CN1079224A - 抗菌素化合物 - Google Patents
抗菌素化合物 Download PDFInfo
- Publication number
- CN1079224A CN1079224A CN93101472A CN93101472A CN1079224A CN 1079224 A CN1079224 A CN 1079224A CN 93101472 A CN93101472 A CN 93101472A CN 93101472 A CN93101472 A CN 93101472A CN 1079224 A CN1079224 A CN 1079224A
- Authority
- CN
- China
- Prior art keywords
- tetramethyleneimine
- hydroxyethyl
- carboxyl
- formic acid
- formamyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 131
- 230000000843 anti-fungal effect Effects 0.000 title description 2
- 229940121375 antifungal agent Drugs 0.000 title description 2
- 150000002148 esters Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 230000007062 hydrolysis Effects 0.000 claims abstract description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- -1 C 1-4Alkyl Chemical group 0.000 claims description 263
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 188
- BSHRJMFSUUNQRJ-LOASFGFYSA-N (5R)-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC(O)C1[C@H]2C(C)C=C(N2C1=O)C(O)=O BSHRJMFSUUNQRJ-LOASFGFYSA-N 0.000 claims description 169
- 238000000034 method Methods 0.000 claims description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000006239 protecting group Chemical group 0.000 claims description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 229910021529 ammonia Inorganic materials 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- SDUUPTGMMHGKRG-KPPVHYKDSA-N (5R)-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC(O)C1[C@H]2CC=C(N2C1=O)C(O)=O SDUUPTGMMHGKRG-KPPVHYKDSA-N 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 4
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 45
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 250
- 239000002585 base Substances 0.000 description 217
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 207
- 235000019439 ethyl acetate Nutrition 0.000 description 88
- 239000000243 solution Substances 0.000 description 88
- 239000011734 sodium Substances 0.000 description 82
- 238000004587 chromatography analysis Methods 0.000 description 79
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 239000000203 mixture Substances 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
- 238000009833 condensation Methods 0.000 description 54
- 230000005494 condensation Effects 0.000 description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 50
- 238000010828 elution Methods 0.000 description 50
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 44
- 239000002253 acid Substances 0.000 description 39
- 239000002994 raw material Substances 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 34
- 238000001704 evaporation Methods 0.000 description 29
- 238000005937 allylation reaction Methods 0.000 description 28
- 150000003014 phosphoric acid esters Chemical class 0.000 description 28
- 150000001412 amines Chemical class 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 26
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 238000005406 washing Methods 0.000 description 25
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 24
- 229910052786 argon Inorganic materials 0.000 description 22
- 150000002828 nitro derivatives Chemical class 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 230000008020 evaporation Effects 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 17
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
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- 239000001301 oxygen Substances 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 239000000284 extract Substances 0.000 description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- 239000011574 phosphorus Substances 0.000 description 10
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- 125000000217 alkyl group Chemical group 0.000 description 9
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- 239000010410 layer Substances 0.000 description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
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- 238000005984 hydrogenation reaction Methods 0.000 description 7
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- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
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- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WDRWZVWLVBXVOI-QTNFYWBSSA-L dipotassium;(2s)-2-aminopentanedioate Chemical compound [K+].[K+].[O-]C(=O)[C@@H](N)CCC([O-])=O WDRWZVWLVBXVOI-QTNFYWBSSA-L 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QUMITRDILMWWBC-UHFFFAOYSA-N nitroterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 QUMITRDILMWWBC-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- GSTMUCQFCYOPDY-UHFFFAOYSA-N prop-2-enyl 4-fluoro-3-nitrobenzoate Chemical compound [O-][N+](=O)C1=CC(C(=O)OCC=C)=CC=C1F GSTMUCQFCYOPDY-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- LPXPTNMVRIOKMN-UHFFFAOYSA-N sodium;nitrous acid Chemical compound [Na+].ON=O LPXPTNMVRIOKMN-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 235000015870 tripotassium citrate Nutrition 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
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- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及碳代青霉烯并提供了一种式(Ⅰ)化
