N)[C@H](CC(C)C)NC(=O)C LQWJHHIKGNXXPC-KKUMJFAQSA-N 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- SXYKEYGJJVQNKT-ULQDDVLXSA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCN(CC)[C@H]1CC(=CC[C@H]1[C@H](CC(C)C)NC(=O)C)C(=O)O SXYKEYGJJVQNKT-ULQDDVLXSA-N 0.000 claims description 3
- AJXNEYPDRZIWNY-AVGNSLFASA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-aminocyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@H]1CC=C(C[C@@H]1N)C(=O)O)NC(=O)C AJXNEYPDRZIWNY-AVGNSLFASA-N 0.000 claims description 3
- 235000019082 Osmanthus Nutrition 0.000 claims description 3
- 241000333181 Osmanthus Species 0.000 claims description 3
- 238000007281 aminoalkylation reaction Methods 0.000 claims description 3
- 239000012954 diazonium Substances 0.000 claims description 3
- 150000001989 diazonium salts Chemical class 0.000 claims description 3
- 238000006193 diazotization reaction Methods 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 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 3
- PNQZYYUYEMTMQA-UNLWNTODSA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-(diethylamino)cyclohexene-1-carboxylic acid hydrochloride Chemical compound CCN(CC)[C@@H]1CC(=CC[C@@H]1[C@H](CC(C)C)NC(=O)C)C(=O)O.Cl PNQZYYUYEMTMQA-UNLWNTODSA-N 0.000 claims description 2
- QPHDSXOBRLTFNJ-GMSSCWEGSA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-aminocyclohexene-1-carboxylic acid hydrochloride Chemical compound CC(C)C[C@@H]([C@@H]1CC=C(C[C@H]1N)C(=O)O)NC(=O)C.Cl QPHDSXOBRLTFNJ-GMSSCWEGSA-N 0.000 claims description 2
- VJHCWGRTRVCOLV-FRRDWIJNSA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-hydroxycyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@H]1CC=C(C[C@H]1O)C(=O)O)NC(=O)C VJHCWGRTRVCOLV-FRRDWIJNSA-N 0.000 claims description 2
- ZKQFXZNPDHEPBJ-FRRDWIJNSA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-nitrocyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@H]1CC=C(C[C@H]1[N+](=O)[O-])C(=O)O)NC(=O)C ZKQFXZNPDHEPBJ-FRRDWIJNSA-N 0.000 claims description 2
- SBHPKYLXSDVSPJ-FRRDWIJNSA-N (4R,5R)-4-[(1S)-1-acetamido-3-methylbutyl]-5-sulfanylcyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@H]1CC=C(C[C@H]1S)C(=O)O)NC(=O)C SBHPKYLXSDVSPJ-FRRDWIJNSA-N 0.000 claims description 2
- RGPAMSKAQKZATB-SQNIBIBYSA-N (4S,5S)-4-[(1S)-1-acetamido-2-ethylbutyl]-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCC(CC)[C@@H]([C@@H]1CC=C(C[C@@H]1N(CC)CC)C(=O)O)NC(=O)C RGPAMSKAQKZATB-SQNIBIBYSA-N 0.000 claims description 2
- XBLPAWXLLSMYKW-IHRRRGAJSA-N (4S,5S)-4-[(1S)-1-acetamido-2-ethylbutyl]-5-aminocyclohexene-1-carboxylic acid Chemical compound CCC(CC)[C@@H]([C@H]1CC=C(C[C@@H]1N)C(=O)O)NC(=O)C XBLPAWXLLSMYKW-IHRRRGAJSA-N 0.000 claims description 2
- DYXCCLVOBUKKPA-PMPSAXMXSA-N (4S,5S)-4-[(1S)-1-acetamido-2-methylpropyl]-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCN(CC)[C@H]1CC(=CC[C@H]1[C@H](C(C)C)NC(=O)C)C(=O)O DYXCCLVOBUKKPA-PMPSAXMXSA-N 0.000 claims description 2
- RPKFVSZCMUZFOA-SRVKXCTJSA-N (4S,5S)-4-[(1S)-1-acetamido-2-methylpropyl]-5-aminocyclohexene-1-carboxylic acid Chemical compound CC(C)[C@@H]([C@H]1CC=C(C[C@@H]1N)C(=O)O)NC(=O)C RPKFVSZCMUZFOA-SRVKXCTJSA-N 0.000 claims description 2
- PNQZYYUYEMTMQA-FRKSIBALSA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-(diethylamino)cyclohexene-1-carboxylic acid hydrochloride Chemical compound CCN(CC)[C@H]1CC(=CC[C@H]1[C@H](CC(C)C)NC(=O)C)C(=O)O.Cl PNQZYYUYEMTMQA-FRKSIBALSA-N 0.000 claims description 2
- QPHDSXOBRLTFNJ-QKWXXBCPSA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-aminocyclohexene-1-carboxylic acid hydrochloride Chemical compound CC(C)C[C@@H]([C@H]1CC=C(C[C@@H]1N)C(=O)O)NC(=O)C.Cl QPHDSXOBRLTFNJ-QKWXXBCPSA-N 0.000 claims description 2
- VJHCWGRTRVCOLV-AVGNSLFASA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-hydroxycyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@@H]1CC=C(C[C@@H]1O)C(=O)O)NC(=O)C VJHCWGRTRVCOLV-AVGNSLFASA-N 0.000 claims description 2
- ZKQFXZNPDHEPBJ-AVGNSLFASA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-nitrocyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@@H]1CC=C(C[C@@H]1[N+](=O)[O-])C(=O)O)NC(=O)C ZKQFXZNPDHEPBJ-AVGNSLFASA-N 0.000 claims description 2
- SBHPKYLXSDVSPJ-AVGNSLFASA-N (4S,5S)-4-[(1S)-1-acetamido-3-methylbutyl]-5-sulfanylcyclohexene-1-carboxylic acid Chemical compound CC(C)C[C@@H]([C@@H]1CC=C(C[C@@H]1S)C(=O)O)NC(=O)C SBHPKYLXSDVSPJ-AVGNSLFASA-N 0.000 claims description 2
- AVFJVOUPENULTB-JYJNAYRXSA-N (4S,5S)-4-[(1S)-1-acetamidobutyl]-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCC[C@@H]([C@@H]1CC=C(C[C@@H]1N(CC)CC)C(=O)O)NC(=O)C AVFJVOUPENULTB-JYJNAYRXSA-N 0.000 claims description 2
- AHIHHMZVSQNPKN-SRVKXCTJSA-N (4S,5S)-4-[(1S)-1-acetamidobutyl]-5-aminocyclohexene-1-carboxylic acid Chemical compound CCC[C@@H]([C@H]1CC=C(C[C@@H]1N)C(=O)O)NC(=O)C AHIHHMZVSQNPKN-SRVKXCTJSA-N 0.000 claims description 2
- IHYMWTNXDJLLLE-BPNCWPANSA-N (4S,5S)-4-[(1S)-1-acetamidoethyl]-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCN(CC)[C@H]1CC(=CC[C@H]1[C@H](C)NC(=O)C)C(=O)O IHYMWTNXDJLLLE-BPNCWPANSA-N 0.000 claims description 2
- MVXGNAXPJWZLKU-QUNWWBBNSA-N (4S,5S)-4-[(1S)-1-acetamidoethyl]-5-aminocyclohexene-1-carboxylic acid Chemical compound C[C@@H]([C@H]1CC=C(C[C@@H]1N)C(=O)O)NC(=O)C MVXGNAXPJWZLKU-QUNWWBBNSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- SXYKEYGJJVQNKT-UHFFFAOYSA-N 4-(1-acetamido-3-methylbutyl)-5-(diethylamino)cyclohexene-1-carboxylic acid Chemical compound CCN(CC)C1CC(=CCC1C(CC(C)C)NC(=O)C)C(=O)O SXYKEYGJJVQNKT-UHFFFAOYSA-N 0.000 claims description 2
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- 238000004807 desolvation Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
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- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
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- 239000001530 fumaric acid Substances 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
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- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a compound expressed by a general formula I, or its pharmaceutically acceptable salt, and an analyzed enantiomer and a purified diastereomer, wherein R<1>is H or C1-12 alkyl groups; R<2> is H, -C(O)R<1a>, -C(O)OR<1a> or -S(O)2R<1b>, wherein R<1a> is H or C1-6 alkyl groups, R<1b> is selected from H or C1-6 alkyl groups halogenated hydrocarbon, phenyl or aryl group; R<3> is selected from C1-4 alkyl groups substituted amino, halogen, hydroxyl, sulfydryl, guanidyl, nitryl or cyano group; and R<4> is -(CH2)nCO2H, -(CH2)nP(O)(OH)2, -(CH2)nCO2R<1a> and -(CH2)nP(O)(OR<1a>)2, wherein R<1a> is H or C1-6 alkyl groups, n is an integer between 0 and 4, or a salt of the above groups. The invention also provides a preparation method of the cyclohexene compound expressed by the general formula I, and an application of the cyclohexene compound taken as an influenza virus neuraminidase inhibitor for preparing the medicines to prevent or treat the influenza diseases.
Description
Technical field
The present invention relates to the new tetrahydrobenzene compound of a class, or this compounds pharmacy acceptable salt, their preparation method, and they are as the application of influenza virus neuraminidase inhibitor prevention or treatment influenza disease.
Background technology
Influenza is a kind of global infectious diseases that is caused by influenza virus, is having a strong impact on human orthobiosis always, and that gives human society has stablely brought great threat.
At present, the influenza virus prevention is to use the neuraminidase inhibitor medicine with the Main Means for the treatment of, and this medicine is as target spot take the neuraminidase on influenza virus surface (NA).Neuraminidase is a kind of mushroom-shaped tetramer glycoprotein that is, and finishes influenza virus and copies in the process that breaks away from host cell, and neuraminidase plays an important role.When influenza virus enters host cell and copies by hemagglutinin after, the hemagglutinin on ripe virocyte surface contacts by sialic acid and host's cytolemma, because neuraminidase has enzymic activity, can be hydrolyzed sialic acid residues, finally impel virocyte to break away from the host.Therefore, effectively suppress neuraminidase, can stop influenza virus propagation in vivo.
Von Itzstein, the people such as M. are in patent WO9116320, and Colman, and the people such as P.M. disclose the compound of being combined with neuraminidase in WO9206691, and show that it has the interior resisting virus activity.Babu, the people such as S.Y. disclose some benzene derivative and can be used as influenza virus neuraminidase inhibitor in US Patent No. 5602277.U.S. Gilead sciences company discloses the six-ring compound that can be used as neuraminidase inhibitor in patent WO9626933.Chand, the people such as P. disclose the 5-membered ring compounds with neuraminic acid enzyme inhibition activity in WO9933781.In addition, Xu etc. have done the neuraminidase inhibitor of development in recent years and have summarized (Curr.Med.Chem.2007,14,2872-2891; J.Int.Pharm.Res.2010,37,241-248).
Yet in disclosed report, there are no synthetic C-4 ' tetrahydrobenzene compound that contains alkyl and amide group replacement, and such new compound influenza neuraminidase suppresses active research.
For fear of the variation of influenza virus, need the exploitation novel compound as influenza virus neuraminidase inhibitor, with the medicine for the preparation for the treatment of or flu-prevention virus.
Summary of the invention
For the deficiencies in the prior art, the present invention for seeking the novel inhibitors that influenza neuraminidase suppresses activity that have more, provide the new C-4 ' position of a class to contain tetrahydrobenzene compound and the synthetic method thereof of alkyl and amide group replacement, simultaneously it has been carried out preliminary influenza neuraminidase and suppressed active testing.
The compound that a first aspect of the present invention provides general formula I to represent:
Formula I
Or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein:
R
1H or C
1-12Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-6Alkyl, R
1bTo be selected from H or C
1-6Alkyl, C
1-6Halogenated alkane, the group of phenyl or aryl;
R
3Amino, C
1-4The amino that alkyl replaces, halogen, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group;
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above carboxylic acid and phosphonyl group.
The compound Neuraminidase in Influenza Virus of general formula I of the present invention has certain restraining effect.