合物或其可药用盐或可体内水解的酯,其中R1、R2、
R3、R4和R5如说明书中所定义。本发明还涉及该
化合物的制备方法,制备它们的中间体,它们作为治
疗剂的应用以及含有它们的药物组合物。
Description
本发明涉及碳代青霉烯(carbapenems),特别是涉及含有羧基取代的苯基的这类化合物。本发明还涉及它们的制备方法,制备它们的中间体,它们作为治疗剂的用途以及含有它们的药物组合物。
本发明的化合物是抗菌素并且可用于治疗任何通常用抗菌素治疗的疾病,例如治疗哺乳动物包括人体的细菌感染。
首先于1974年由发酵介质中分离出了碳代青霉烯并且发现其具有广谱抗菌活性。由于该发现,已研究出许多新的碳代青霉烯衍生物并且公开和发表了几百篇专利和科学论文。
首先,至今唯一商业销售的碳代青霉烯是imipenem(N-亚胺甲基噻吩阿霉素。该化合物具有广谱的抗菌活性。
本发明提供了具有广谱抗菌活性包括抗革兰氏阳性和阴性、需氧和厌氧细菌活性的化合物。它们对β-内酰胺酶具有良好的稳定性。此外,本发明的有代表性的化合物具有非常好的持久作用。
本发明所涉及的碳代青霉烯衍生物根据通常所认可的半系统命名法命名:
因此,本发明提供了一种式(Ⅰ)的化合物或其可药用的盐或可体内水解的酯:
其中:
R1是1-羟基乙基、1-氟乙基或羟甲基;
R2是氢或C1-4烷基;
R3是氢或C1-4烷基;
R4和R5是相同或不同的,并且选自氢、囟素、氰基、C1-4烷基、硝基、羟基、羧基、C1-4烷氧基、C1-4烷氧羰基、氨基磺酰基、C1-4烷基氨基磺酰基、二-C1-4烷基氨基磺酰基、氨基甲酰基、C1-4烷基氨基甲酰基、二-C1-4烷基氨基甲酰基、三氟甲基、磺酸、氨基、C1-4烷基氨基、二C1-4烷基氨基、C1-4链烷酰氨基、C1-4链烷酰基(N-C1-4烷基)氨基、C1-4烷磺酰氨基和C1-4烷基S(O)-n,其中n是0、1或2:条件是在与-NR3-连接的链的邻位上没有羟基或羧基取代基。
本发明所用的烷基包括直链和支链取代基,例如甲基、乙基、正丙基、异丙基、正丁基和异丁基。
R1优选的是1-羟基乙基。
R2为氢或C1-4烷基例如甲基、乙基、正丙基、异丙基或正丁基。R2优选的是氢或甲基,R2特别优选的是甲基。
R3为氢或C1-4烷基例如甲基、乙基、正丙基、异丙基或正丁基。R3优选的是氢。
R4和R5是相同或不同的,并且选自氢;囟素例如氟、溴或氯;氰基;C1-4烷基例如甲基、乙基、正丙基、异丙基或正丁基;硝基;羟基;羧基;C1-4烷氧基例如甲氧基或乙氧基;C1-4烷氧羰基例如甲氧羰基、乙氧羰基和正丙氧羰基;氨基磺酰基;C1-4烷基氨基磺酰基例如甲氨磺酰基和乙氨磺酰基;二-C1-4烷基氨基磺酰基例如二甲氨基磺酰基、甲乙氨基磺酰基和二乙氨基磺酰基;氨基甲酰基;C1-4烷基氨基甲酰基例如甲基氨基甲酰基或乙基氨基甲酰基;二-C1-4烷基氨基甲酰基例如二甲基氨基甲酰基或二乙基氨基甲酰基;三氟甲基;磺酸;氨基;C1-4烷基氨基例如甲氨基或乙氨基;二-C1-4烷基氨基例如二甲氨基或二乙氨基;C1-4链烷酰氨基例如乙酰氨基或丙酰氨基;C1-4链烷酰基(N-C1-4烷基)氨基例如N-甲基乙酰氨基;C1-4烷磺酰氨基例如甲磺酰氨基;以及C1-4烷基S(O)n-例如甲硫基、甲基亚磺酰基或甲磺酰基。
具体地说,一类合适的化合物是那些化合物,其中R4和R5是相同或不同的,并且选自氢、氟、氯、羟基、羧基、氰基、硝基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、氨基甲酰基、甲基氨基甲酰基、二甲基氨基甲酰基、三氟甲基、磺酸、甲基亚磺酰基、甲磺酰基、甲磺酰氨基或乙酰氨基。
R4和R5可以都不是氢,但通常特别优选的是R4和R5中至少一个是氢。
特别优选的化合物是那些化合物,其中R4是氢、羧基、氟、氯、甲基、甲氧基、氰基、磺酸或甲氧羰基,而R是氢。
本发明包括式(Ⅰ)化合物的所有差向立体异构、非对映异构及互变异构形式,其中在5-位的绝对立体化学如式(Ⅰ)中所示。当一个键用一个楔表示时,这表明在三维上该键将从纸面出来,而当一个键是阴影时,这表明在三维上该键将返入纸面中。式(Ⅰ)化合物具有许多其它的立体中心,即:在R1基团(当R1是1-羟基乙基或1-氟乙基时)中;在6-位上;在1-位(当R2是C1-4烷基)上;以及在吡咯烷环中的2′和4′位上:
优选的化合物是那些化合物,其中β-内酰胺环质子相互呈反式构型。当R1是1-羟基乙基或1-氟乙基时,优选的是其8-取代基具有R-构形。因此,优选类型的化合物是式(Ⅲ)的化合物及其可药用的盐和可体内水解的酯:
其中R2、R3、R4和R5如前述定义。
当R2是C1-4烷基例如甲基,优选的是该化合物为1R构型的形式。
优选的化合物是那些化合物,其中吡咯烷环在其2′-和4′-位上具有下列绝对的立体化学:
本发明的优选的一类化合物是式(Ⅳ)的化合物及其可药用的盐和可体内水解的酯:
其中R3、R4和R5如前述式(Ⅰ)中所定义。
式(Ⅳ)中特别优选的化合物是那些化合物,其中R3是氢,而R4和R5是相同或不同的并且选自氢、氟、氯、羟基、羧基、氰基、硝基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、氨基甲酰基、甲基氨基甲酰基、二甲基氨基甲酰基、甲基磺酰基、三氟甲基、磺酸、甲基亚磺酰基、甲磺酰氨基或乙酰氨基。
式(Ⅳ)中特别优选的化合物是那些化合物,其中R3和R5都为氢,而R4是氢、羧基、氟、氯、甲基、甲氧基、氰基、磺酸或甲氧羰基。
合适的药用盐包括酸加成盐例如盐酸盐、氢溴酸盐、柠檬酸盐、马来酸盐以及与磷酸和硫酸形成的盐。另一方面,合适的盐是碱性盐例如碱金属盐如钠或钾盐;碱土金属盐如钙或镁盐;有机胺盐如三乙胺、吗啉、N-甲基哌啶、N-乙基哌啶、普鲁卡因、二苄基胺、N,N-二苄基乙胺或氨基酸如赖氨酸盐。为了避免疑问,可能有一个、两个或三个成盐阳离子,但这要取决于羧酸官能团的数量以及所述阳离子的价数。
优选的药用盐是钠和钾盐。然而,为了便于在制备过程中分离该盐,不论其是否可药用,在所选溶剂中不易溶解的盐可能是优选的。
可体内水解的酯是那些在人体内水解生成母体化合物的可药用酯。该酯类可以通过对试验动物给药例如静脉内给药试验化合物然后检测该试验动物的体液进行鉴定。合适的对羧基可体内水解的酯包括C1-4烷氧基甲基酯例如甲氧基甲基酯、C1-6链烷酰氧基甲基酯例如新戊酰氧基甲基酯、2-苯并〔C〕呋喃酮基酯、C3-8环烷氧羰基氧基C1-6烷基酯例如1-环己氧羰基氧乙基酯;1,3-二氧戊环-2-酮基甲基酯例如5-甲基-1,3-二氧戊环-2-酮基甲基酯;和C1-6烷氧羰氧基乙基酯例如1-甲氧羰氧基乙基酯并且可以在本发明化合物的任何羧基上形成。合适的对羟基可体内水解的成酯基团包括乙酰基、丙酰基、新戊酰基、C1-4烷氧羰基例如乙氧羰基和苯乙酰基。
本发明的具体化合物是:
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-羟基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,4-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-羟基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,5-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(2-氨基甲酰基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2-二甲氨基羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(5R,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2S,4′S)-2-(2-(3-羧基-6-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4,6-二甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-三氟甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4,6-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲基亚磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-N′-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,及其可药用的盐和可体内水解的酯。
本发明的优选化合物是:
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,4-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,5-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,及其可药用的盐。
为了使用式(Ⅰ)化合物或其可药用的盐或可体内水解的酯治疗哺乳动物包括人,特别是治疗感染,一般按照标准的药物实践配制成药物组合物。
因此,另一方面,本发明提供了一种药物组合物,它包含式(Ⅰ)化合物或其可药用的盐或可体内水解的酯以及可药用的载体。
对于希望治疗的疾病情况,可用标准的方式,例如通过口服、直肠或肠胃外给药来给药本发明的药物组合物。为此,本发明的化合物可用本领域已知的方式配制成例如片剂、胶囊、水或油溶液或悬浮液、乳液、可分散的粉末、栓剂和无菌注射水或油溶液或悬浮液的形式。
本发明的化合物可以配制成填充干粉的管形瓶,它可以单独地或以无水掺混物的形式含有本发明化合物。例如本发明的酸性化合物可以与碱金属碳酸盐或碳氢酸盐掺混。本发明化合物单独的或以与标准赋形剂的混合物形式的冻干制剂是可以接受的。标准的赋形剂包括结构形成剂、低温防护剂和pH改进剂,例如甘露糖醇、山梨糖醇、乳糖、葡萄糖、氯化钠、葡聚糖、蔗糖、麦芽糖、明胶、牛血清清蛋白、甘氨酸、甘露糖、核糖、聚乙烯基吡咯烷酮、纤维素衍生物、谷氨酰胺、肌醇、谷氨酸钾、赤藓醇、丝氨酸及其它氨基酸和缓冲剂例如磷酸氢二钠和柠檬酸钾。
除本发明化合物以外,本发明的药物组合物还可以含有一种或多种已知药物或与其共同给药,所述已知药物选自其它可临床使用的抗菌剂(例如其它β-内酰胺或氨基苷)、β-内酰胺酶的抑制剂(例如棒酸)、肾管封阻剂(如4-(二丙基氨磺酰基)苯甲酸)及降低对肾脏的副作用的代谢酶的抑制剂(例如脱氢肽水解酶的抑制剂,如Z-2-酰氨基-3-取代的丙烯酸酯例如cilastatin)和N-酰基化的氨基酸(例如参见EP-A-178911)。
一种合适的本发明的药物组合物是适于口服给药的单位剂量形式的药物组合物,例如含有100mg~1g本发明化合物的片剂或胶囊。
优选的本发明的药物组合物是适于静脉内、皮下或肌内注射的药物组合物,例如含有1~50%w/w本发明组合物的无菌注射液。
以1%水溶液的形式构成、冻干并且可以通过加0.9%氯化钠水溶液达到所需浓度而制成的组合物的具体实例如下:
组合物1
实施例1的化合物 50mg
组合物2
实施例1的化合物 50mg
甘氨酸 31mg
组合物的其它具体实例如上,但用实施例2~37的任一种化合物代替实施例1的化合物。
为了治疗由细菌引起的感染,将以与imipenem所用相同的通用方式对人给药本发明的药物组合物,而剂量方面要考虑本发明化合物相对于imipenem的临床应用的作用效力和持久性。因此,每个病人将接受的静脉内、皮下或肌内日注射剂量为0.05~5g,优选为0.1~2.5g的本发明化合物,该组合物每天给药1~4次,优选是1天1或2次。可以通过快速浓注给药静脉内、皮下和肌内注射剂量。另一方面,可以通过连续输液一段时间给药静脉注射剂量。另外,每个病人将接受的日口服剂量约等于所述日肠胃外给药剂量。因此,合适的日口服剂量是0.05~5g本发明的化合物,该组合物每天给药1~4次。
另一方面,本发明提供了一种制备式(Ⅰ)化合物或其可药用盐或可体内水解的酯的方法,该方法包括使式(Ⅴ)化合物脱保护:
其中R2、R4和R5如前所定义(如果合适的话,R4和R5可被任意保护);-COOR6和-COOR7是羧基或被护羧基;R8是基团R3或氨基保护基;R9是氢或氨基保护基;而R10是基团R1,被护的1-羟基乙基或被护的羟甲基;其中存在至少一个保护基;
并且以下如果需要;
(ⅰ)形成可药用的盐,
(ⅱ)酯化形成可体内水解的酯。
保护基通常可选自文献中所述的或专业化学家已知适于保护所述基团的任何基团,并且可通过常规的方法引入。
保护基可以通过文献中所述的或专业化学家已知适于脱除所述保护基的任何常规方法脱除,选择这样的方法以便达到脱除保护基而最小地干扰分子中的其它基团的效果。
式(Ⅴ)化合物是新的并且构成本发明的另一个方面。
为了方便起见,下面给出了保护基的具体实例,其中“低级”表示用它来表示的基团最好具有1-4个碳原子。应该理解,这些实例不是详尽的。下面给出了脱除保护基的方法的具体实例,但这些实例是相似的而且不是详尽的。使用未具体提及的保护基和脱保护方法当然也在本发明的范围内。
羧基保护基可以是成酯的脂族或芳脂族醇或成酯的硅烷醇(所述醇或硅烷醇优选含有1-20个碳原子)的残基。
羧基保护基的实例包括直链或支链(C1-12)烷基(如异丙基、叔丁基);低级烷氧基低级烷基(如甲氧基甲基、乙氧基甲基、异丁氧基甲基);低级脂族酰氧基低级烷基(如乙酰氧甲基、丙酰氧甲基、丁酰氧甲基、新戊酰氧甲基);低级烷氧基低级烷基(如1-甲氧羰氧基乙基、1-乙氧羰氧基乙基);芳基低级烷基(如对甲氧基苄基、邻硝基苄基、对硝基苄基、二苯甲基和2-苯并〔C〕呋喃酮基);三(低级烷基)甲硅烷基(如三甲基甲硅烷基和叔丁基二甲基甲硅烷基);三(低级烷基)甲硅烷基低级烷基(如三甲基甲硅烷基乙基);以及(C2-6)链烯基(如烯丙基和乙烯基乙基)。
特别适于脱除羧基保护基的方法包括例如酸-、碱-、金属-或酶-催化水解。
羟基保护基的实例包括低级链烯基(如烯丙基);低级链烷酰基(如乙酰基);低级烷氧羰基(如叔丁氧羰基);低级链烯氧羰基(如烯丙氧羰基);芳基低级烷氧羰基(如苯甲酰氧羰基、对甲氧基苄氧羰基、邻硝基苄氧羰基、对硝基苄氧羰基);三低级烷基甲硅烷基(如三甲基甲硅烷基、叔丁基二甲基甲硅烷基)和芳基低级烷基(如苄基)。
氨基保护基的实例包括甲酰基、芳烷基(如苄基和取代的苄基,例如对甲氧基苄基、硝基苄基和2,4-二甲氧基苄基,以及三苯甲基);二对甲氧苯基甲基和呋喃基甲基;低级烷氧羰基(如叔丁氧羰基);低级链烯氧羰基(如烯丙氧羰基);芳基低级烷氧羰基(如苄氧羰基、对甲氧基苄氧羰基、邻硝基苄氧羰基、对硝基苄氧羰基;三烷基甲硅烷基(如三甲基甲硅烷基和叔丁基二甲基甲硅烷基);亚烷基(如亚甲基);亚苄基和取代的亚苄基。
适于脱除羟基和氨基保护基的方法包括例如酸-、碱-、金属-或酶-催化水解,对于诸如对硝基苄氧羰基的基团,氢化,以及对于诸如邻硝基苄氧羰基的基团,光解。
对于式(Ⅰ)化合物中的羧基和羟基,优选的保护基是烯丙基和对硝基苄基。脱除该烯丙基的优选方法是用四(三苯基膦)钯和Meldrum酸在偶极非质子传递溶剂四氢呋喃混合物,例如二甲基亚砜/四氢呋喃或1,3-二甲基-2-氧代四氢嘧啶/四氢呋喃或醇/四氢呋喃混合物,例如异丙醇/四氢呋喃或乙醇/四氢呋喃中,最好在室温下通过钯催化进行的。另外,在二氯甲烷中,可以用甲基苯胺代替Meldrum酸。这些条件使得在加入钠盐例如2-乙基己酸钠后可通过沉淀其钠盐而分离出该产物。
脱除对硝基苄基的优选方法是用钯催化剂进行氢化。
本发明的另一方面,式(Ⅰ)和(Ⅴ)化合物可以如下制备:
a)使式(Ⅵ)化合物与式(Ⅶ)化合物反应:
其中R2、R4-R10如前所定义,且L是离去基团,或
b)使式(Ⅷ)化合物环化:
其中R2、R4-R10如前所定义,而R11-R13独立地选自C1-6烷氧基、芳氧基、二C1-6烷基氨基和二芳基氨基或R11-R13的任意两个代表邻亚苯二氧基;或R11-R13之一是C1-4烷基、烯丙基、苄基或苯基,而其它两个独立地选自C1-4烷基、三氟甲基或苯基,其中任何苯基可被C1-3烷基或C1-3烷氧基任意取代;
并且任何官能团可被任意保护,以及以下如有必要:
(ⅰ)脱除任何保护基;
(ⅱ)形成可药用的盐;
(ⅲ)酯化形成可体内水解的酯。
适于式(Ⅵ)化合物的L是羟基的反应基如磺酸酯(例如C1-6烷磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、甲苯磺酰氧基)、磷酸酯(例如二芳基磷酸酯如二苯基磷酸酯或L是囟化物(例如氯化物)。另一方面,L是亚砜例如-SOCH=CH-NHCOCH3,它可容易地被置换。L优选的是二苯基磷酸酯(-OP(O)(OPh)2)。
式(Ⅵ)化合物及其制备方法是碳代青霉烯文献中所公知的,例如参加EP-A-126587,EP-A-160391,EP-A-243686和EP-A-343499。
式(Ⅵ)和式(Ⅶ)化合物间的反应通常在碱例如有机胺如二异丙基乙基胺或无机碱如碱金属碳酸盐诸如碳酸钾存在下进行。该反应通常在-25℃至室温,合适的是在约-20℃的温度下进行。该反应通常在有机溶剂例如乙腈或二甲基甲酰胺中进行。该反应通常以与文献中对类似反应所述的类似方式进行。
式(Ⅶ)的化合物是新的并且构成本发明的另一个方面。
式(Ⅶ)的化合物可通过使式(Ⅸ)的化合物脱保护而制备:
其中R4-R6、R8和R9如前所定义,R14是保护基,例如C1-6链烷酰基、C1-6烷氧羰基或苯甲酰基。R14优选为乙酰基和叔丁氧羰基。式(Ⅸ)的化合物可用标准的脱保护方法转化为式(Ⅶ)的化合物,例如,乙酰基可通过在链硅烷醇或链烯醇例如烯丙醇的水溶液中进行碱性水解而除去。
式(Ⅸ)的化合物是新的并且构成本发明的另一个方面。
式(Ⅸ)的化合物可通过使式(Ⅹ)的化合物的活性衍生物(可就地形成)与式(Ⅺ)的化合物反应而制备:
其中R4-R6、R8、R9和R14如前所定义。式(Ⅹ)化合物的活性衍生物包括酰囟、酸酐和“活化的”酯例如相应于(Ⅹ)的硫代羧酸的1H苯并〔1,2,3〕三唑-1-基、五氟苯基和2,4,5-三氯苯基酯或苯并咪唑-2-基酯。式(Ⅹ)和式(Ⅺ)的化合物的反应在标准方法下,例如在Vilsmier试剂(如此就地形成(Ⅹ)的反应性衍生物)存在下,在-30~25℃,优选是-20~5℃的温度下进行。
式(Ⅹ)和(Ⅺ)的化合物通过专业化学家已知的标准方法例如以下实施例中的方法、EP-A-126587中所述的方法或通过与其相似或类似的方法制备。
合适的是,在式(Ⅷ)的化合物中,R11-R13独立地选自C1-6烷基氨基例如甲氧基、乙氧基、异丙氧基、正丙氧基或正丁氧基;芳氧基例如任选的苯氧基;二C1-6烷基氨基例如二甲氨基或二乙氨基;二芳基氨基例如二苯氨基或者R11-R13的任何两个代表邻亚苯二氧基。优选的是,R11-R13的每个具有相同的定义并且是C1-6烷氧基例如甲氧基、乙氧基、异丙氧基或正丁氧基或是苯氧基。
式(Ⅷ)化合物在本领域公知的常规条件下进行环化形成式(Ⅴ)的化合物。一般的条件是在基本上惰性的有机溶剂例如甲苯、二甲苯或乙酸乙酯中在60-150℃的温度下加热。通常,该反应在氮气氛中进行并在自由基清除剂例如氢醌存在下进行。
式(Ⅷ)的化合物可以就地形成和环化。式(Ⅷ)的化合物通常可以通过使式(Ⅻ)的化合物与式(ⅩⅢ)的化合物反应而制备:
其中R2和R4-R13如前所定义。
合适的式(ⅩⅢ)化合物是亚磷酸盐或是这种化合物的官能等价物。
式(Ⅻ)化合物与式(ⅩⅢ)化合物的反应通常在有机溶剂例如甲苯、二甲苯、乙酸乙酯、氯仿、二氯甲烷、乙腈或二甲基甲酰胺中进行。该反应通常在较高的温度例如60-150℃下进行。
式(Ⅻ)化合物可用许多本领域公知的方法制备。例如,式(Ⅻ)化合物可通过用式(ⅩⅤ)的化合物使式(ⅩⅣ)化合物的酰基化而制备:
其中R2、R4-R6和R8-R10如前所定义
其中R7如前所定义。
式(ⅩⅣ)的化合物可通过使式(ⅩⅥ)的化合物与式(Ⅶ)的化合物反应而制备:
其中R2和R10如前所定义。式(ⅩⅥ)的化合物是本领域已知的并且可以用本领域公知的常规酰基化方法与式(Ⅶ)的化合物反应。
式(Ⅶ)、(Ⅻ)和(ⅩⅣ)的化合物是新的并且如此构成本发明的另一个方面。
下列生物试验方法、数据和实施例用于说明本发明。
抗菌活性
本发明的可药用的碳代青霉烯化合物是有效的抗菌剂,它对用于鉴别抗病菌活性的标准实验室微生物,革兰氏阴性及革兰氏阳性具有广谱的体外活性。具体化合物的抗菌谱和效力可以用标准的测试系统测试。具体地讲,本发明的碳代青霉烯对β-内酰胺酶具有良好的稳定性并且在哺乳动物中具有特别好的消去半衰期。一般说来,该化合物具有优于imipenem的显著改进。
本发明化合物的抗菌性能也可以用常规的试验进行体内实验说明。
通常,已发现碳代青霉烯对温血动物来说是无毒的,而这个通则也适用于本发明的化合物。将本发明的有代表性的化合物以能预防细菌感染所需的过量剂量对小鼠给药,未注意到由该给药的化合物所引起的明显的中毒症兆或副作用。
对于有代表性的化合物,用诊断敏感性试验对标准的体外试验系统进行试验,得到下列结果。根据由琼脂稀释方法以104CFU/点的接种物大小测定的最小抑制浓度(MIC)表示抗菌活性。
在实施例中:
(a)NMR谱在200MHz或400MHz进行;
(b)烯丙氧基是指丙烯-1-基氧基-OCH2CH=CH2;
(c)THF是指四氢呋喃;
(d)DMF是指二甲基甲酰胺;
(e)Meldrum酸是2,2-二甲基-1,3-二噁烷-4,6-二酮;
(f)在减压下蒸发溶剂;
(g)EtOAc是指乙酸乙酯;
(h)EEDQ是指N-乙氧羰基-2-乙氧基-1,2-二氢喹啉;
(i)DMSO是指二甲基亚砜;
(j)DCCI是指二环己基碳化二亚胺;
(k)在DMSO-d和乙酸d所取的NMR谱中的峰位根据DMSO与乙酸的比例而变化。
在NMR谱中:
acetic acid是指乙酸;
obscured是模糊的;
part obscured是部分模糊的;
quintet是五重峰;
overlapping是重叠;
broad是宽峰;
mixture of rotamers是旋转异构体的混合物。
实施例1
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-羟基苯基氨基甲酰基)-吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-羧酸,二钠盐
在氩气氛下,向(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧基羰基-2-(3-烯丙氧基-5-烯丙氧羰基苯基氨基甲酰基)-吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯(500mg,0.72mM)和2,2-二甲基-1,3-二噁烷-4,6-二酮(Meldrum酸,829mg,5.75mM)于DMF(8ml)和THF(4ml)的混合物中的溶液中加入四(三苯基膦)钯(83mg,0.072mM)。在氩气以及无光照的条件下将该溶液搅拌2小时。用乙醚(40ml)稀释该溶液,离心分离所得的沉淀物,移出上层清液。洗涤所得产物,方法是将该产物再悬浮于乙醚中然后离心分离,最后在高真空下干燥该产物。将该粗产物溶于水(10ml)中并用NaHCO3将pH调至6.8。过滤后,该溶液在Diaion CHP20P树脂上进行层析,合并合适的级分,得到标题产物(66%)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.18(d,6H);1.82(m,part obscured,1H);2.79(m,1H);3.03(dd,1H);3.22(dd,1H);3.38(quintet,1H);3.57(dd,1H);3.82(quintet,1H);3.99(quintet,1H);4.19(dd+m,2H);7.13(t,1H);7.44(t,1H);7.65(t,1H).