Another aspect of the present invention provides the midbody compound with general formula 5 of preparation compound of Formula I:
Formula 5
Or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein:
R
1H or C
1-12Alkyl;
Boc is tertbutyloxycarbonyl; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a, or-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above group.
Another aspect of the present invention provides the midbody compound with general formula 6 of preparation compound of Formula I:
Formula 6
Or pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H or C
1-12Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-6Alkyl, R
1bTo be selected from H or C
1-6Alkyl, halogenated alkane, the group of phenyl or aryl; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above carboxylic acid and phosphonyl group.
Another aspect of the present invention provides a kind of preparation method who prepares compound of Formula I, comprising:
Formula I
Steps A: will be with amino alcohol and the Boc anhydride reaction of the replacement of following formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain the propenal through the replacement of amido protecting with following formula 2 with the Wittig reagent react again;
Formula 1 formula 2
Step B: will under the first base catalysis, react with phosphonic acid ester and the Paraformaldehyde 96 of following formula 3, then add the tosic acid reflux dewatering, then in the presence of the second alkali, addition reaction occurs with Nitromethane 99Min., obtain the intermediate with following formula 4;
Formula 3 formulas 4
Step C: with formula 2 through Michael/Horner-Wadsworth-Emmons (HWE) reaction of under the 3rd base catalysis, connecting of the propenal of the replacement of amido protecting and the intermediate of formula 4, through separating the tetrahydrobenzene intermediate that can obtain with the replacement of following formula 5;
Formula 5
Step D: the tetrahydrobenzene intermediate of the replacement of formula 5 is sloughed the Boc protecting group under acidic conditions, alternatively, then generates intermediate with following formula 6 with acyl chlorides or SULPHURYL CHLORIDE under the 4th base catalysis; And
Formula 6
Alternatively, step e: the nitro in the intermediate of formula 6 obtains the compound of general formula I, wherein each substituent R through a step or the conversion of multistep substituting group
1, R
2, R
3, R
4As defined above.
Another aspect of the present invention provides the preparation method of another preparation compound of Formula I, comprising:
Formula I
Steps A ': will be with amino alcohol and the excess acetyl chloride of the replacement of following formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain with the amino of the following formula 2 ' propenal through the replacement of ethanoyl protection with the Wittig reagent react again;
Formula 1 formula 2 '
Step B ': will under the first base catalysis, react with phosphonic acid ester and the Paraformaldehyde 96 of following formula 3, then add the tosic acid reflux dewatering, then in the presence of the second alkali, addition reaction occurs with Nitromethane 99Min., obtain the intermediate with following formula 4;
Formula 3 formulas 4
Step C ': the amino of formula 2 ' is reacted through the propenal of the replacement of ethanoyl protection and the intermediate of formula 4 Michael/Horner-Wadsworth-Emmons (HWE) that connects under the 3rd base catalysis, can obtain tetrahydrobenzene intermediate with the replacement of following formula 5 ' through separation;
Formula 5 '
Step D ': the tetrahydrobenzene intermediate of the replacement of formula 5 ' deacetylate protecting group under acidic conditions alternatively, then generates intermediate with following formula 6 with acyl chlorides or SULPHURYL CHLORIDE under the 4th base catalysis; And
Formula 6
Alternatively, step e ': the nitro in the intermediate of formula 6 obtains the compound of general formula I, wherein each substituent R through a step or the conversion of multistep substituting group
1, R
2, R
3, R
4As defined above.
Compound or its pharmacy acceptable salt that a kind of general formula I is provided on the one hand more of the present invention, and the diastereomer of the enantiomer of resolving and purifying for the preparation of treat or the medicine of flu-prevention virus in application.
Another aspect of the present invention provides a kind of compound of Formula I or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying is as the application of influenza virus neuraminidase inhibitor.
Another aspect of the present invention provides a kind of compound of Formula I or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying is for the preparation of the application in the medicine of inhibition influenza neuraminidase.
The present invention is to provide the new C-4 ' position of a class and contain the tetrahydrobenzene compound of alkyl and amide group replacement, it has influenza neuraminidase and suppresses active, can be for the preparation for the treatment of or the medicine of flu-prevention virus, avoid the variation of influenza virus and the resistance that causes.
Embodiment
The compound that a specific embodiment of the present invention provides general formula I to represent:
Formula I
Or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein:
R
1H or C
1-12Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-6Alkyl, R
1bTo be selected from H or C
1-6Alkyl, halogenated alkane, the group of phenyl or aryl;
R
3Amino, C
1-4The amino that alkyl replaces, halogen, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group;
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above carboxylic acid and phosphonyl group.
In an embodiment, compound of the present invention or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein pharmacy acceptable salt can be the sour formed salt that is selected from following group: hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, Hydrogen bromide, acetic acid, phenylformic acid and tosic acid.
In a preferred embodiment, compound of the present invention or its pharmacy acceptable salt, and enantiomer and the diastereomer of purifying, the wherein substituent R of resolving
4Salt can be sodium salt, sylvite or ammonium salt.
In a preferred embodiment, compound of the present invention or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1Can be H or C
1-8Alkyl;
R
2Can be H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-4Alkyl, R
1bH, C
1-6Alkyl, halogenated alkane or replacement or unsubstituted phenyl;
R
3Can be amino, C
1-4The amino that alkyl replaces, Cl, Br, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group; And
R
4Can be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aCan be H or C
1-6Alkyl, n are 0 to 2 integers, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
In a preferred embodiment, compound of the present invention or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H, methyl, ethyl, 1-propyl group, 2-propyl group, 2-methyl isophthalic acid-ethyl, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group, the tertiary butyl, 1-amyl group, 2-methyl butyl, 3-methyl butyl, neo-pentyl, 2-amyl group, 3-amyl group, 1-hexyl, 1-heptyl, 1-octyl group or 2-ethylhexyl;
R
2Can be H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aCan be H, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, R
1bH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, trifluoromethyl, chloromethyl, dichloromethyl, 2,2,2-three chloroethyls, 2,2,2-trifluoroethyl, trichloromethyl or p-methylphenyl;
R
3Can be amino, diethylamino, Cl, Br, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group;
R
4Can be-(CH
2)
2CO
2H ,-CH
2CO
2H ,-CO
2H ,-(CH
2)
4P (O) (OH)
2,-(CH
2)
3P (O) (OH)
2,-(CH
2)
2P (O) (OH)
2,-CH
2P (O) (OH)
2,-(CH
2)
4P (O) (OR
1a)
2,-(CH
2)
3P (O) (OR
1a)
2,-(CH
2)
2P (O) (OR
1a)
2,-CH
2P (O) (OR
1a)
2, R wherein
1aCan be H, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
The compound Neuraminidase in Influenza Virus of general formula I of the present invention has certain restraining effect.
Another embodiment provides the midbody compound with general formula 5 for preparing compound of Formula I:
Formula 5
Or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein:
R
1Can be H or C
1-12Alkyl;
Boc can be tertbutyloxycarbonyl; And
R
4Can be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a, or-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aCan be H or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above group.Another embodiment of the present invention provides the midbody compound with general formula 6 of preparation compound of Formula I:
Formula 6
Or pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1Can be H or C
1-12Alkyl;
R
2Can be H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-6Alkyl, R
1bH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, trifluoromethyl, chloromethyl, dichloromethyl, 2,2,2-three chloroethyls, 2,2,2-trifluoroethyl, trichloromethyl or p-methylphenyl; And
R
4Can be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aCan be H or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above carboxylic acid and phosphonyl group.
Another embodiment of the present invention also provides a kind of preparation method who prepares compound of Formula I, comprising:
Formula I
Steps A: will be with amino alcohol and the Boc anhydride reaction of the replacement of following formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain the propenal through the replacement of amido protecting with following formula 2 with the Wittig reagent react again;
Formula 1 formula 2
Step B: will under the first base catalysis, react with phosphonic acid ester and the Paraformaldehyde 96 of following formula 3, then add the tosic acid reflux dewatering, then in the presence of the second alkali, addition reaction occurs with Nitromethane 99Min., obtain the intermediate with following formula 4;
Formula 3 formulas 4
Step C: with formula 2 through Michael/Horner-Wadsworth-Emmons (HWE) reaction of under the 3rd base catalysis, connecting of the propenal of the replacement of amido protecting and the intermediate of formula 4, through separating the tetrahydrobenzene intermediate that can obtain with the replacement of following formula 5;
Formula 5
Step D: the tetrahydrobenzene intermediate of the replacement of formula 5 is sloughed the Boc protecting group under acidic conditions, alternatively, then generates intermediate with following formula 6 with acyl chlorides or SULPHURYL CHLORIDE under the 4th base catalysis; And
Formula 6
Alternatively, step e: the nitro in the intermediate of formula 6 obtains the compound of general formula I, wherein each substituent R through a step or the conversion of multistep substituting group
1, R
2, R
3, R
4As defined above.
In another embodiment, the preparation method of another preparation compound of Formula I is provided, comprising:
Formula I
Steps A ': will be with amino alcohol and the excess acetyl chloride of the replacement of following formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain with the amino of the following formula 2 ' propenal through the replacement of ethanoyl protection with the Wittig reagent react again;
Formula 1 formula 2 '
Step B ': will under the first base catalysis, react with phosphonic acid ester and the Paraformaldehyde 96 of following formula 3, then add the tosic acid reflux dewatering, then in the presence of the second alkali, addition reaction occurs with Nitromethane 99Min., obtain the intermediate with following formula 4;
Formula 3 formulas 4
Step C ': the amino of formula 2 ' is reacted through the propenal of the replacement of ethanoyl protection and the intermediate of formula 4 Michael/Horner-Wadsworth-Emmons (HWE) that connects under the 3rd base catalysis, can obtain tetrahydrobenzene intermediate with the replacement of following formula 5 ' through separation;
Formula 5 '
Step D ': the tetrahydrobenzene intermediate of the replacement of formula 5 ' deacetylate protecting group under acidic conditions alternatively, then generates intermediate with following formula 6 with acyl chlorides or SULPHURYL CHLORIDE under the 4th base catalysis; And
Formula 6
Alternatively, step e ': the nitro in the intermediate of formula 6 obtains the compound of general formula I, wherein each substituent R through a step or the conversion of multistep substituting group
1, R
2, R
3, R
4As defined above.
In an embodiment, the synthetic method of compound of the present invention, wherein,
Steps A or steps A ': the amino alcohol of the replacement of formula 1 can be chirality or achiral;
Step B or step B ': the first alkali can be selected from diethylamine, triethylamine, diisopropylethylamine, thanomin, diethanolamine, trolamine, Diisopropylamine, dipropyl amine, tripropyl amine, piperidines, pyridine, tetramethyleneimine, and the second alkali can be selected from sodium methylate, sodium ethylate, sodium tert-butoxide, cesium carbonate, cesium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, piperidines;
Step C or step C ': the 3rd alkali is selected from cesium carbonate, salt of wormwood, yellow soda ash, cesium fluoride, Potassium monofluoride, Sodium Fluoride, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine, diethylamine, piperidines, pyridine, tetramethyleneimine wherein separate and can realize by silica gel column chromatography or other suitable separation methods;
Step D or step D ': acid is selected from trifluoroacetic acid, tosic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, and the 4th alkali is selected from triethylamine, diethylamine, diisopropylethylamine, piperidines, pyridine, tetramethyleneimine, yellow soda ash, cesium carbonate, salt of wormwood alternatively;
Alternatively, step e: the reduction that a step of nitro or multistep substituting group are converted to nitro, wherein each substituent R
1, R
2, R
3, R
4Define as defined above.
In a preferred embodiment, the synthetic method of compound of the present invention, wherein:
Step e: the aminocompound that a step of nitro or multistep substituting group are converted to the general formula I that will obtain behind the nitroreduction is substituted the base conversion again; can be selected from amino alkylation, amino acidylate, amino diazotization, amino by hydroxyl displacement, amino by sulfydryl displacement, amino by halogen displacement, amino by further esterified, the hydrolysis of diazonium salt of guanidine radicals displacement, the hydroxyl that obtains, the hydrolysis of ester group, to obtain the further substituent R of conversion
3Or the substituent R of optional further conversion
4, each substituent R wherein
1, R
2, R
3, R
4As defined above.