原料如下制备:
3-烯丙氧基-5-氨基苯甲酸烯丙基酯
将3-羟基-5-硝基苯甲酸(3.9g,21.3mM)溶于DMF(55ml)中,在搅拌下加入无水K2CO3(11.78g,76.5mM)。加入烯丙基溴(5.4ml,62.4mM),将该混合物在室温下搅拌18小时。蒸除溶剂,残留物用水处理,将pH调至5.5,并将产物提取到乙酸乙酯中。合并的提取液用NaH2PO4水溶液、水、盐水洗涤,并用MgSO4干燥。蒸发后的残留物在硅胶上进行层析,用汽油/乙酸乙酯(10∶1)的混合物洗脱,得到3-烯丙氧基-5-硝基苯甲酸烯丙基酯(5.94g,90%)。
Nmr(CDCl3):δ 4.66(dt,2H);4.87(dt,2H);5.31-5.52(m,4H);5.94-6.14(m,2H);7.92(m,2H);8.46(t,1H).
Ms(CI):264(MH)+
将上述酯(2g,7.6mM)溶于乙酸乙酯(15ml)中,在氩气氛下加入SnCl2·2H2O(13.7g,61mM)于乙酸乙酯(35ml)中加热回流的悬浮液中。将该混合物加热回流4小时,冷却,并倒入880氨(20ml)和水(20ml)的混合物中。分离出有机层并用乙酸乙酯再提取三次。合并的提取液用稀氨溶液、水和盐水洗涤,用MgSO4干燥,并蒸发得到3-烯丙氧基-5-氨基苯甲酸烯丙基酯的黄色油状物(1.53g,86%)。
Nmr(CDCl3):δ 3.60(br,2H);4.53(dt,2H);4.78(dt,2H);5.25-5.44(m,4H);5.96-6.12(m,2H);6.43(dt,1H);7.00(m,2H).
Ms(CI):233(MH)+
侧链吡咯烷-4-基硫代乙酸酯的制备
将4-乙酰硫基-1-烯丙氧羰基-2-羧基吡咯烷的环己胺盐(5.6g,15mM)悬浮于乙酸乙酯中,顺序用2M HCl(20ml和10ml)、水和盐水振摇,用MgSO干燥乙酸乙酯层。蒸发得到游离酸。制备Vilsmeier试剂,方法是在氩气氛下用草酰氯(0.52ml,6mM)于二氯甲烷(5ml)中的溶液处理二甲基甲酰胺(0.51ml,6.6mM)于二氯甲烷(20ml)中的溶液30分钟。将4-乙酰硫基-1-烯丙氧羰基-2-羧基吡咯烷(1.64g,6mM)于二氯甲烷(7ml)中的溶液一次加入该溶液,接着加入N-甲基吗啉(0.79ml,7.2mM)于二氯甲烷(3ml)中的溶液,继续在-10℃下搅拌30分钟。冷至-20℃后,滴加溶于二氯甲烷(15ml)中的3-烯丙氧基-5-氨基苯甲酸烯丙基酯(1.39g,5.9mM)和N-甲基吗啉(0.79ml,7.2mM)。使温度升至0℃,将该反应保持18小时。用二氯甲烷(100ml)稀释后,该混合物用2MHCl、HO和饱和NaHCO3洗涤,用MgSO4干燥,并蒸发。粗产物通过在硅胶上中压层析进行纯化,用汽油在二氯甲烷中的溶液(3∶1~2∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧基-5-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯,为胶状物(2.37g,81%)。
Nmr(CDCl3):δ 2.32(s,3H);2.58(br,2H);3.39(dd,1H);4.03(quintet,1H);4.13(dd,1H);4.55(t,part obscured,1H);4.58(dt,2H)4.68(dt,2H);4.81(dt,2H);5.23-5.49(m,6H);5.84-6.15(m,3H);7.36(t,1H);7.57(t,1H);7.66(t,1H);9.10(br,1H).
Ms(+ve FAB):489(MH)+,511(M+Na)+
转化为吡咯烷-4-基硫醇
将(2S,4S)-4-乙酰硫基-1-烯丙氧羰基-2-(3-烯丙氧基-5-烯丙氧羰基苯基氨基甲酰基)吡咯烷(1.89g,3.9mM)溶于烯丙醇(25ml)并用氩气充气该溶液。加入1M氢氧化钠(4ml,4mM),该混合物在室温下搅拌2小时,然后蒸发至干。将残留物溶于乙酸乙酯(100ml)中,用2MHCl、NaHCO3、盐水洗涤,干燥(MgSO4)并蒸发,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧基-5-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫醇,为胶状物(1.57g,76%)。粗产物直接用于下个阶段。
被护的碳代青霉烯的制备
在氩气氛下将(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸烯丙基酯(1.5g,3mM)溶于无水乙腈(18ml)中,冷至-20°,加入二异丙基乙基胺(0.63ml,3.6mM),接着滴加(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧基-5-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫醇(1.57g,3.5mM)于乙腈(12ml)中的溶液。然后将该反应混合物在-20℃下保存3天。蒸发溶剂,该残留物在硅胶上用梯度洗脱(二氯甲烷/乙酸乙酯40∶60至70∶30)通过中压层析进行纯化,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧基-5-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯,为胶状物(1.25g,60%)。
Nmr(CDCl3):δ 1.23(d,3H);1.35(d,3H);2.65(br,2H);3.26,3.31(dd overlapping m,2H);3.46(m,1H);3.79(quintet,1H);4.01(dd,1H);4.19-4.29(m,2H);4.50-4.78(m,9H);5.19-5.46(m,8H);5.83-6.12(m,4H);7.36(br s,1H);7.64(m,2H);9.00(br,1H).
Ms(+ve FAB):696(MH)+,718(M+Na)+
(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸烯丙基酯如下制备:
在0℃和氩气氛下,向(1R,5S,6S,8R)-6-(1-羟基乙基)-1-甲基-2-氧代碳代青霉烯-3-甲酸烯丙基酯(2.66mmol)〔由2-二偶氮-3-氧-4-甲基-4-(3-(1-羟基乙基)-2-氧代氮杂环丁烷-4-基)丁酸烯丙基酯和辛酸铑就地制备:参见例如EP-A-208889〕和二异丙基乙基胺(1.1当量乙腈溶液)的溶液中滴加氯磷酸二苯基酯(1.1当量)。将该溶液在室温下搅拌30分钟,形成相应的2-二苯磷酰氧基碳代青霉烯。
制备下列进一步的实施例:
实施例2
用与实施例1相同的一般方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羟基-4-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸二钠盐,所不同的是在加入钯催化剂后,将该溶液缓慢温热以溶解该催化剂并在氩气氛和无光照的条件下搅拌1小时。加入2-乙基己酸钠于THF中的溶液并在剧烈搅拌下将合并的溶液到入THF中。离心分离所得的沉淀物并移出上层清液。通过使该产物再悬浮于THF中然后离心分离而将其洗涤两次,最后在高真空下干燥,得到标题产物。
Nmr(DMSO-d6+acetic acid-d4):δ 1.17(d,6H);1.85(m,obscured,1H);2.73(m,obscured,1H);2.95(dd,1H);3.21(dd,1H);3.40(m,1H);3.54(dd,1H);3.78(quintet,1H);3.99(t,1H);4.11(t,1H);4.18(dd,1H);7.41(d,1H);7.75(dd,1H);8.06(d,1H).