An again embodiment of the present invention provides a kind of compound of Formula I or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying for the preparation of treat or the medicine of flu-prevention virus in application.
Another embodiment of the present invention provides a kind of compound of Formula I or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying is as the application of influenza virus neuraminidase inhibitor.
Another aspect of the present invention provides a kind of compound of Formula I or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying is for the preparation of the application in the medicine of inhibition influenza neuraminidase.
Further embodiment of the present invention provides the method for a kind for the treatment of or flu-prevention virus, comprise giving that it is had the individuality prevention of needs or compound of Formula I or its pharmacy acceptable salt for the treatment of significant quantity, or the enantiomer of resolving and the diastereomer of purifying.
The below will describe exemplary of the present invention in detail.Yet these embodiments are not intended to limit the scope of the invention only for the purpose of illustration.
As used herein, if for concrete restriction is provided, term of the present invention has following implication.
" halogen " comprises fluorine, chlorine, bromine and iodine.
" alkyl " refers to the stable hydrocarbon group of straight or branched, such as C
1-20Alkyl is preferably C
1-12Alkyl, more preferably C
1-6Alkyl is preferably C again
1-4Alkyl, methyl (Me) especially for example, ethyl (Et), propyl group (for example, n-propyl and sec.-propyl), butyl (for example, normal-butyl, isobutyl-, the tertiary butyl), amyl group (for example, n-pentyl, isopentyl, neo-pentyl), n-hexyl etc.Wherein, in the group of each substituted alkyl or alkyl replacement, the alkyl definition is the same.
" alternatively " mean that subsequently event or the situation described can occur or can not occur, described description comprises example that wherein said event or situation occur and its example of not occuring wherein.
" treatment significant quantity " refers to when needing the Mammals of such treatment, is enough to the effectively amount of the general formula compound for the treatment of.The treatment significant quantity will depend on given activity, the patient's of used healing potion the existence of age, physiological situation, Other diseases state and nutritional status and change.In addition, the other medicines treatment that may just accept of patient will affect treatment significant quantity definite of the healing potion that will give.
" treatment " means any treatment for disease in the mammalian body, comprising:
(i) prevent disease, namely cause the clinical symptom of disease not develop;
(ii) suppress disease, that is, stop the development of clinical symptom; And/or
(iii) palliate a disease, that is, cause disappearing of clinical symptom.
In many cases, compound of the present invention can form acid and/or basic salt owing to the existence of amino and/or carboxylic group, acid group or group similarly." compound " of the present invention refers to comprise all steric isomers, geometrical isomer, tautomer, and isotropic substance.
Compound of the present invention can be asymmetric, for example, has one or more steric isomers.Except as otherwise noted, all steric isomers all comprise, such as enantiomorph and diastereomer.The compound that contains the Asymmetrical substitute carbon atom of the present invention can be separated with optical activity pure form or racemic form.The pure form of optical activity can be from racemic mixture, or by using chiral raw material or chiral reagent synthetic.
Compound of the present invention also comprises tautomeric forms.Tautomeric forms derives from a singly-bound and exchanges the migration of also following a proton with adjacent two keys.
Compound of the present invention also comprises all isotopic atoms, no matter is at intermediate or last compound.Isotopic atom comprises having identical atomicity, but the different mass number.For example, the isotropic substance of hydrogen comprises tritium and deuterium.
Compound of the present invention also comprises pharmacy acceptable salt.Pharmacy acceptable salt refers to the form of the conversion of the basic group in parent compound salify.Pharmacy acceptable salt include but not limited to, and basic group is the inorganic or organic acid salt of amine (ammonia) base for example.Pharmacy acceptable salt of the present invention can be synthetic by parent compound, i.e. the acid of the basic group in the parent compound and 1-4 equivalent is reacted in a solvent systems.Suitable salt is set forth in Remington ' s Pharmaceutical Sciences, 17
ThEd., Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, in 66,2 (1977).
Pharmaceutically acceptable acid salt can be by inorganic and organic acid preparation.Mineral acid by the derived acids additive salt comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.Organic acid by the derived acids additive salt comprises acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, oxysuccinic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment, Phenylsulfonic acid etc.The mineral acid of derived acids additive salt and organic acid especially are selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, Hydrogen bromide, acetic acid, phenylformic acid and tosic acid.
As used herein, " pharmaceutically acceptable carrier " comprise any and whole solvents, dispersion medium, dressing, antibacterium and antifungal medicine, etc. blend absorption delay agent etc.Such medium and medicament are used for pharmaceutically active substances and are well known in the art.Unless any conventional media or medicament and activeconstituents are incompatible, its application in therapeutic composition is expected.The activeconstituents that replenishes also can be incorporated in the composition.
Said composition preferably is formulated into unit dosage.Term " unit dosage " refers to and is suitable for use as the physics discrete unit that gives human experimenter and other mammiferous single doses, and per unit contains and calculates to produce the predetermined amount of the effective active substance of needed treatment and relevant suitable pharmaceutical excipient (such as tablet, capsule, ampoule).The compound of general formula I is the active drug amount that effectively and usually gives in dosage range widely.Preferably, for oral administration, each dose unit comprises the compound of Formula I of 10mg to 2g, and more preferably 10 to 700mg, and for administered parenterally, is preferably 10 to 700mg compound of Formula I, and more preferably from about 50 to 200mg.Yet, should understand, the amount of the actual compound of Formula I that gives will be determined according to relevant situation by the doctor, comprise the illness that to treat, the route of administration of selecting, the pragmatize compound that gives with and relative reactivity, each patient's age, body weight and reaction, the seriousness of patient's symptom etc.
In order to prepare solids composition such as tablet, main active ingredient is mixed to form solid preformulation composition with drug excipient (or carrier), it comprises the uniform mixture of compound of the present invention.When claiming that these preformulation composition are uniform, it refers to that active ingredient is dispersed in the whole composition, so that composition can easily be subdivided into identical effective unit dosage such as tablet, pill and capsule.
Tablet of the present invention or pill can be applied or otherwise by compound so that a kind of formulation with prolongation effect advantage to be provided, or protection tablet or pill are avoided the effect of acidic conditions in the stomach.For example, tablet or pill can comprise interior dosage and external dose composition, and the latter has the form of the crust on the former.Can separate two kinds of compositions with enteric layer, wherein enteric layer is used for stoping disintegration under one's belt and allows interior complete components to enter duodenum or be delayed release.Various materials can be used for such enteric layer or coating, and above-mentioned materials comprises many polymer acids and polymer acid and such material such as the mixture of shellac, cetyl alcohol and cellulose acetate.
The composition that is used for inhalation or insufflation is included in solution and the suspension of pharmaceutically acceptable water-containing solvent or organic solvent or its mixture and powder.The liquid or solid composition can comprise suitable pharmaceutical excipient as indicated above.Preferably, give these compositions to obtain part or systemic effect by oral or nasal respiration approach.Can be by the composition that atomizes with rare gas element in the preferred acceptable solvent of pharmacy.Can directly suck atomized soln from atomisation unit, or atomisation unit can be connected in face shield account shape thing or intermittent positive pressure breathing machine.Can be by the device of sending in a suitable manner formulation, preferred oral or nose approach give solution, suspensoid or powder composite.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvate or hydrate.In general, the form form of solvate or hydrate and non-solvent or non-hydrated is equal to, and contains within the scope of the invention.Some compound among the present invention might exist polycrystal or unbodied form.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
The present invention also comprises the prodrug of described compound.Prodrug is a pharmacology material (medicine), is derived by parent drug.In case enter in the body, prodrug just is transformed into parent drug by metabolism.Prodrug can replace by the one or more functional groups to parent drug and prepare, and its substituted radical will be degraded in vivo and discharge parent compound.The preparation of prodrug and use can be at T.Higuchi and V.Stella, " Pro-drugs as Novel Delivery Systems; " Vol.14 of the A.C.S.Symposium Series, with Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press finds in 1987.
The present invention also provides the pharmaceutical composition that comprises compound of Formula I or its pharmacologically acceptable salts or its prodrug and at least a pharmaceutically acceptable carrier.Pharmaceutical composition of the present invention can be oral, injection injection, and spraying sucks, the skin external application, rectum usefulness, nasal cavity usefulness, vagina usefulness, abdominal cavity usefulness, or use by implanting the approach such as reservoir or transdermal patch.
In yet another aspect, the invention provides the method that suppresses the influenza neuraminidase activity with compound of Formula I." it is active to suppress influenza neuraminidase " term herein means in a single day influenza neuraminidase contacts with the tetrahydrobenzene compound of replacement of the present invention, descends to some extent in the situation of its activity with respect to not this compound contact.Therefore, the invention provides a kind of tetrahydrobenzene compound with replacing contacts to suppress the influenza neuraminidase activity with influenza neuraminidase method.
Compound of Formula I of the present invention can be used for suppressing neuraminidase, as the H1N1 neuraminidase of recombinating, influenza A virus, Influenza B virus, such as the anti-95-359 (H3N2) of the influenza A virus Chinese, 72-243 (H3N2) is prevented in Guangdong, the anti-90-15 (H3N2) of Ji, East Lake, Jiangxi 2006-312 (H3N2), Shandong 93-9 (H3N2), 98-10 (H3N2) is prevented in Zhejiang, Sydney 97-5 (H3N2), Guangdong Luohu 2006-219 (H1N1), Beijing 97-53 (H1N1), Beijing 96-25 (H1N1), 95-10 (H1N1) is prevented in osmanthus, the anti-97-13 of Influenza B virus Ji, Beijing 97-172, Beijing 93-184, Shenzhen 97-12, Shenzhen 2005-155 etc.
Another aspect of the present invention relates to the synthetic method for preparing compound of Formula I.
Compound of the present invention can use following method and program (synthetic schemes 1) preparation:
Synthetic schemes 1
Concrete experimental procedure is described below:
Steps A: the amino alcohol 1 of formula 1 (can be chirality or achiral) and Boc anhydride reaction, then become aldehyde radical through Swern oxidation or IBX oxidation hydroxyl, obtain again the compound aldehyde 2 of formula 2 with the Wittig reagent react.
Step B: the phosphonic acid ester 3 of formula 3 is at first reacted under alkali (such as diethylamine, triethylamine, piperidines) catalysis with Paraformaldehyde 96, then add the tosic acid reflux dewatering, addition reaction occurs in last and Nitromethane 99Min. (such as sodium methylate, cesium carbonate, triethylamine) under alkaline condition, obtains the midbody compound 4 of formula 4.
Step C: with the midbody compound 4 of the compound aldehyde 2 of formula 2 and formula 4 at alkali (such as cesium carbonate, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine) series connection Michael/Horner-Wadsworth-Emmons (HWE) reaction occurs under the catalysis, separate the tetrahydrobenzene midbody compound 5 that can obtain formula 5 through silica gel column chromatography.
Step D: the tetrahydrobenzene intermediate 5 (such as trifluoroacetic acid, hydrochloric acid, tosic acid) under acidic conditions of formula 5 is sloughed the Boc protecting group; alternatively, the midbody compound 6 of production 6 under alkali (such as triethylamine, diethylamine, diisopropylethylamine) catalysis with acyl chlorides or SULPHURYL CHLORIDE then.
Alternatively; step e: the midbody compound 6 of formula 6 is changed (such as the reduction of nitro and alternatively further substituting group conversion through simple substituting group; be selected from amino acidylate, amino alkylation, amino diazotization, amino by hydroxyl displacement, amino by sulfydryl displacement, amino by halogen displacement, amino by guanidine radicals displacement, the esterification of hydroxyl, the hydrolysis of diazonium salt, the hydrolysis of ester group, have the substituent R of further conversion with acquisition
3The target compound of general formula I.