Ms(+ve FAB):532/534(MH)+,(Na salt)+;554/556(Na2salt)+
所用原料如下制备:
基本上按实施例1中的方法将2-氯-5-硝基苯甲酸烯丙基化,所不同的是,最后的提取溶液是甲苯,得到2-氯-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.89(dt,2H);5.33-5.51(m,2H);5.96-6.15(m,1H);7.66(d,1H);8.27(dd,1H);8.72(d,1H).
Ms(CI):241/243 M+,259/261(M+NH4)+
在氩气层下使氯化锡二水合物在乙醇中回流,得到一个溶液。停止加热,加入上述硝基化合物于乙醇中的溶液。继续回流3小时,将该混合物冷却,脱除溶剂。将残留物溶于乙酸乙酯,用880氨处理直至为碱性。由沉淀的锡盐倾析出有机相,将该淤浆用更多的溶剂类似地再提取。合并的有机相然后用稀氨水、水和盐水洗涤,然后用MgSO4干燥。蒸发得到5-氨基-2-氯苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.74(br,2H);4.81(dt,2H);5.27-5.47(m,2H);5.93-6.13(m,1H);6.73(dd,1H);7.15(d,1H);7.24(d,1H).
Ms(CI):212/214 M+,229/231(M+NH4)+
按实施例1的方法将上述胺与脯氨酸缩合,通过层析进行纯化,用二氯甲烷/乙醚(100∶0至95∶5)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-4-氯苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.57(br,2H);3.39(dd,1H);4.03(quintet,1H);4.13(dd,1H);4.55(t,1H);4.66(dt,2H)4.83(dt,2H);5.24-5.47(m,4H);5.85-6.02(m,2H);7.36(d,1H);7.70(dd,1H);7.92(d,1H);9.32(br,1H).
Ms(+ve FAB):467/469(MH)+,489/491(M+Na)+
按实施例1的方法将上述硫基乙酸酯脱乙酰基化为硫醇并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-4-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.36(d,3H);2.65(br,2H);3.25(dd overlapping m,2H);3.48(m,1H);3.80(quintet,1H);3.98(dd,1H);4.20-4.31(dd overlapping quintet,2H);4.52(t,1H);4.51-4.76(m,4H);4.83(dt,2H);5.20-5.47(m,6H);5.85-6.11(m,3H);7.39(d,1H);7.77(dd,1H);7.99(d,1H);9.05(br,1H).
Ms(+ve FAB):674/676(MH)+,696/698(M+Na)+
实施例3
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸二钠盐。
(DMSO-d6+acetic acid-d4):δ 1.16(d,3H);1.19(d,3H);1.82(m,obscured,1H);2.70(dd overlapping m,2H);3.22(dd,1H);3.35-3.60(overlapping m,3H);3.95-4.08(overlapping m,2H);4.16(dd,1H);7.57(d,1H);7.69(dd,1H);8.36(d,1H).
Ms(+ve FAB):532/534(MH)+,(Na salt)+;554/556(Na2salt)+
所用原料如下制备:
基本上按上述实施例1中的方法使4-氯-3-硝基苯甲酸烯丙基化,得到4-氯-3-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.86(d,2H);5.31-5.48(m,2H);5.94-6.13(m,1H);7.50(d,1H);8.18(dd,1H);8.52(d,1H).
Ms(CI):241/243 M+,259/261(M+NH4)+
用实施例2的方法还原上述硝基化合物,得到3-氨基-4-氯苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.08(br,2H);4.79(dt,2H);5.25-5.44(m,2H);5.92-6.11(m,1H);7.30(d,1H);7.38(dd,1H);7.47(d,1H).
Ms(CI):212/241 M+,229/231(M+NH4)+
按实施例1的方法将上述胺与脯氨酸缩合,通过层析进行纯化,用二氯甲烷/乙醚(100∶0至95∶5)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氯苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.56(br,1H);2.66(br,1H);3.43(dd,1H);4.04(quintet,1H);4.16(dd,1H);4.61(t,1H);4.66(dt,2H);4.82(dt,2H);5.21-5.45(m,4H);5.84-6.11(m,2H);7.45(d,1H);7.77(dd,1H);9.00(d,1H);9.08(br,1H).
Ms(+ve FAB):467/469(MH)+,489/491(M+Na)+
按实施例1的方法将上述硫基乙酸酯脱乙酰基化为硫醇并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.23(d,3H);1.36(d,3H);2.65(br,2H);3.24(dd overlapping m,2H);3.88(quintet,1H);4.08(m,1H);4.19-4.30(dd overlapping quintet,2H);4.60(t,1H);4.67(m,4H);4.82(dt,2H);5.18-5.45(m,6H);5.82-6.01(m,3H);7.44(d,1H);7.76(dd,1H);9.04(d,1H);8.98(br,1H).
Ms(+ve FAB):674/676(MH)+,696/698(M+Na)+
实施例4
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是使用DMSO和THF的混合物。
Nmr(DMSO-d6+acetic acid-d4):δ 1.18(d,6H);1.94(m,obscured,1H);2.85(m,1H);3.10(dd,1H);3.23(dd,1H);3.40(quintet,1H);3.66(dd,1H);3.89(quintet,1H);3.99(t,1H);4.21(dd,1H);4.27(t,1H);7.46(t,1H);7.71(d,1H);7.86(d,1H);8.27(s,1H).
Ms(+ve FAB):498(MH)+;(Na salt)+;520(Na2salt)+
所用原料如下制备:
基本上按实施例1中的方法使3-硝酸苯甲酸烯丙基化,所不同的是,最后的提取溶剂是乙醚,得到3-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.88(d,2H);5.33-5.49(m,2H);5.96-6.17(m,1H);7.66(t,1H);8.41(td,2H);8.88(t,1H).
用实施例2的方法还原上述硝基化合物,所不同的是溶剂为甲醇,得到3-氨基苯甲酸烯丙基酯。
(CDCl3):δ 3.38(br,2H);4.79(dt,2H);5.24-5.44(m,2H);5.93-6.09(m,1H);6.86(dm,1H);7.21(t,1H);7.37(t,1H);7.45(dt,1H).
侧链吡咯烷-4-基硫基乙酸酯的制备
将(2S,4S)-4-乙酰硫基-1-烯丙氧羰基-2-羧基吡咯烷(2.54g,9.3mM)、3-氨基苯甲酸烯丙基酯(1.5g,8.5mM)和2-乙氧基-1-乙氧羰基-1,2-二氢喹啉(2.72g,11mM)溶于甲苯(50ml)并在室温下搅拌18小时。该反应混合物用乙酸乙酯(150ml)稀释并用2MHCl(3×30ml)、水、饱和NaHCO3和盐水洗涤。用MgSO4干燥并蒸发,得到(2S,4S)-4-乙酰硫基-1-烯丙氧羰基-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷,为胶状物(3.7g,100%),呈足以进一步使用的纯态。
Nmr(CDCl3):δ 2.32(s,3H);2.60(br,2H);3.40(dd,1H);4.03(quintet,1H);4.13(dd,1H);4.57(t,1H);4.66(dm,2H);4.82(dt,2H);5.23-5.46(m,4H);5.86-6.12(m,2H);7.41(t,1H);7.82(d,1H);7.91(d,1H);8.07(t,1H);9.18(br,1H).
按实施例1的方法将上述硫基乙酸酯脱乙酰基化为硫醇并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯/二氯甲烷1∶1进行梯度洗脱,得到(1R,5S,6S,RR,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。Nmr(CDCl3):δ 1.24(d,3H);1.36(d,3H);2.64(br,2H);3.26,3.28(dd overlapping m,2H);3.48(m,1H);3.81(quintet,1H);4.01(dd,1H);4.22-4.32(m,2H);4.54(t,1H);4.62-4.75(m,4H);4.82(m,2H);5.19-5.45(m,8H);5.82-6.10(m,4H);7.41(d,1H);7.81(d,1H);7.92(dm,1H);8.11(t,1H);8.98(br,1H).
Ms(+ve FAB):640(MH)+,662(M+Na)+
实施例5
按实施例1中所述的方法由适当保护的碳代青霉烯制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,6H);1.99(quintet,1H);2.75(m,part obscured,1H);2.87(dd,1H);3.22(s,3H);3.25(dd,part obscured,1H);3.44(quintet,1H);3.62(dd,1H);3.75(quintet,1H);4.03(quintet,1H);4.16-4.23(m,2H);7.90(dd,1H);8.17(d,1H);9.00(d,1H).
Ms(+ve FAB):554(MH)+,576(Na salt)+,598(Na2salt)+
所用的原料如下制备:
基本上按实施例1中的方法使4-甲磺酰基-3-硝基苯甲酸烯丙基化,所不同的是通过硅胶层析进行纯化,用二氯甲烷至二氯甲烷/乙醚9∶1进行梯度洗脱,得到4-甲磺酰基-3-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.45(s,3H);4.90(dt,2H);5.30-5.49(m,2H);5.96-6.12(m,1H);8.29(d,1H);8.40-8.46(m,2H).
按实施例1的方法还原,所不同的是溶剂为甲醇,得到3-氨基-4-甲磺酰基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.07(s,3H);4.82(dt,2H);5.05(br,2H);5.29-5.44(m,2H);5.95-6.11(m,1H);7.46(m,2H);7.81(d,1H).
Ms(+ve FAB):256(MH)+,273(M+NH4)+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,用二氯甲烷/乙醚(100∶0至90∶10)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.31(s,3H);2.41(m,1H);2.80(m,1H);3.11(s,3H);3.51(dd,1H);4.00-4.18(m,2H);4.53(dd,1H);4.65(2m,2H)4.87(dt,2H);5.23-5.47(m,4H);5.83-6.13(m,2H);7.93(dd,1H);8.03(d,1H);9.09(br s,1H).
Ms(+ve FAB):511(MH)+,533(M+Na)+
按实施例1所述使上述硫基乙酸酯脱乙酰基化为硫醇并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。Nmr(CDCl3):δ 1.21(d,3H);1.35(d,3H);2.43(m,1H);2.75(br,1H);3.08(s,3H);3.23(dd overlapping m,2H);3.55(dd,1H);3.85-4.08(m,2H);4.19-4.28(m,2H);4.53-4.68(m,5H);4.86(dt,2H);5.17-5.47(m,6H);5.79-6.12(m,3H);7.92(dd,1H);8.00(d,1H);9.16(br s,1H);10.14(br,1H).
Ms(+ve FAB):718(MH)+,740(M+Na)+
实施例6
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸
在氩气氛下向(1R,5S,6S,8R,2′S,4′S)-2-(1′-烯丙氧羰基-2′-(3-烯丙氧羰基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯(199mg,0.3mM)和2,2-二甲基-1,3-二噁烷-4,6-二酮(Meldrum酸,259mg,1.8mM)于DMF(1.5ml)中的溶液中加入四(三苯基膦)钯(10mg,0.009mM)于THF(0.1ml)中的溶液。将该溶液在氩气氛下搅拌2小时,加入四(三苯基膦)钯(5mg,0.0045mM)于THF(0.1ml)中的溶液。搅拌30分钟后,加入THF(3ml)和乙醚(9ml),滤出所得的固体,用乙醚(9ml)洗涤,在高真空下干燥,得到标题产物(72mg,49%)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.30(d,6H);2.00(m,part obscured,1H);2.91(m,part obscured,1H);3.13(dd,1H);3.36(dd,1H);3.55(dq,1H);3.73(dd,1H);3.95(m,1H);4.12(m,1H);4.29(dd,1H);4.34(dd,1H);7.40(dd,1H);7.98(m,1H);8.32(dd,1H).
Ms(+ve FAB):494(MH)+,516(M+Na)+
所用原料如下制备:
5-氨基-2-氟苯甲酸烯丙基酯
将2-氟-5-硝基苯甲酸(4.16g,22.5mM)溶于DMF(45ml),在搅拌下加入无水K2CO3(4.65g,33.7mM)。加入烯丙基溴(2.38ml,28.01mM),将该混合物在室温下搅拌18小时,然后倒入水(450ml)中,并用乙醚(3×100ml)提取。合并的提取液用MgSO4干燥,蒸发,得到黄色油状物(5.4g)。该油状物通过硅胶层析进行纯化,用乙酸乙酯/己烷(12.5∶87.5)的混合物洗脱,得到2-氟-5-硝基苯甲酸烯丙基酯(4.64g,92%)。
Nmr(CDCl3):δ 4.89(d,2H);5.30-5.50(m,2H);5.90-6.10(m,1H);7.32(t,1H);8.38-8.46(m,1H);8.86(dd,1H).
Ms(EI):226(MH)+;(CI):225M+,243(M+NH4)+
将上述酯(2.47g,10.97mM)溶于甲醇(40ml),向搅拌的同时保持在5~15℃的该溶液中加入氯化锡二水合物(9.89g,43.76mM)于浓HCl(9ml)中的溶液。然后将该混合物在室温下搅拌过夜,然后倒入水(200ml)中并用固体NaHCO3(17.6g)中和至pH为6。该混合物用氯仿(3×200ml)提取,合并的提取液用MgSO4干燥,蒸发,得到5-氨基-2-氟苯甲酸烯丙基酯(2.09g,98%),为黄色油状物。
Nmr(CDCl3):δ 3.60(br s,2H);4.82(dt,2H);5.25-5.48(m,2H);5.93-6.12(m,1H);6.78(ddd,1H);6.93(dd,1H);7.20(dd,1H).
Ms(EI):195M+;(CI):196(MH)+;213(M+NH4)+
按实施例的方法将上述胺与脯氨酸缩合。所得产物通过硅胶层析进行纯化,用乙酸乙酯/己烷(42.5∶57∶5)洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.50-2.70(br s,2H);3.40(d,1H);3.98-4.20(m,2H);4.56(t,1H);4.67(dt,2H);4.84(dt,2H);5.20-5.50(m,4H);5.83-6.12(m,2H);7.10(dd,1H);7.80-7.89(m,1H);7.93(dd,1H);8.90-9.40(br s,1H).
Ms(+ve FAB):451(MH)+,473(M+Na)+
转化为吡咯烷-4-基硫醇
将(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基乙酸乙酯(1.33g,2.96mM)溶于烯丙醇(30ml)中并用氩气充气该溶液。加入1M氢氧化钠(3.1ml,3.1mM),该混合物在室温下搅拌30分钟,用乙酸(0.3ml)处理,再搅拌5分钟,然后蒸发至干。将残留物溶于乙酸乙酯(60ml),用饱和NaHCO3水溶液(60ml)、盐水洗涤,干燥(MgSO4)并蒸发,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫醇,为胶状物(1.07g,89%)。该粗产物如此直接用于下一阶段。
按实施例1中的方法使该硫醇与碳代青霉烯磷酸酯缩合,所得产物通过硅胶层析进行纯化,用乙酸乙酯/二氯甲烷(75∶25)洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-羧基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.35(d,3H);2.40-2.80(br,2H);3.24-3.28(m,2H);3.40-3.58(br,1H);3.80(dq,1H);3.99(dd,1H);4.19-4.33(m,2H);4.53(t,1H);4.59-4.77(m,4H);4.77-4.88(m,2H);5.17-5.50(m,6H);5.80-6.13(m,3H);7.10(dd,1H);7.82-7.95(m,1H);8.00(dd,1H);8.70-9.20(br s,1H).
Ms(+ve FAB):658(MH)+
实施例7
如实施例6中所述由适当保护的碳代青霉烯制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸。
Nmr(DMSO-d6+acetic acid-d4):δ 1.30(d,6H);1.84(m,1H);2.80-2.93(m,2H);3.36(dd,1H);3.58(m,1H);3.66(dd,1H);3.81(m,1H);4.09(dq,1H);4.21(m,1H);4.31(dd,1H);7.56(dd,1H);8.07(m,1H);8.90(d,1H).
Ms(+ve FAB):494(MH)+,516(M+Na)+
所用原料如下制备:
3-氨基-4-氟苯甲酸烯丙基酯
如实施例6中所述使4-氟-3-硝基苯甲酸烯丙基化,得到4-氟-3-硝基苯甲酸烯丙基酯
Nmr(CDCl3):δ 4.87(dt,2H);5.48-5.32(m,2H);5.95-6.14(m,1H);7.40(dd,1H);8.30-8.38(m,1H);8.76(dd,1H).
Ms(EI):225M+;(CI):225M+,243(M+NH4)+
基本上如实施例2中所述还原上述酯,所不同的是用甲醇作溶剂,得到3-氨基-4-氟苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.70(br,2H);4.79(dt,2H);5.25-5.44(m,2H);5.96-6.09(m,1H);7.02(dd,1H);7.41-7.54(m,2H).
Ms(EI):195M+;(CI):196(MH)+
如实施例1中所述使上述胺与脯氨酸缩合,通过硅胶层析纯化该产物,用乙酸乙酯/己烷(50∶50)作洗脱剂,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氟苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.62(br,2H);3.40(dd,1H);3.98-4.20(m,2H);4.60(t,1H);4.67(dt,2H);4.82(dt,2H);5.2-5.5(m,4H);5.8-6.15(m,2H);7.16(dd,1H);7.83(ddd,1H);8.97(dd,1H);9.27(br,1H).
Ms(EI):451(MH)+;(CI):451(MH)+
如实施例6中所述使上述硫基乙酸酯脱乙酰基化为硫醇,并与碳代青霉烯磷酸酯缩合,所得产物通过层析(用乙酸乙酯洗脱)进行纯化,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.90(m,part obscured,1H);2.78(m,1H);3.22(dd,1H);3.26(m,1H);3.52(m,1H);3.83-4.03(m,2H);4.09(dd,1H);4.22(m,1H);4.53(m,1H);4.53-4.65(m,4H);4.80(dt,2H);5.05-5.43(m,6H);5.73-5.98(m,2H);5.98-6.09(m,1H);7.38(dd,1H);7.78(br s,1H);8.49(m,1H);8.62(d,1H).
Ms(+ve FAB):658(MH)+,680(M+Na)+
实施例8
按实施例7中的方法由适当保护的碳代青霉烯制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2,4-二氟苯基氨基甲酰基吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸。
Nmr:(DMSO-d6+acetic acid-d4):δ 1.29(d,6H);1.94-1.99(m,part boscured 1H);2.81-3.07(m,1H);3.05(dd,1H);3.37(dd,1H);3.56(m,1H);3.75(dd,1H);3.92(q,1H);4.10(dq,1H);4.29-4.38(m,2H);7.22(t,1H);8.07(m,1H).