Compound of the present invention can also utilize following method and program (synthetic schemes 2) preparation:
Synthetic schemes 2
Concrete experimental procedure is described below:
Steps A ': with amino alcohol 1 (can be chirality or achiral) and the excess acetyl chloride of the replacement of formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain with the amino of the following formula 2 ' propenal 2 ' through the replacement of ethanoyl protection with the Wittig reagent react again;
Step B ': the phosphonic acid ester 3 of formula 3 is at first reacted under the first alkali (such as diethylamine, triethylamine, piperidines) catalysis with Paraformaldehyde 96, then add the tosic acid reflux dewatering, then with Nitromethane 99Min. under alkaline condition (such as sodium methylate, cesium carbonate, triethylamine) addition reaction occurs, obtain the midbody compound 4 of formula 4;
Step C ': with the amino of formula 2 ' through the midbody compound 4 of the propenal 2 ' of the replacement of ethanoyl protection and formula 4 at alkali (such as cesium carbonate, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine) series connection Michael/Horner-Wadsworth-Emmons (HWE) reaction occurs under the catalysis, through separating the tetrahydrobenzene midbody compound 5 ' of the replacement that can obtain formula 5 ';
Step D ': the tetrahydrobenzene intermediate 5 ' of the replacement of formula 5 ' is (such as trifluoroacetic acid, hydrochloric acid, tosic acid) deacetylate protecting group under acidic conditions, alternatively, the midbody compound 6 of production 6 under alkali (such as triethylamine, diethylamine, diisopropylethylamine) catalysis with acyl chlorides or SULPHURYL CHLORIDE then;
Alternatively; step e ': the nitro in the midbody compound 6 of formula 6 is changed (such as the reduction of nitro and alternatively further substituting group conversion through simple substituting group; be selected from amino acidylate, amino alkylation, amino diazotization, amino by hydroxyl displacement, amino by sulfydryl displacement, amino by halogen displacement, amino by guanidine radicals displacement, the esterification of hydroxyl, the hydrolysis of diazonium salt, the hydrolysis of ester group, have the target compound of general formula I of the substituent R 3 of further conversion with acquisition.
As the mixture of enantiomorph, the enantiomorph of the compound of intermediate formula 5 and formula 6 can split by chiral hplc or by chiral resolving agent.
As the mixture of enantiomorph, the enantiomorph of the compound of intermediate formula 5 ' and formula 6 ' can split by chiral hplc or by chiral resolving agent.
As the mixture of enantiomorph, the enantiomorph of the compound of general formula I also can split by chiral hplc or by chiral resolving agent.
Synthetic example:
Embodiment 1
The preparation of compound (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate
Steps A: (S, E)-6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde
With L-leucinol (1.29 grams, 11.0 mmole) be dissolved in the methyl alcohol (50 milliliters), at room temperature dropwise add Boc acid anhydrides (or tert-Butyl dicarbonate, 2.64 grams, 12.1 in methyl alcohol mmole) (10 milliliters) solution, stirring at normal temperature 14 hours.The lower rotation of decompression is evaporated to the solvent evaporate to dryness, wash with saturated sodium bicarbonate solution (3 * 20 milliliters) after adding methylene dichloride (30 milliliters), merge organic phase and with behind the anhydrous sodium sulfate drying, removal of solvent under reduced pressure gets colourless transparent liquid (2.27 gram).Under the nitrogen protection, oxalyl chloride (2.00 gram, 15.7 mmoles) is dissolved in the methylene dichloride (25 milliliters), dropwise adds methylene dichloride (5 milliliters) solution of DMSO (2.45 grams, 31.4 mmoles) after being cooled to-78 ℃, added in 25 minutes.Slowly splash in the reaction system after the colorless liquid product of above-mentioned gained (2.27 gram) is dissolved in methylene dichloride (20 milliliters), added in 50 minutes.-70 ℃ of lower reactions 10 minutes, the mixing solutions of triethylamine (11 milliliters) with methylene dichloride (5 milliliters) slowly splashed in the reaction system.Naturally be warmed up to 0 ℃, add 1N HCl (40 milliliters), separatory gets organic phase, and water layer merges organic phase with methylene dichloride (3 * 10 milliliters) extraction, and removal of solvent under reduced pressure behind the anhydrous sodium sulfate drying obtains yellow liquid 2.03 grams.This yellow liquid (2.03 gram) is dissolved in the toluene (15 milliliters), at 0 ℃ of lower formyl chloride methylene tri Phenylphosphine (3.12 gram that add, 10.3 mmole) reaction is 10 minutes, slowly splash into triethylamine (1.7 milliliters), solution colour is become dark red by yellow, forward under the room temperature to stir 4 hours.Toluene is removed in decompression, add methylene dichloride (25 milliliters), methanol aqueous solution with 40% (3 * 25 milliliters) washing, merge organic phase and use anhydrous sodium sulfate drying, concentrated by purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 20) get yellow oily title product 1.88 grams (productive rate 71%).
1H?NMR(400MHz，CDCl
3，ppm)δ：9.57(d，J＝7.7Hz，1H)，6.87-6.59(m，1H)，6.19(dd，J＝7.7，15.7Hz，1H)，4.65(s，1H)，4.45(s，1H)，1.96-1.56(m，2H)，1.44(s，10H)，0.96(d，J＝6.6Hz，6H)；
13C?NMR(100MHz，CDCl
3，ppm)δ：193.3，158.5，155.2，130.6，79.2，49.9，42.9，28.2，24.6，22.6，21.7。
Step B:2-phosphono-4-nitro butanic acid triethyl
Paraformaldehyde 96 (0.62 gram, 20.6 mmoles) and piperidines (0.1 milliliter, 1.0 mmoles) are dissolved in the methyl alcohol (50 milliliters), dropwise add phosphine acyl acetic acid three ethyl (2.31 grams, 10.3 mmoles) under the normal temperature, added in 30 minutes.After refluxing 24 hours, the evaporated under reduced pressure solvent obtains colourless liquid 2.49 grams.This liquid (2.49 gram) is dissolved in the toluene (50 milliliters), adds tosic acid (0.17 gram, 1.0 mmoles), reflux is 16 hours in water trap, and removal of solvent under reduced pressure gets yellow liquid 1.97 grams.Under the nitrogen protection, this yellow liquid (1.97 gram) is dissolved in the Nitromethane 99Min. (30 milliliters), places under the ice bath, dropwise add methyl alcohol (15 milliliters) solution of sodium methylate (0.65 gram, 12.0 mmoles) with constant pressure funnel.Dropwise the rear room temperature that slowly is warmed up to, stir and add water (10 milliliters) cancellation reaction after 36 hours, separatory is got organic phase, water layer extracts with methylene dichloride (3 * 10 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is through column chromatography purification (ethyl acetate: sherwood oil=1: 5) get reddish-brown oily title product 2.1 grams (productive rate 73%).
1H?NMR(400MHz，CDCl
3，ppm)δ：4.54(ddd，J＝7.1，13.9，30.5Hz，2H)，4.32-4.07(m，6H)，3.12(dt，J＝7.3，24.1Hz，1H)，2.59(dq，J＝6.9，14.1Hz，2H)，1.42-1.25(m，9H)；
13C?NMR(100MHz，CDCl
3，ppm)δ：167.8(d，
2J
P-C＝5.6Hz)，73.0(d，
3J
P-C＝12.6Hz)，63.1(d，
2J
P-C＝6.7Hz)，62.0，42.1(d，
1J
P-C＝131.7Hz)，24.5(d，
2J
P-C＝4.2Hz)，16.2(dd，
3J
P-C＝2.6，6.0Hz)，14.0。
Step C:(4R, 5S)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
With (S; E)-(121 milligrams of 6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde; 0.5 mmole) and the 2-phosphono-(149 milligrams of 4-nitro butanic acid triethyls; 0.5 mmole) be dissolved in the methylene dichloride (2 milliliters); under 0 ℃, dropwise add organic alkali 1; (152 milligrams in 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU); 1 mmole); stir after 8 hours under the room temperature; add saturated ammonium chloride (2 milliliters); separatory is got organic phase; water layer extracts with methylene dichloride (3 * 2 milliliters); merge organic phase and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is through column chromatography purification (ethyl acetate: sherwood oil=1: 16) get 35 milligrams of title compounds (productive rate 18%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.96 (s, 1H), 4.75-4.54 (m, 1H), 4.27 (d, J=8.3Hz, 1H), 4.21 (q, J=7.1Hz, 2H), (3.97-3.77 m, 1H), 3.21-2.98 (m, 1H), 2.75 (d, J=15.4Hz, 1H), 2.58-2.24 (m, 2H), 2.16 (s, 1H), 1.70-1.47 (m, 2H), 1.43 (s, 10H), (1.29 t, J=7.1Hz, 3H), 0.98-0.87 (m, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 165.4,155.5,137.0,126.9,83.1,79.7,60.8,48.2,41.5,39.6,29.8,28.2,25.0,24.8,23.0,21.9,14.2; HRMS (ESI): m/z[M+Na]
+, for [C
19H
32N
2O
6Na]
+Calculated value is: 407.2158, and measured value is: 407.2156.
Step D:(4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
With (4R, 5S)-(140 milligrams of 4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitros-1-cyclohexene carboxylate ethyl ester, 0.36 mmole) be dissolved in the methylene dichloride (2 milliliters), at 0 ℃ of lower (0.3 milliliter of trifluoroacetic acid that adds, 0.4 be warmed up to gradually room temperature mmole) and stirred 3 hours, add saturated sodium bicarbonate (5 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 5 milliliters), merge organic phase and use anhydrous sodium sulfate drying, add methylene dichloride (2 milliliters) dissolving after the removal of solvent under reduced pressure, under 0 ℃, add successively (93 milligrams of diisopropylethylamine, 0.72 mmole) and (37 milligrams of Acetyl Chloride 98Min.s, 0.47 mmole), stirring at room adds saturated ammonium chloride (5 milliliters) cancellation reaction after 3 hours, water layer extracts with methylene dichloride (3 * 5 milliliters), merge organic phase and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (ethyl acetate: sherwood oil=1: 2) get 86 milligrams of title compounds (productive rate 73%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.95 (s, 1H), 5.28 (d, J=8.6Hz, 1H), 4.63 (td, J=5.6,9.8Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 4.15-4.10 (m, 1H), 3.06-3.01 (m, 1H), 2.81-2.75 (m, 1H), 2.66-2.39 (m, 2H), 2.22-2.05 (m, 1H), 1.95 (s, 3H), 1.70-1.37 (m, 3H), (1.29 t, J=7.1Hz, 3H), (1.39-1.12 m, 6H), 0.93 (dd, J=18.6,6.5Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 170.1,165.4,136.8,126.8,83.0,60.9,47.6,40.3,39.6,29.7,25.6,25.1,23.2,23.1,21.8,14.2.HRMS (ESI): m/z[M+Na]
+, for [C
16H
26N
2O
5Na]
+Calculated value is: 349.1739, and measured value is: 349.1724.
Step e: (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate
With (4R, 5S)-(43 milligrams of 4-((S)-1-acetamido-3-methyl butyl)-5-nitros-1-cyclohexene carboxylate ethyl ester, 0.13mmol) be dissolved in the ethanol (3 milliliters), at 0 ℃ of lower (425 milligrams of zinc powder that add, 6.5 mmole), slowly drip (0.49 milliliter of trimethylchlorosilane, 3.9 mmole), stir after 2 hours, decompress filter is removed zinc powder, adds ammoniacal liquor (2 milliliters), water layer extracts with trichloromethane (3 * 5 milliliters), merge organic phase, use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (methyl alcohol: methylene dichloride=1: 30) get 20 milligrams of weak yellow liquids.This weak yellow liquid (20 milligrams) is dissolved in the tetrahydrofuran (THF) (1 milliliter), adds 1N potassium hydroxide solution (1 milliliter), stirring at normal temperature 3 hours.Rotary evaporation adds Zeo-karb Amberlite IR-120 adjusting pH=3-4 after removing tetrahydrofuran (THF), suction filtration is removed resin, and the lower rotary evaporation solvent evaporated of decompression gets 9.3 milligrams of title compounds (productive rate 26%) by C18 reversed phase column chromatography (moving phase is pure water).
1H NMR (400MHz, D
2O, ppm) δ: 6.84 (s, 1H), 4.01 (d, J=9.2Hz, 1H), 3.12 (td, J=5.2,10.5Hz, 1H), (2.77-2.58 m, 1H), 2.43 (d, J=19.0Hz, 1H), (2.31-2.17 m, 1H), 2.10-1.83 (m, 5H), 1.62-1.47 (m, 2H), 1.21 (dd, J=5.5,9.8Hz, 1H), (0.81 dd, J=6.3,17.6Hz, 6H);
13C NMR (100MHz, D
2O, ppm) δ: 175.5,171.4,138.4,127.3,48.4,46.3,40.6,39.9,28.9,24.6,24.3,22.2,21.4,20.9.HRMS (ESI): m/z[M+Na]
+, for [C
14H
24N
2O
3Na]
+Calculated value is: 291.1685, and measured value is: 291.1681.