Ms(+ve FAB):512(MH)+,534(M+Na)+
所用原料如下制备:
3-氨基-2,6-二氟苯甲酸烯丙基酯
如实施例6中所述使2,6-二氟-3-硝基苯甲酸烯丙基化,得到2,6-二氟-3-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):4.90(dt,2H);5.33-5.50(m,2H);5.95-6.03(m,1H);7.09-7.27(ddd,1H);8.22-8.27(ddd,1H).
Ms(EI):244(MH)+;(CI):261(M+NH4)+
如实施例2中所述还原上述酯,所不同的是用甲醇作溶剂,得到3-氨基-2,6-二氟苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.86(dt,2H);5.27-5.49(m,2H);5.95-6.09(m,1H);6.77-6.86(m,2H).
MS(EI):213M+;(CI):214(MH)+
如实施例1中所述使上述胺与脯氨酸缩合,通过层析进行纯化并用乙酸乙酯/己烷(40∶60)洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.60(br,2H);3.40(dd,1H);3.95-4.19(m,2H);4.57(t,1H);4.67(dt,2H);4.86(dt,2H);5.20-5.50(m,4H);5.81-6.13(m,2H);6.95(ddd,1H);8.4(ddd,1H);9.2(br,1H).
MS(+ve FAB):469(MH)+
如实施例6中所述使上述硫基乙酸酯脱乙酰基化为硫醇并与碳代青霉烯磷酸酯缩合。所得产物通过硅胶层析进行纯化,用乙酸乙酯洗脱,得到(1R,5S,6S,8R,2S′,4S′)-2-(1-烯丙氧羰基-2-(3-羧基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙酯。
Nmr(CDCl3):δ 1.26(d,3H);1.36(d,3H);1.80(d,1H);2.62(br,2H);3.19-3.36(m,2H);3.44(dd,1H);3.08(q,1H);4.05(dd,1H);4.19-4.33(m,2H);4.50-4.80(m,5H);4.86(dt,2H);5.17-5.50(m,6H);5.82-6.10(m,3H);6.95(dt,1H);8.38(dt,1H);9.00(br,1H).
Ms(+ve FAB):676(MH)+,698(M+Na)+
实施例9
采用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,4-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,三钠盐,所不同的是使用DMSO和THF的混合物。
Nmr(DMSO-d6+acetic acid-d4):δ 1.18(d,6H);1.84(m,part obscured,1H);2.78(m,1H);3.02(dd,1H);3.23(dd,1H);3.40(quintet,1H);3.58(dd,1H);3.83(quintet,1H);4.00(quintet,1H);4.20(dd overlapping m,2H);7.92(dd,1H);8.17(d,1H);8.33(d,1H).
Ms(+ve FAB):542(MH)+,(Na salt)+;564(Na2salt)+
所用的原料如下制备:
按实施例1的方法使2-羧基-4-硝基苯甲酸烯丙基化,得到2-烯丙氧羰基-4-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.85(dt,4H);5.29-5.47(m,4H);5.91-6.12(m,2H);7.88(d,1H);8.38(dd,1H);8.63(d,1H).
用实施例2的方法还原上述硝基化合物,通过硅胶中压层析进行纯化,用二氯甲烷/乙醚(100∶0至90∶10)进行梯度洗脱,得到2-烯丙氧羰基-4-氨基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.94(br,2H);4.71-4.80(m,4H);5.22-5.42(m,4H);5.88-6.10(m,2H);6.69(dd,1H);6.75(d,1H);7.74(d,1H).
如实施例1中所述使上述胺与脯氨酸缩合,通过硅胶中压层析进行纯化,采用由二氯甲烷至20%乙醚的二氯甲烷溶液的梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3,4-二烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.59(br,2H);3.37(dd,1H);4.03(quintet,1H);4.12(dd,1H);4.56(t,1H);4.67(d,2H);4.77(t,4H);5.25-5.42(m,6H);5.84-6.11(m,3H);7.79(m,3H);9.52(br,1H).
如实施例1中所述使上述硫基乙酸酯脱乙酰基化为硫醇并不用进一步纯化而直接与碳代青霉烯磷酸酯缩合,最后通过硅胶中压层析进行纯化,用二氯甲烷/乙酸乙酯3∶2作为洗脱剂,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3,4-二烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.35(d,3H);2.62(br,2H);3.26(dd overlapping m,2H);3.47(br,1H);3.81(quintet,1H);3.97(dd,1H);4.19-4.29(overlapping m,2H);4.53(t,1H);4.62-4.82(m,8H);5.19-5.44(m,8H);5.84-6.07(m,4H);7.82(s,3H);9.30(br,1H).
实施例10
采用实施例1的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-羟基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,所不同的是该粗酸具有足够的纯度,而不需要层析。
(DMSO-d6+acetic acid-d4):δ 1.17(d,6H);1.95(m,obscured,1H);2.87(m,obscured,1H);3.17(dd,1H);3.25(dd,1H);3.42(dt,1H);3.75(dd,1H);3.99-4.05(m,2H);4.22(dd,1H);4.33(t,1H);6.76(d,1H);7.56(dd,1H);7.97(d,1H).
Ms(+ve FAB):492(MH)+,514(M+Na)+
所用原料如下制备:
基本上按实施例1中的方法使2-羟基-5-硝基苯甲酸烯丙基化,所不同的是最终的提取溶剂是乙醚,得到2-烯丙氧基-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.82(m,4H);5.26-5.55(m,4H);5.97-6.13(m,2H);7.49(d,1H);8.41(dd,1H);8.52(d,1H).
用实施例2的方法还原上述硝基化合物,所不同的是,溶剂为甲醇,用NaHCO溶液碱化,得到2-烯丙氧基-5-氨基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.23(br,2H);4.53(dt,1H);4.79(d,2H);5.21-5.49(m,4H);5.93-6.14(m,2H);6.80(m,2H);7.16(d,1H).
如实施例1中所述使上述胺与脯氨酸缩合,通过层析进行纯化,用二氯甲烷/乙醚(100∶0至85∶15)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(4-烯氧基-3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.56(br,2H);3.39(dd,1H);4.01(quintet,1H);4.13(dd,1H);4.52(t,1H);4.60(dt,2H)4.66(m,2H);4.81(dt,2H);5.23-5.51(m,6H);5.85-6.13(m,3H);6.91(d,1H);7.76(dd,1H);7.81(d,1H);8.97(br,1H).
如实施例1所述将上述硫基乙酸酯脱乙酰基化为硫醇,并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,采用由二氯甲烷至乙酸乙酯的梯度洗脱剂,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(4-烯丙氧基-3-烯丙氧羰基苯基氨基甲酰基吡咯烷)-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.36(d,3H);2.57(br,2H);3.25,3.28(dd overlapping quintet,2H);3.47(br,1H);3.78(quintet,1H);4.01(dd,1H);4.18-4.27(dd overlapping m,2H);4.51(t,1H);4.58-4.79(m,6H);4.79(dt,2H);5.19-5.51(m,8H);5.83-6.12(m,4H);6.93(d,1H);7.79(dd,1H);7.85(d,1H);8.88(br,1H).
Ms(+ve FAB):696(MH)+,718(M+Na)+
实施例11
用实施例1的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,5-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,所不同的是,所得粗酸具有足够的纯度并且不需要层析。
Nmr(DMSO-d6+acetic acid-d4):δ 1.15(d,6H);1.77(m,part obscured,1H);2.69(m,part obscured,1H);2.85(m,part obscured,1H);3.19(dd,1H);3.33-3.51(m,2H);3.71(quintet,1H);3.94(quintet,1H);4.03(t,1H);4.15(dd,1H);8.18(t,1H);8.45(d,2H).
Ms(+ve FAB):520(MH)+,542(M+Na)+
所用原料如下制备:
基本上按实施例1所述使3-羧基-5-硝基苯甲酸烯丙基化,得到3-烯丙氧羰基-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.89-4.93(m,4H);5.33-5.50(m,4H);5.97-6.17(m,2H);9.00(t,1H);9.04(d,2H).
用实施例2的方法还原上述硝基化合物,得到3-烯丙氧羰基-5-氨基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.91(br,2H);4.80-4.84(m,4H);5.26-5.45(m,4H);5.96-6.11(m,2H);7.53(d,2H);8.09(t,1H).
如实施例1所述使上述胺与脯氨酸缩合,得到(2S,4S)-1-烯丙氧羰基-2-(3,5-二烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.60(br,2H);3.40(dd,1H);4.03(quintet,1H);4.14(dd,1H);4.58(t,1H);4.65-4.70(m,2H);4.83-4.87(m,4H);5.24-5.47(m,6H);5.84-6.16(m,3H);8.39(d,2H);8.45(t,1H);9.36(br,1H).
按实施例1的方法将上述硫基乙酸酯脱乙酰基化为硫醇并与碳代青霉烯磷酸酯缩合,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3,5-二烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.23(d,3H);1.35(d,3H);2.63(br,2H);3.25,3.29(dd overlapping m,2H);3.49(br,1H);3.84(quintet,1H);3.98(dd,1H);4.19-4.30(m,2H);4.55(t,1H);4.63-4.78(m,4H);4.84(d,4H);5.19-5.45(m,8H);5.84-6.12(m,4H);8.46(s,3H);9.18(br,1H).