Embodiment 2
The preparation of compound (4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums
Steps A: (S, E)-6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde
Title compound is according to the described method preparation of embodiment 1 steps A.
Step B:3-nitro propyl group-1, the 1-ethyl diphosphonic acid
With Tetraethyl diphosphonomethane (11.7 grams, 40.7 mmole) be dissolved in the anhydrous methanol (100 milliliters), add successively Paraformaldehyde 96 (6.1 grams, 203.5 mmole) and (4.2 milliliters of diethylamine, 40.7 mmole), reflux 24 hours, the lower rotary evaporation solvent evaporated of decompression gets yellow liquid 12.3 grams.This yellow liquid (12.3 gram) is dissolved in the toluene (100 milliliters), adds tosic acid (344 milligrams, 2.0 mmoles), reflux is 24 hours in water trap.Removal of solvent under reduced pressure, further boiling point 105-125 ℃/20 mmhg cuts are got in underpressure distillation, get weak yellow liquid 9.3 grams.In the mixing solutions of Nitromethane 99Min. (90 milliliters) and tetrahydrofuran (THF) (60 milliliters), add (167.0 milligrams of sodium methylates, 3.1 mmole), stirring at room adds tetrahydrofuran (THF) (30 milliliters) solution of weak yellow liquid obtained above (9.3 gram) after 1 hour, stirring at room is the rotary evaporation solvent evaporated after 12 hours, add pure water (60 milliliters), extract with methylene dichloride (3 * 50 milliliters), merge organic phase, anhydrous sodium sulfate drying, concentrated by column chromatography (ethyl acetate: sherwood oil=1: 2) get title compound 9.6 grams (productive rate 65%).
1H?NMR(400MHz，CDCl
3，ppm)δ：4.72(t，J＝6.8Hz，2H)，4.27-4.17(m，8H)，2.66-2.44(m，3H)，1.37(t，J＝7.1Hz，12H)；
13P?NMR(162MHz，CDCl
3，ppm)δ：21.79。
Step C:(4S, 5R)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate
With (S, E)-(121 milligrams of 6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde, 0.5 mmole) and 3-nitro propyl group-1, (181 milligrams of 1-ethyl diphosphonic acids, 0.5 mmole) be dissolved in the methylene dichloride (2 milliliters), under 0 ℃, dropwise add (152 milligrams of highly basic DBU, 1 mmole), stirring at room adds saturated ammonium chloride (2 milliliters) cancellation reaction after 8 hours, separatory is got organic phase, water layer extracts with methylene dichloride (3 * 2 milliliters), merge organic phase and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is through purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 2) get 47 milligrams of title compounds (productive rate 21%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.66 (d, J=21.2Hz, 1H), 4.73-4.67 (m, 2H), 4.08-3.94 (m, 4H), 3.60-3.44 (m, 1H), (2.77 s, 2H), 2.49-2.10 (m, 3H), 1.71-1.43 (m, 2H), 1.36 (s, 9H), 1.27 (t, J=7.1Hz, 6H), 1.23-1.19 (m, 1H), (0.81 dd, J=6.6,20.1Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 153.2,137.9 (d,
2J
P-C=7.3Hz), 122.0 (d,
1J
P-C=187.1Hz), 80.2 (d,
2J
P-C=11.7Hz), 77.2,59.4 (t,
2J
P-C=4.6Hz), 47.4,39.3,38.2,25.7,24.6 (d,
2J
P-C=13.9Hz), 22.4,20.9,18.8,13.8 (dd,
3J
P-C=2.5,6.2Hz);
13P NMR (162MHz, CDCl
3, ppm) δ: 17.26.HRMS (ESI): m/z[M+Na]
+For [C
20H
37N
2O
7PNa]
+Calculated value is: 471.2236, and measured value is: 471.2231.
Step D:(4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate
Under the room temperature at (4S, 5R)-(224 milligrams of 4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitros-1-tetrahydrobenzene diethyl phosphonate, 0.5 add 2N hydrochloric acid diethyl ether solution (10 milliliters) mmole), stir and add saturated sodium bicarbonate solution (25 milliliters) cancellation reaction after 3 hours, water layer extracts with methylene dichloride (3 * 15 milliliters), merge organic phase and use anhydrous sodium sulfate drying, add methylene dichloride (2 milliliters) dissolving after the removal of solvent under reduced pressure, under 0 ℃, add successively (129 milligrams of diisopropylethylamine, 1 mmole) and (51 milligrams of Acetyl Chloride 98Min.s, 0.65 mmole), be raised to stirring at room 3 hours, add saturated ammonium chloride (10 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 10 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (methyl alcohol: methylene dichloride=1: 30) get 103 milligrams of title compounds (productive rate 53%).
1HNMR (400MHz, CDCl
3, ppm) δ: 6.69 (d, J=21.1Hz, 1H), 5.96 (d, J=9.4Hz, 1H), 4.69 (dd, J=6.3,13.3Hz, 1H), 4.21-3.91 (m, 5H), 2.82 (s, 2H), (2.59-2.20 m, 3H), 1.97 (s, 3H), (1.60-1.54 m, 1H), 1.46-1.18 (m, 8H), (0.85 dd, J=6.6,21.4Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 170.5,140.2 (d,
2J
P-C=9.0Hz), 124.6 (d,
1J
P-C=187.0Hz), 82.7 (d,
3J
P-C=11.7Hz), 62.0 (d,
2J
P-C=4.9Hz), 48.4,41.7,40.6,27.9 (d,
3J
P-C=11.7Hz), 27.0 (d,
2J
P-C=18.2Hz), 24.9,23.5,23.1,21.3,16.3 (dd,
3J
P-C=3.4,6.3Hz);
13P NMR (162MHz, CDCl
3, ppm) δ: 17.10.HRMS (ESI): m/z[M+Na]
+For [C
17H
31N
2O
6PNa]
+Calculated value is: 413.1817, and measured value is: 413.1811.
Step e: (4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums
With (4S, 5R)-(39 milligrams of 4-((S)-1-acetamido-3-methyl butyl)-5-nitros-1-tetrahydrobenzene diethyl phosphonate, 0.1 mmole) be dissolved in the ethanol (3 milliliters), at 0 ℃ of lower (327 milligrams of zinc powder that add, 5 mmoles), slowly drip (0.5 milliliter of trimethylchlorosilane, 4 mmoles), stir after 2 hours, decompress filter is removed zinc powder, adds ammoniacal liquor (2 milliliters), water layer extracts with trichloromethane (3 * 5 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (methyl alcohol: methylene dichloride=1: 20) get 19 milligrams of weak yellow liquids.Under the nitrogen protection; this weak yellow liquid (19 milligrams) is dissolved in the methylene dichloride (1 milliliter); at 0 ℃ of lower (0.13 milliliter of bromotrimethylsilane that slowly drips; 1 mmole); be raised to stirring at room 18 hours, the evaporated under reduced pressure solvent adds ultrapure water (1.5 milliliters) and stirred 2 hours; moisture is removed in decompression again, gets 9.0 milligrams of title compounds (productive rate 25%) through C18 reversed phase column chromatography (moving phase is the 0.1N ammonium bicarbonate soln).
1H NMR (400MHz, D
2O, ppm) δ: 6.48 (d, J=20.8Hz, 1H), (3.96-3.92 m, J=6.7Hz, 1H), 3.23-2.97 (m, 1H), 2.65-2.46 (m, 1H), 2.46-2.14 (m, 2H), 2.10-1.73 (m, 5H), (1.56-1.39 m, 2H), 1.20-1.10 (m, 1H), 0.89-0.63 (m, 6H);
13C NMR (100MHz, D
2O, ppm) δ: 175.5,139.8 (d,
2J
P-C=8.5Hz), 125.3 (d,
1J
P-C=184.1Hz), 48.2 (d,
3J
P-C=13.4Hz), 46.4,40.5,39.8,28.7 (d,
3J
P-C=12.0Hz), 24.9 (d,
2J
P-C=19.6Hz), 24.5,22.2,21.5,20.8;
13P NMR (162MHz, D
2O, ppm) δ: 12.46.HRMS (ESI): m/z[M+Na]
+For [C
13H
31N
4O
4PNa]
+Calculated value is: 361.1981, and measured value is: 361.1979.
Embodiment 3
The preparation of compound (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
Steps A: (S, E)-6-methyl-4-acetamido-2-heptenic aldehyde
L-leucinol (3.52 grams, 30.0 mmoles) is dissolved among the THF (15 milliliters), adds 15 milliliters of 4NNaOH under zero degree, add Acetyl Chloride 98Min. (2.2 milliliters, 34.0 mmoles) again, zero degree stirs and spends the night.The lower rotation of decompression is evaporated to the solvent evaporate to dryness, wash with saturated sodium bicarbonate solution (3 * 60 milliliters) after adding methylene dichloride (90 milliliters), merge organic phase and with behind the anhydrous sodium sulfate drying, get oily liquids (S)-2-acetamido-4-methyl amyl alcohol (3.20 grams, productive rate 67%) with purification by silica gel column chromatography after concentrated.
1H?NMR(400MHz，CDCl
3，ppm)δ：6.22(d，J＝8.1Hz，1H)，4.06-3.98(m，1H)，3.67-3.49(m，2H)，2.00(s，3H)，1.68-1.58(m，1H)，1.41-1.30(m，2H)，0.92(dd，J＝4.1，6.5Hz，6H)；
13C?NMR(100MHz，CDCl
3，ppm)δ：171.1，65.6，49.9，40.1，24.8，23.2，22.9，22.2。
2-iodoxy phenylformic acid (1.68 grams, 6.0 mmoles) is joined in ethyl acetate (30 milliliters) solution of (S)-2-acetamido-4-methyl amyl alcohol (582 milligrams, 2.0 mmoles) stirring and refluxing 3 hours.Be cooled to suction filtration after the room temperature, filtrate is washed with saturated sodium bicarbonate solution (20 milliliters) and saturated aqueous common salt (20 milliliters), use anhydrous sodium sulfate drying, concentrate to get colorless oil (S)-2-acetamido-283 milligrams of 4-methyl pentanals (productive rate 90%).Compound can without purifying, directly carry out next step reaction.
1H?NMR(400MHz，CDCl
3，ppm)δ：9.47(s，1H)，6.85(d，J＝6.8Hz，1H)，4.41-4.36(m，1H)，1.98(s，4H)，1.70-1.56(m，4H)，0.89-0.87(m，12H)；?
13C?NMR(100MHz，CDCl
3，ppm)δ：200.2，170.9，57.3，37.3，24.5，22.9，22.6，21.6。
With (283 milligrams of (S)-2-acetamido-4-methyl pentanals, 1.8 mmole) be dissolved in the toluene (3 milliliters), at 0 ℃ of lower (608 milligrams of formyl chloride methylene tri Phenylphosphine that add, 2.0 mmole) reaction is 10 minutes, slowly splash into triethylamine (0.34 milliliter), solution colour is become dark red by yellow, forward under the room temperature to stir 4 hours.Toluene is removed in decompression, add methylene dichloride (5 milliliters), methanol aqueous solution with 40% (3 * 5 milliliters) washing, merge organic phase and use anhydrous sodium sulfate drying, concentrated by purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 3) get yellow oily title compound (S, E)-6-methyl-264 milligrams of 4-acetamido-2-heptenic aldehyde (productive rate 80%).
1H?NMR(400MHz，CDCl
3，ppm)δ：9.53-9.44(m，1H)，6.77-6.65(m，1H)，6.19-6.05(m，1H)，5.31-5.22(m，1H)，4.78-4.67(m，1H)，2.01(s，3H)，1.67-1.32(m，3H)，0.93-0.84(m，6H)；
13C?NMR(100MHz，CDCl
3，ppm)δ：193.5，169.9，157.8，130.8，48.6，42.8，24.7，22.9，22.7，21.9。
Step B:2-phosphono-4-nitro butanic acid triethyl
Title compound is according to the described method preparation of embodiment 1 step B.
Step C:(4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
With (S; E)-(92 milligrams of 6-methyl-4-acetamido-2-heptenic aldehyde; 0.5 mmole) and the 2-phosphono-(149 milligrams of 4-nitro butanic acid triethyls; 0.5 mmole) be dissolved in the methylene dichloride (2 milliliters); under 0 ℃, dropwise add organic alkali 1; (152 milligrams in 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU); 1 mmole); stir after 8 hours under the room temperature; add saturated ammonium chloride (2 milliliters); separatory is got organic phase; water layer extracts with methylene dichloride (3 * 2 milliliters); merge organic phase and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is through column chromatography purification (ethyl acetate: sherwood oil=1: 2) get 29 milligrams of title compounds (productive rate 18%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.95 (s, 1H), 5.28 (d, J=8.6Hz, 1H), 4.63 (td, J=5.6,9.8Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 4.15-4.10 (m, 1H), 3.06-3.01 (m, 1H), 2.81-2.75 (m, 1H), 2.66-2.39 (m, 2H), 2.22-2.05 (m, 1H), 1.95 (s, 3H), 1.70-1.37 (m, 3H), (1.29 t, J=7.1Hz, 3H), (1.39-1.12 m, 6H), 0.93 (dd, J=18.6,6.5Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 170.1,165.4,136.8,126.8,83.0,60.9,47.6,40.3,39.6,29.7,25.6,25.1,23.2,23.1,21.8,14.2.HRMS (ESI): m/z[M+Na]
+, for [C
16H
26N
2O
5Na]
+Calculated value is: 349.1739, and measured value is: 349.1724.
Embodiment 4
The preparation of compound (4S, 5R)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
Steps A: (S, E)-6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde
Title compound is according to the described method preparation of embodiment 1 steps A.
Step B:2-phosphono-4-nitro butanic acid triethyl
Title compound is according to the described method preparation of embodiment 1 step B.
Step C:(4S, 5R)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
With (S; E)-(121 milligrams of 6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde; 0.5 mmole) and the 2-phosphono-(149 milligrams of 4-nitro butanic acid triethyls; 0.5 mmole) be dissolved in the methylene dichloride (2 milliliters); under 0 ℃, dropwise add organic alkali 1; (152 milligrams in 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU); 1 mmole); stir after 8 hours under the room temperature; add saturated ammonium chloride (2 milliliters); separatory is got organic phase; water layer extracts with methylene dichloride (3 * 2 milliliters); merge organic phase and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is through column chromatography purification (ethyl acetate: sherwood oil=1: 16) get 31 milligrams of title compounds (productive rate 16%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.94 (s, 1H), 4.76 (dd, J=6.5,13.7Hz, 1H), 4.63 (d, J=9.4Hz, 1H), (4.21 q, J=7.1Hz, 2H), 3.74-3.47 (m, 1H), (3.02-2.91 m, 2H), 2.51-2.21 (m, 3H), 1.73-1.49 (m, 2H), 1.43 (s, 10H), 1.30 (t, J=7.1Hz, 4H), 0.89 (dd, J=6.5,16.5Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 165.5,155.7,136.4,126.6,82.9,79.5,60.7,49.8,41.7,40.8,28.2,27.8,26.7,24.9,23.4,21.3,14.1.HRMS (ESI): m/z[M+Na]
+For [C
19H
32N
2O
6Na]
+Calculated value is: 407.2158, and measured value is: 407.2153.
Step D:(4S, 5R)-4-((S)-1-is to Methyl benzenesulfonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
With compound (4S, 5R)-(140 milligrams of 4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitros-1-cyclohexene carboxylate ethyl ester, 0.36 mmole) be dissolved in the methylene dichloride (2 milliliters), at 0 ℃ of lower (0.3 milliliter of trifluoroacetic acid that adds, 0.4 be raised to gradually room temperature mmole), stir after 5 hours, add saturated sodium bicarbonate (5 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 5 milliliters), merge organic phase and use anhydrous sodium sulfate drying, add methylene dichloride (2 milliliters) dissolving after the removal of solvent under reduced pressure, under 0 ℃, add successively (73 milligrams of triethylamines, 0.72 mmole) and (89 milligrams of Tosyl chlorides, 0.47 mmole), after the stirring at room 5 hours, add saturated ammonium chloride (5 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 5 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (ethyl acetate: sherwood oil=1: 1) get title compound (82 milligrams, productive rate 52%).
1H?NMR(400MHz，CDCl
3，ppm)δ：7.65-7.63(m，2H)，7.25-7.21(m，2H)，6.86(s，1H)，4.90-4.68(m，1H)，4.62(d，J＝8.4Hz，1H)，4.25-4.06(m，2H)，3.69-3.65(m，?1H)，3.50-3.30(m，1H)，3.17-3.11(m，1H)，2.55-2.51(m，1H)，2.36(s，3H)，2.30-2.06(m，2H)，1.36-1.22(m，9H)，0.72-0.52(m，6H)；
13C?NMR(100MHz，CDCl
3，ppm)δ：164.3，142.9，135.9，135.8，128.8，126.3，126.2，125.9，81.5，59.9，49.9，41.5，36.9，29.9，28.7，23.5，23.1，21.5，20.7，20.5，13.2。
Embodiment 5
The preparation of compound (4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
Steps A: (S, E)-6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde
Title compound is according to the described method preparation of embodiment 1 steps A.
Step B:2-phosphono-4-nitro butanic acid triethyl
Title compound is according to the described method preparation of embodiment 1 step B.
Step C:(4R, 5S)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
Title compound is according to the described method preparation of embodiment 3 step C.
Step D:(4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
With compound (4S, 5R)-(140 milligrams of 4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitros-1-cyclohexene carboxylate ethyl ester, 0.36 mmole) be dissolved in the methylene dichloride (2 milliliters), at 0 ℃ of lower (0.3 milliliter of trifluoroacetic acid that adds, 0.4 mmole), be raised to stirring at room after 3 hours, add saturated sodium bicarbonate (5 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 5 milliliters), merge organic phase, anhydrous sodium sulfate drying, add methylene dichloride (2 milliliters) dissolving after the removal of solvent under reduced pressure, under 0 ℃, add successively (93 milligrams of diisopropylethylamine, 0.72 mmole) and (37 milligrams of Acetyl Chloride 98Min.s, 0.47 mmole), stirring at room adds saturated ammonium chloride (5 milliliters) cancellation reaction after 3 hours, water layer extracts with methylene dichloride (3 * 5 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (ethyl acetate: sherwood oil=1: 3) get title compound (85 milligrams, productive rate 73%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.92 (s, 1H), 5.38 (d, J=9.5Hz, 1H), (4.69 td, J=5.6,8.3, Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 4.14-4.00 (m, 1H), 3.15-2.82 (m, 2H), (2.62-2.24 m, 3H), 2.00 (s, 3H), 1.57 (qd, J=6.6,13.2, Hz, 1H), 1.33-1.25 (m, 5H), 0.89 (dd, J=6.6,13.5Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 170.3,165.5,136.5,126.7,83.3,60.9,49.0,42.2,41.1,28.6,28.0,25.1,23.4,23.2,21.5,14.2.HRMS (ESI): m/z[M+Na]
+For [C
16H
26N
2O
5Na]
+Calculated value is: 349.1739, and measured value is: 349.1733.
Embodiment 6
The preparation of compound (4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate
Steps A: (S, E)-6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde
Title compound is according to the described method preparation of embodiment 1 steps A.
Step B:3-nitro propyl group-1, the 1-ethyl diphosphonic acid
Title compound is according to the described method preparation of embodiment 2 step B.
Step C:(±)-4-(1-tertbutyloxycarbonyl amido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate diastereomer
With (S, E)-(121 milligrams of 6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde, 0.5 mmole) and 3-nitro propyl group-1, (181 milligrams of 1-ethyl diphosphonic acids, 0.5 mmole) be dissolved in the methylene dichloride (2 milliliters), under 0 ℃, dropwise add (152 milligrams of highly basic DBU, 1 mmole), stirring at room adds saturated ammonium chloride (2 milliliters) cancellation reaction after 8 hours, separatory is got organic phase, water layer extracts with methylene dichloride (3 * 2 milliliters), merge organic phase and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is through purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 2) get 61 milligrams of title compounds (productive rate 27%).
Step D:(4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate
Under the room temperature, (224 milligrams of 4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitros-1-tetrahydrobenzene diethyl phosphonate diastereomer, 0.5 add 2N hydrochloric acid diethyl ether solution (10 milliliters) mmole), stir after 3 hours, add saturated sodium bicarbonate (25 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 15 milliliters), merge organic phase and then use anhydrous sodium sulfate drying, add methylene dichloride (2 milliliters) dissolving after the removal of solvent under reduced pressure, at 0 ℃ of lower (129 milligrams of diisopropylethylamine that add, 1 mmole), add again (51 milligrams of Acetyl Chloride 98Min.s, 0.65 mmole), be raised to stirring at room 3 hours, add saturated ammonium chloride (10 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 10 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (methyl alcohol: methylene dichloride=1: 30) get 45 milligrams of title compounds (productive rate 23%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.74 (d, J=21.4Hz, 1H), 6.40-6.37 (m, 1H), (4.63 td, J=5.6,9.6Hz, 1H), 4.23-3.99 (m, 5H), (2.92-2.59 m, 2H), 2.56-2.47 (m, 2H), 2.31-2.16 (m, 1H), 1.96 (s, 3H), 1.68-1.43 (m, 2H), (1.36 dt, J=4.9,14.1Hz, 6H), 1.27-1.21 (m, 1H), 0.92 (dd, J=6.5,15.3Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 170.6,141.3 (d,
2J
P-C=9.0Hz), 124.3 (d,
1J
P-C=188.6Hz), 82.8 (d,
3J
P-C=11.8Hz), 62.0 (dd,
2J
P-C=5.8,8.5Hz), 46.6,41.0,39.2,30.0 (d,
3J
P-C=11.4Hz), 25.3 (d,
2J
P-C=18.4Hz), 25.0,22.9,21.9,16.3 (dd,
3J
P-C=3.4,6.3Hz);
13P NMR (162MHz, CDCl
3, ppm) δ: 16.82.HRMS (ESI): m/z[M+Na]
+For [C
17H
31N
2O
6PNa]
+Calculated value is: 413.1817, and measured value is: 413.1811.
Embodiment 7
The preparation of compound (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate
Steps A: (S, E)-6-methyl-4-t-butoxycarbonyl amino-2-heptenic aldehyde
Title compound is according to the described method preparation of embodiment 1 steps A.
Step B:3-nitro propyl group-1, the 1-ethyl diphosphonic acid
Title compound is according to the described method preparation of embodiment 2 step B.
Step C:(±)-4-(1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate diastereomer
Title compound is according to the described method preparation of embodiment 5 step C.
Step D:(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate
Under the room temperature, (224 milligrams of 4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitros-1-tetrahydrobenzene diethyl phosphonate diastereomer, 0.5 add 2N hydrochloric acid diethyl ether solution (10 milliliters) mmole), stir after 3 hours, add saturated sodium bicarbonate (25 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 15 milliliters), merge organic phase and then use anhydrous sodium sulfate drying, add methylene dichloride (2 milliliters) dissolving after the removal of solvent under reduced pressure, at 0 ℃ of lower (129 milligrams of diisopropylethylamine that add, 1 mmole), add again (51 milligrams of Acetyl Chloride 98Min.s, 0.65 mmole), be raised to stirring at room 3 hours, add saturated ammonium chloride (10 milliliters) cancellation reaction, water layer extracts with methylene dichloride (3 * 10 milliliters), merge organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure is by column chromatography purification (methyl alcohol: methylene dichloride=1: 30) get 61 milligrams of title compounds (productive rate 31%).
1H NMR (400MHz, CDCl
3, ppm) δ: 6.74 (d, J=21.3Hz, 1H), 5.49 (d, J=9.1Hz, 1H), 4.86 (s, 1H), (4.11-3.90 m, 5H), 2.90-2.53 (m, 2H), (2.43-2.10 m, 3H), 1.87 (s, 3H), (1.64-1.47 m, 2H), 1.29-1.23 (m, 7H), (0.85 dd, J=6.5,16.3Hz, 6H);
13C NMR (100MHz, CDCl
3, ppm) δ: 170.4,141.4 (d,
2J
P-C=9.0Hz), 123.9 (d,
1J
P-C=186.3Hz), 79.7 (d,
3J
P-C=11.1Hz), 62.1 (d,
2J
P-C=5.0Hz), 61.8 (d,
2J
P-C=5.9Hz), 48.5,41.5,40.1,28.4 (d,
3J
P-C=11.9Hz), 27.0 (d,
2J
P-C=18.2Hz), 24.9,23.6,23.2,21.5,16.3 (t,
3J
P-C=6.7Hz);
13PNMR (162MHz, CDCl
3, ppm) δ: 17.66.HRMS (ESI): m/z[M+Na]
+For [C
17H
31N
2O
6PNa]
+Calculated value is: 413.1817, and measured value is: 413.1811.
Embodiment 8
The preparation of compound (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate
With embodiment 1 steps A-E, obtain intermediate (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester.Get 0.25 mmole intermediate (74 milligrams), be dissolved in the acetonitrile (8 milliliters), add (30 milligrams of triethylamines, 0.25 mmole), Anhydrous potassium carbonate (240 milligrams), (270 milligrams of iodoethane, 1.74 mmole), 80 degree reactions 24 hours add 5 milliliters of layerings of water, get organic layer.After organic layer washes with water again, anhydrous sodium sulfate drying, decompression desolventizes, and column chromatography obtains 45 milligrams of liquid, productive rate 51%.Should be dissolved in the tetrahydrofuran (THF) (2 milliliters) by light color liquid (45 milligrams), add 1N potassium hydroxide solution (2 milliliters), stirring at normal temperature 4 hours.Rotary evaporation adds Zeo-karb Amberlite IR-120 adjusting pH=4-5 after removing tetrahydrofuran (THF), filters, and resin uses 10% ammonia scrubbing, collects washing lotion decompression desolvation, gets the title compound product, productive rate 55% after the 40 degree vacuum-dryings.HRMS (ESI): m/z[M-H]
-For [C
18H
31N
2O
3]
-Calculated value is: 323.2340, and measured value is: 323.2347.
Embodiment 9
The preparation of compound (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate
With embodiment 1 steps A-E, obtain intermediate (4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester.Get 0.25 mmole intermediate (74 milligrams), be dissolved in the dimethyl formamide (8 milliliters), add triethylamine (0.1 gram, 0.99 mmole), N, N '-two-Boc-S-methyl-isothiourea (92 milligrams, 0.31 mmole) and HgCl
2(80 milligrams, 0.25 mmole), behind the room temperature reaction 40 hours, add 4 milliliters in water, use ethyl acetate extraction (15 milliliters * 3), use saturated common salt washing (10 milliliters * 2) after organic layer merges, again through anhydrous sodium sulfate drying, decompression desolventizes, and purification by silica gel column chromatography gets solid (67mg, productive rate 50%).Solid (67 milligrams, 0.12 mmole) is dissolved in the methylene dichloride (8 milliliters), adds 0.3 milliliter of trifluoroacetic acid, stirring at room 16 hours, decompression desolventizes.Behind the gained solid ether eccysis impurity, be dissolved in 2 milliliters of tetrahydrofuran (THF)s, add sodium hydroxide solution (2N) 2 milliliters, stirring at room 4 hours, decompression use sodium type Zeo-karb Amberlite-IR 120 to regulate pH to 4-5 except tetrahydrofuran (THF), filter, filtrate discards.Zeo-karb uses 10% ammoniacal liquor wash-out, collects elutriant, and decompression dewaters, and vacuum-drying gets title compound product (17 milligrams, two step productive rates 45%).HRMS (ESI): m/z[M+Na]
+For [C
15H
26N
4NaO
3]
+Calculated value is: 333.1903, and measured value is: 333.1907.
Embodiment 10
The preparation of compound (4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums
With embodiment 2 steps A-E, obtain intermediate (4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate, with embodiment 7, get intermediate (4R, 5R)-and 4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene diethyl phosphonate, with embodiment 2 step e, get title compound.HRMS (ESI): m/z[M+Na]
+For [C
17H
39N
4NaO
4P]
+Calculated value is: 417.2607, and measured value is: 417.2611.
Embodiment 11
The preparation of compound (4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums
With embodiment 2 steps A-E, obtain intermediate (4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate, with embodiment 8, get intermediate (4R, 5R)-and 4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene diethyl phosphonate, with embodiment 2 step e, get title compound.HRMS (ESI): m/z[M+Na]
+For [C
14H
33N
6NaO
4P]
+Calculated value is: 403.2199, and measured value is: 403.2197.
According to the method for embodiment 1-11, change reaction raw materials wherein, can also prepare following compound:
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate sodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate hydrochloride,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate sodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate hydrochloride,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate sodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate sodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate sodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate tosilate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate sodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate hydrochloride,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate sodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate hydrochloride,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate sodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate hydrochloride,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5 diethyl-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5S)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4R, 5S)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
(4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4R, 5S)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(±)-4-(1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(±)-4-(1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate, and
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate.Compound of the present invention uses program described below to test to the inhibition of influenza virus in neuraminic acid enzymeinhibition and the cell.
The test implementation example
Test implementation example A: the test of neuraminic acid enzyme inhibition activity
Test compounds is dissolved among the DMSO.H1N1 neuraminidase (rH1N1 Neuraminidase, R﹠amp will recombinate; D Systems, Catalog # 4858-NM) with buffered soln (50mM Tris, 5mM CaCl
2, 200mMNaCl, pH=7.5) and be diluted to 0.10ng/ μ L.Substrate 2 '-(4-methyl umbelliferone base)-α-D-N-acetyl neuraminic acid (2 '-(4-Methylumbelliferyl)-α-D-N-acetylneuraminic acid) (Sigma, Catalog#M8639) is diluted to 400 μ M with buffered soln.In being applicable to 96 orifice plates of fluoroscopic examination, add above-mentioned neuraminic acid enzyme solution 50 μ L (0.10ng/ μ L), add again 10 μ L testing compound solutions, 15 μ L damping fluids, hatch 20min for 37 ℃ behind the mixing.Add 25 μ L substrates, behind the mixing with microplate reader (Tecan M1000 type) fluorescence intensity (exciting light 365nm, utilizing emitted light 445nm, bandwidth 5nm).Suppress percent value and be to calculate with respect to the average fluorescent strength of not measuring in compound (blank) situation according to the average fluorescent strength of compound.Table 1 has provided each compound will reach the needed concentration (IC of 50% inhibiting rate
50, μ M).Simultaneously, utilize oseltamivir (Oseltamivir) to carry out controlled trial.
Embodiment B: influenza A virus in the mdck cell (95-359, H3N2 prevented in the Chinese) suppresses active test
Test compounds is dissolved among the DMSO.MDCK (dog kidney) cell is seeded in 96 well culture plates, places 5%CO
2, cultivated 24 hours for 37 ℃.In mdck cell, add influenza first C-type virus C (95-359, H3N2 prevented in the Chinese) 10
-5, 37 ℃ of absorption hypsokinesis in 2 hours venom of preventing or cure a disease adds respectively the maintenance medium of different dilution test compounds.Carry out simultaneously virus control and cell control experiment, 37 ℃ are cultured to virus control group lesion degree (CPE) and observe the cytopathic degree (CPE) of respectively organizing (about 36 hours) when reaching 4+.Table 1 has provided each compound will reach the needed concentration (IC of 50% inhibiting rate
50, μ g/mL).Simultaneously, utilize oseltamivir (Oseltamivir) to carry out controlled trial.
Embodiment C: Influenza B virus in the mdck cell (the anti-97-13 of Ji) suppresses active test
Test compounds is dissolved among the DMSO.MDCK (dog kidney) cell is seeded in 96 well culture plates, places 5%CO
2, cultivated 24 hours for 37 ℃.Add again Influenza B virus (the anti-97-13 of Ji) 1/310 in the mdck cell
-2, 37 ℃ of absorption hypsokinesis in 2 hours venom of preventing or cure a disease adds respectively the maintenance medium of different dilution test compounds.Carry out simultaneously virus control and cell control experiment, 37 ℃ of cultivations treat that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing (about 36 hours) when reaching 4+.Table 1 has provided each compound will reach the needed concentration (IC of 50% inhibiting rate
50, μ g/mL).Simultaneously, utilize oseltamivir (Oseltamivir) to carry out controlled trial.
Table 1
From the results shown in Table 1, embodiment 1 and 2 compound reach the required concentration of 50% inhibiting rate to neuraminidase and are higher than oseltamivir (Oseltamivir), but also can reach μ M rank, and good neuraminic acid enzyme inhibition activity is arranged.Similarly, embodiment 1 and 2 compound reach the required concentration of 50% inhibiting rate to the influenza A virus in the mdck cell (95-359 prevented in the Chinese) and Influenza B virus (the anti-97-13 of Ji) and are higher than oseltamivir (Oseltamivir), but have shown that also certain inhibition is active.
Compound of Formula I of the present invention can be used for suppressing neuraminidase, as the H1N1 neuraminidase of recombinating, influenza A virus, Influenza B virus, such as the anti-95-359 (H3N2) of the influenza A virus Chinese, 72-243 (H3N2) is prevented in Guangdong, the anti-90-15 (H3N2) of Ji, East Lake, Jiangxi 2006-312 (H3N2), Shandong 93-9 (H3N2), 98-10 (H3N2) is prevented in Zhejiang, Sydney 97-5 (H3N2), Guangdong Luohu 2006-219 (H1N1), Beijing 97-53 (H1N1), Beijing 96-25 (H1N1), 95-10 (H1N1) is prevented in osmanthus, the anti-97-13 of Influenza B virus Ji, Beijing 97-172, Beijing 93-184, Shenzhen 97-12, Shenzhen 2005-155 etc.
The present invention is to provide the new C-4 ' position of a class and contain the tetrahydrobenzene compound of alkyl and amide group replacement, it has influenza neuraminidase and suppresses active, can be for the preparation for the treatment of or the medicine of flu-prevention virus, avoid the variation of influenza virus and the resistance that causes.
Although the illustrative embodiments in conjunction with current consideration is described the present invention; but be to be understood that; the present invention is not limited to disclosed embodiment, is included in the various modifications in spirit of the present invention and the claims scope and is equal to replacement all should be included within the application's the protection domain.
Claims (19)
1. compound that is represented by following general formula I:
Formula I
Or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein:
R
1H or C
1-12Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-6Alkyl, R
1bTo be selected from H or C
1-6Alkyl, C
1-6Halogenated alkane, the group of phenyl or aryl;
R
3Amino, C
1-4The amino that alkyl replaces, halogen, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group;
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above carboxylic acid and phosphonyl group.
2. compound according to claim 1 or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein said pharmacy acceptable salt is the sour formed salt that is selected from following group: hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, Hydrogen bromide, acetic acid, phenylformic acid and tosic acid.
3. compound according to claim 1 or its pharmacy acceptable salt, and enantiomer and the diastereomer of purifying, the wherein substituent R of resolving
4Described salt be sodium salt, sylvite or ammonium salt.
4. according to claim 1～3 each described compound or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H or C
1-8Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-4Alkyl, R
1bH, C
1-6Alkyl, halogenated alkane or replacement or unsubstituted phenyl;
R
3Amino, C
1-4The amino that alkyl replaces, Cl, Br, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 2 integers, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
5. according to claim 1～3 each described compound or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H, methyl, ethyl, 1-propyl group, 2-propyl group, 2-methyl isophthalic acid-ethyl, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group, the tertiary butyl, 1-amyl group, 2-methyl butyl, 3-methyl butyl, neo-pentyl, 2-amyl group, 3-amyl group, 1-hexyl, 1-heptyl, 1-octyl group or 2-ethylhexyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, R
1bH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, trifluoromethyl, chloromethyl, dichloromethyl, 2,2,2-three chloroethyls, 2,2,2-trifluoroethyl, trichloromethyl or p-methylphenyl;
R
3Amino, diethylamino, Cl, Br, hydroxyl, sulfydryl, guanidine radicals, nitro or cyano group;
R
4Be-(CH
2)
2CO
2H ,-CH
2CO
2H ,-CO
2H ,-(CH
2)
4P (O) (OH)
2,-(CH
2)
3P (O) (OH)
2,-(CH
2)
2P (O) (OH)
2,-CH
2P (O) (OH)
2,-(CH
2)
4P (O) (OR
1a)
2,-(CH
2)
3P (O) (OR
1a)
2,-(CH
2)
2P (O) (OR
1a)
2,-CH
2P (O) (OR
1a)
2, R wherein
1aH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
6. according to claim 1～3 each described compound or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein said compound is selected from:
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate sodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate hydrochloride,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate sodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate hydrochloride,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate sodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate sodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate sodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate sodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate hydrochloride,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate tosilate,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-amino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-diethylamino-1-cyclohexene carboxylate,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate sodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate hydrochloride,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate sodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate hydrochloride,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-cyclohexene carboxylate tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate sodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate hydrochloride,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-cyclohexene carboxylate tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-cyclohexene carboxylate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium,
(±)-4-(1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids di-ammonium salts hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium salt hydrochlorate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammonium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids disodium tosilate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-sulfydryl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-hydroxyl-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-cyano group-1-tetrahydrobenzene phosphonic acids two ammoniums, and
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene phosphonic acids two ammoniums.
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-amino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-guanidine radicals-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-ethyl-butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido-2-methyl-propyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido ethyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido propyl group)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4S, 5S)-4-((S)-1-acetamido butyl)-5-diethylamino-1-tetrahydrobenzene phosphonic acids two ammoniums,
(4R, 5S)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4R, 5S)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4R, 5S)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-(4-aminomethyl phenyl sulfoamido)-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester
(4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-acetamido-3-methyl butyl)-5-nitro-1-cyclohexene carboxylate ethyl ester,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-cyclohexene carboxylate ethyl ester,
(4S, 5R)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4R, 5S)-4-((S)-1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(±)-4-(1-t-butoxycarbonyl amino-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4S, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4R, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(±)-4-(1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate,
(4R, 5R)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate,
(4S, 5S)-4-((S)-1-acetamido-3-methyl butyl)-5-nitro-1-tetrahydrobenzene diethyl phosphonate, and
(±)-4-(1-acetamido-3-methyl butyl)-5-amino-1-tetrahydrobenzene diethyl phosphonate.
7. intermediate by 5 expressions of following general formula:
Formula 5
Or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein:
R
1H or C
1-12Alkyl;
Boc is tertbutyloxycarbonyl; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a, or-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above group.
8. intermediate according to claim 7 or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H or C
1-8Alkyl; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 2 integers, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
9. according to claim 7～8 each described intermediate or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H, methyl, ethyl, 1-propyl group, 2-propyl group, 2-methyl isophthalic acid-ethyl, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group, the tertiary butyl, 1-amyl group, 2-methyl butyl, 3-methyl butyl, neo-pentyl, 2-amyl group, 3-amyl group, 1-hexyl, 1-heptyl, 1-octyl group or 2-ethylhexyl; And
R
4Be-(CH
2)
2CO
2H ,-CH
2CO
2H ,-CO
2H ,-(CH
2)
4P (O) (OH)
2,-(CH
2)
3P (O) (OH)
2,-(CH
2)
2P (O) (OH)
2,-CH
2P (O) (OH)
2,-(CH
2)
4P (O) (OR
1a)
2,-(CH
2)
3P (O) (OR
1a)
2,-(CH
2)
2P (O) (OR
1a)
2,-CH
2P (O) (OR
1a)
2, R wherein
1aH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
10. intermediate by 6 expressions of following general formula:
Formula 6
Or pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H or C
1-12Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-6Alkyl, R
1bTo be selected from H or C
1-6Alkyl, halogenated alkane, the group of phenyl or aryl; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 4 integers, or the salt of above carboxylic acid and phosphonyl group.
11. intermediate according to claim 10 or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H or C
1-8Alkyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH or C
1-4Alkyl, R
1bH, C
1-6Alkyl, halogenated alkane or replacement or unsubstituted phenyl; And
R
4Be-(CH
2)
nCO
2H ,-(CH
2)
nP (O) (OH)
2,-(CH
2)
nCO
2R
1a,-(CH
2)
nP (O) (OR
1a)
2, R wherein
1aH or C
1-6Alkyl, n are 0 to 2 integers, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
12. according to claim 10～11 each described intermediate or its pharmacy acceptable salt, and the enantiomer of resolving and the diastereomer of purifying, wherein
R
1H, methyl, ethyl, 1-propyl group, 2-propyl group, 2-methyl isophthalic acid-ethyl, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group, the tertiary butyl, 1-amyl group, 2-methyl butyl, 3-methyl butyl, neo-pentyl, 2-amyl group, 3-amyl group, 1-hexyl, 1-heptyl, 1-octyl group or 2-ethylhexyl;
R
2H ,-C (O) R
1a,-C (O) OR
1aOr-S (O)
2R
1b, R wherein
1aH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, R
1bH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, trifluoromethyl, chloromethyl, dichloromethyl, 2,2,2-three chloroethyls, 2,2,2-trifluoroethyl, trichloromethyl or p-methylphenyl; And
R
4Be-(CH
2)
2CO
2H ,-CH
2CO
2H ,-CO
2H ,-(CH
2)
4P (O) (OH)
2,-(CH
2)
3P (O) (OH)
2,-(CH
2)
2P (O) (OH)
2,-CH
2P (O) (OH)
2,-(CH
2)
4P (O) (OR
1a)
2,-(CH
2)
3P (O) (OR
1a)
2,-(CH
2)
2P (O) (OR
1a)
2,-CH
2P (O) (OR
1a)
2, R wherein
1aH, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, or the ammonium salt of above carboxylic acid and phosphonyl group, sodium salt, sylvite.
13. the synthetic method of the compound that represents of each described following general formula I according to claim 1～5 comprises:
Formula I
Steps A: will be with amino alcohol and the Boc anhydride reaction of the replacement of following formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain the propenal through the replacement of amido protecting with following formula 2 with the Wittig reagent react again;
Formula 1 formula 2
Step B: will under the first base catalysis, react with phosphonic acid ester and the Paraformaldehyde 96 of following formula 3, then add the tosic acid reflux dewatering, then in the presence of the second alkali, addition reaction occurs with Nitromethane 99Min., obtain the intermediate with following formula 4;
Formula 3 formulas 4
Step C: with formula 2 through Michael/Horner-Wadsworth-Emmons (HWE) reaction of under the 3rd base catalysis, connecting of the propenal of the replacement of amido protecting and the intermediate of formula 4, through separating the tetrahydrobenzene intermediate that can obtain with the replacement of following formula 5;
Formula 5
Step D: the tetrahydrobenzene intermediate of the replacement of formula 5 is sloughed the Boc protecting group under acidic conditions, alternatively, then generates intermediate with following formula 6 with acyl chlorides or SULPHURYL CHLORIDE under the 4th base catalysis; And
Formula 6
Alternatively, step e: the nitro in the intermediate of formula 6 obtains the compound of general formula I, wherein each substituent R through a step or the conversion of multistep substituting group
1, R
2, R
3, R
4Definition as in claim 1～5 defined in each.
14. the synthetic method of the compound that represents of each described following general formula I according to claim 1～5 comprises:
Formula I
Steps A ': will be with amino alcohol and the excess acetyl chloride of the replacement of following formula 1, then through Swern oxidation or IBX oxidizing reaction, obtain with the amino of the following formula 2 ' propenal through the replacement of ethanoyl protection with the Wittig reagent react again;
Formula 1 formula 2 '
Step B ': will under the first base catalysis, react with phosphonic acid ester and the Paraformaldehyde 96 of following formula 3, then add the tosic acid reflux dewatering, then in the presence of the second alkali, addition reaction occurs with Nitromethane 99Min., obtain the intermediate with following formula 4;
Formula 3 formulas 4
Step C ': the amino of formula 2 ' is reacted through the propenal of the replacement of ethanoyl protection and the intermediate of formula 4 Michael/Horner-Wadsworth-Emmons (HWE) that connects under the 3rd base catalysis, can obtain tetrahydrobenzene intermediate with the replacement of following formula 5 ' through separation;
Formula 5 '
Step D ': the tetrahydrobenzene intermediate of the replacement of formula 5 ' deacetylate protecting group under acidic conditions alternatively, then generates intermediate with following formula 6 with acyl chlorides or SULPHURYL CHLORIDE under the 4th base catalysis; And
Formula 6
Alternatively, step e ': the nitro in the intermediate of formula 6 obtains the compound of general formula I, wherein each substituent R through a step or the conversion of multistep substituting group
1, R
2, R
3, R
4Definition as in claim 1～5 defined in each.
15. according to claim 13 or 14 described synthetic methods, wherein,
Steps A or steps A ': the amino alcohol of the replacement of described formula 1 is chirality or achiral;
Step B or step B ': described the first alkali is selected from diethylamine, triethylamine, diisopropylethylamine, thanomin, diethanolamine, trolamine, Diisopropylamine, dipropyl amine, tripropyl amine, piperidines, pyridine, tetramethyleneimine, and described the second alkali is selected from sodium methylate, sodium ethylate, sodium tert-butoxide, cesium carbonate, cesium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, piperidines;
Step C or step C ': described the 3rd alkali is selected from cesium carbonate, salt of wormwood, yellow soda ash, cesium fluoride, Potassium monofluoride, Sodium Fluoride, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylamine, diethylamine, piperidines, pyridine, tetramethyleneimine, wherein said separation realizes by silica gel column chromatography;
Step D or step D ': described acid is selected from trifluoroacetic acid, tosic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, and described the 4th alkali is selected from triethylamine, diethylamine, diisopropylethylamine, piperidines, pyridine, tetramethyleneimine, yellow soda ash, cesium carbonate, salt of wormwood alternatively;
Alternatively, step e: the reduction that a step of described nitro or multistep substituting group are converted to nitro, wherein each substituent R
1, R
2, R
3, R
4Definition as in claim 2～5 defined in each.
16. synthetic method according to claim 15, wherein:
Step e: the aminocompound that a step of described nitro or multistep substituting group are converted to the general formula I that will obtain behind the nitroreduction is substituted the base conversion again; be selected from amino alkylation, amino acidylate, amino diazotization, amino by hydroxyl displacement, amino by sulfydryl displacement, amino by halogen displacement, amino by further esterified, the hydrolysis of diazonium salt of guanidine radicals displacement, the hydroxyl that obtains, the hydrolysis of ester group, to obtain the further substituent R of conversion
3Or the substituent R of optional further conversion
4, each substituent R wherein
1, R
2, R
3, R
4Definition as in claim 1～5 defined in each.
17. according to claim 1-6 each described compound or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying for the preparation of treat or the medicine of flu-prevention virus in application.
18. according to claim 1-6 each described compound or its pharmacy acceptable salt, and the diastereomer of the enantiomer of resolving and purifying is for the preparation of the application in the medicine of inhibition influenza neuraminidase.
19. according to claim 17 or 18 described application, wherein said influenza virus is selected from influenza A virus, Influenza B virus, such as the anti-95-359 (H3N2) of the influenza A virus Chinese, 72-243 (H3N2) is prevented in Guangdong, the anti-90-15 (H3N2) of Ji, East Lake, Jiangxi 2006-312 (H3N2), Shandong 93-9 (H3N2), 98-10 (H3N2) is prevented in Zhejiang, Sydney 97-5 (H3N2), Guangdong Luohu 2006-219 (H1N1), Beijing 97-53 (H1N1), Beijing 96-25 (H1N1), 95-10 (H1N1) is prevented in osmanthus, the anti-97-13 of Influenza B virus Ji, Beijing 97-172, Beijing 93-184, Shenzhen 97-12, Shenzhen 2005-155; Described neuraminidase is restructuring H1N1 neuraminidase.
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