Ms(+ve FAB):724(MH)+,746(M+Na)+
实施例12
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸
向氩气氛和无光的条件下,向(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-烯丙氧羰基苯基氨基甲酰基)-1-(4-硝基苄氧羰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸-4-硝基苄基酯(10g,12mM)和Meldrum酸(5.2g,36mM)于THF(70ml)中的溶液中加入四(三苯基膦)钯(1.4g,1.2mM)。该混合物在室温下搅拌30分钟。将该混合物用乙酸乙酯(230ml)稀释并加入碳酸氢钠(1.5g)于蒸馏水(200ml)中的溶液中。加入10% Pd-炭(4g)并将该混合物在氢气氛中氢化3小时。滤出催化剂,滤液用乙酸乙酯(2×100ml)和乙醚(2×100ml)提取,水层减压浓缩至约250ml。将该溶液分成两份,每个样品通过经过1升的HP20SS柱进行纯化,用水作为洗脱剂。收集纯馏分并冻干,得到标题化合物,为浅黄色固体(3.5g)。
Nmr(DMSO-d6+acetic acid-d4,positions sensitive to exact solvent ratio):δ 1.19(d,6H);1.94(dt,1H);2.97(dt,1H);3.13(dd,1H);3.25(dd,1H);3.42(dt,1H);3.68(dd,1H);3.94(quintet,1H);4.02(quintet,1H);4.22(dd,1H);4.32(t,1H);7.46(t,1H);7.73(dt,1H);7.88(dm,1H);8.27(t,1H).
Ms(+ve FAB):498(Na salt),520(di-Na salt).
所用原料如下制备:
用与实施例1中所述相似的方法使3-硝基苯甲酸(50g,0.3M)烯丙基化。在搅拌下将固体K2CO3(82.7g,0.6M)加入该酸于无水DMF(700ml)中的溶液。有少许放热且该混合物变稠。用30分钟加入烯丙基溴(38.8ml,0.45M)并将该混合物搅拌过夜。通过硅藻土过滤后,减压蒸发该溶液至干,将残留物分配在乙醚和NaHCO3水溶液之间。用稀HCl、盐水和水洗涤乙醚层,干燥并蒸发,得到黄色油状物(62g)。
Nmr(DMSO-d6):δ 4.85-4.92(m,2H);5.27-5.5(m,2H);5.97-6.2(m,1H);7.85(t,1H);8.37-8.42(dt,1H);8.48-8.54(dq,1H);8.64(t,1H).
不用进一步纯化而将该油状物用氯化锡和实施例6中所述的方法直接还原为3-氨基苯甲酸烯丙基酯(53g)。
Nmr(CDCl3):δ 3.6(broad,2H);4.77-4.82(dt,2H);5.24-5.44(m,2H);5.96-6.1(m,1H);6.83-6.88(m,1H);7.17-7.25(m,1H);7.35-7.47(m,2H).
通过将上述3-氨基苯甲酸烯丙基酯(26.6g,0.15M)悬浮于甲苯(750ml)中并加入EEQQ(44.5g,0.18M)而使其与4-乙酰硫基-1-(4-硝基苄氧羰基)-2-羧基吡咯烷(55.2g,0.15M)缩合。将该混合物搅拌过夜,用EtOAc(21)稀释并用稀HCl、水和盐水洗涤。将EtOAc层干燥并蒸发,残留物用乙醇重结晶,得到(2S,4S)-4-乙酰硫基-1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷(67.7g)。
Nmr(DMSO-d6):δ 1.93(quintet,1H);2.9(m,1H);3.35(m,1H);3.91-4.14(m,2H);4.49(quintet,1H);4.81(dd,2H);5.22(dd,2H);5.2-5.44(m,2H);5.95-6.10(m,1H);7.47(d,2H);7.66(t,2H);7.8-7.93(m,2H);8.18-8.3(m,2H);10.31(s,1H).
在0℃下通过将上述硫基乙酸酯(52.7g,0.1M)溶于脱气的烯丙基醇(11)并加入NaOH水溶液(2M,50ml)而将其转化为硫醇。3小时后,加入HCl水溶液(2M,52.5ml),蒸发溶剂并将残留物分配在EtOAc和盐水之间。EtOAc层用MgSO4干燥,过滤并蒸发。该硫醇不用进一步纯化而直接使用。
将(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯基磷酰氧基碳代青霉烯-3-甲酸-4-硝基苄基酯(59.68g,0.1M)于乙腈(500ml)和二氯甲烷(120ml)中的溶液冷至-15℃并缓慢加入乙基二异丙基胺(52.5ml)。在氩气氛下加入(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫醇(0.1M)于乙腈(400ml)中的溶液,将该混合物放置过夜。蒸发溶剂,所得残留物进行硅胶层析,用二氯甲烷、EtOAc和乙腈进行洗脱,得到(1R,5R,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸-4-硝基苄基酯,为黄色固体(52.6g)。
Nmr(DMSO-d6+CD3OD):δ 1.26(d,3H);1.35(d,3H);2.2-2.4(m,1H);2.7-2.95(m,1H);3.28-3.40(m,2H);3.54-3.63(m,1H);3.8(t,1H);4.01-4.1(q,1H);4.21-4.33(m,2H);4.61(dd,1H);4.73(d,2H);5.17-5.45(m,6H);5.93-6.11(m,1H);7.37-8.22(complex pattern of doublets and double doublets,12H).
实施例13
用与实施例12中所述相似的方法进行脱保护和氢化,所不同的是使用(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-烯丙氧羰基-5-氨基甲酰基苯基氨基甲酰基)-1-(4-硝基苄氧羰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸-4-硝基苄基酯(0.44g)。氢化后,将水层冻干,不用HP20SS层析,得到(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,为浅黄色固体(125mg)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.9(d,6H);1.98-2.06(m,1H);2.85-2.98(m,1H);3.16-3.21(m,1H);3.26(dd,1H);3.43(quintet,1H);3.74(dd,1H);3.91-3.97(m,1H);4.0(t,1H);4.23(dd,1H);4.39(t,1H);8.24(t,1H);8.33(t,1H);8.44(t,1H).
所用原料如下制备:
用与实施例1中所述相似的方法用1当量的烯丙基溴(2ml)将5-硝基间苯二甲酸(5g)转化为单烯丙基酯。用NaHCO3水溶液由有机相中提取出所需的酸(2.7g)。该有机层含有二烯丙基酯(2.7g)。得到单酸,3-烯丙氧羰基-5-硝基苯甲酸,为白色固体。
Nmr(CDCl3):4.87(d,2H);5.3-5.5(q,2H);5.97-6.15(m,1H);9.01(t,3H).
Ms(CI):252(MH)+
将DCCI(1.3g)加入上述酸(1.5g)和N-羟基琥珀酰亚胺(0.76g)于二氯甲烷(50ml)中的溶液中,该混合物在室温下搅拌2小时。滤出白色固体并将该溶液蒸发至干。将该活性酯在硅胶上进行纯化,用二氯甲烷进行洗脱,然后将其溶于二氯甲烷并用氨气在5℃下进行处理。沉淀出的白色固体是3-烯丙氧羰基-5-硝基苯甲酰胺(1.1g)。
Nmr(DMSO-d6):δ 4.9(dt,2H);4.88-4.93(m,2H);6.03-6.11(m,1H);7.83(broad s,1H);8.55(broad s,1H);8.75(t,1H);8.84(t,1H);8.94(t,1H).
Ms(CI):268(M+NH4)+
用与实施例12中的还原相似的方法用SnCl2还原3-烯丙氧羰基-5-硝基苯甲酰胺(1g),得到3-烯丙氧羰基-5-氨基苯甲酰胺(0.5g)。
Nmr(DMSO-d6):4.78(dt,2H);5.2-5.8(broad,2H);5.26-5.45(m,2H);5.91-6.13(m,1H);7.22(broad s,1H);7.27(t,1H);7.33(t,1H);7.59(s,1H).
Ms(CI):221(MH)+
用与实施例12中所述相似的方法将(2S,4S)-4-乙酰硫基-1-(4-硝基苄氧羰基)-2-羧基吡咯烷(0.75g)转化为酰氯并与3-烯丙氧羰基-5-氨基苯甲酰氨(0.45g)反应。所得粗产物进行硅胶层析,用EtOAc洗脱,得到4-乙酰硫基-1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基-5-氨基甲酰基苯基氨基甲酰基)吡咯烷(0.58g)。
Nmr(DMSO-d6):δ 1.92-2.06(m,1H);2.3(s,3H);2.79-2.83(m,1H);3.38(dd,1H);3.97-4.12(m,2H);4.49(dd,1H);4.83(dt,2H);5.19(dd,2H);5.25-5.43(m,2H);5.97-6.11(m,1H);7.31(broad s,2H);7.54(d,2H);8.04(d,2H);8.12(t,1H);8.26(t,1H);8.31(t,1H);10.0(s,1H).
用实施例12中所述的方法由上述硫基乙酸酯生成硫醇。
用与实施例12中所述相似的方法使(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸4-硝基苄基酯(0.6g)和(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基-5-氨基氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫醇(0.48g)于乙腈(20ml)中的溶液进行反应。通过快速层析进行纯化,用EtOAc然后用5%MeOH/EtOAc洗脱,得到(1R,5R,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基-5-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸4-硝基苄基酯,为黄色固体(0.44g)。
Nmr(DMSO-d6):δ 1.19-1.22(d,6H);2.0-2.11(m,1H);2.8-2.92(m,1H);3.32(dd,1H);3.42-3.62(m,2H);3.92-4.2(m,2H);4.31(broad d,1H);4.53(q,1H);4.84(d,2H);4.98-5.46(m,6H);5.98-6.14(m,1H);7.42-8.52(complex pattern of doublets and double doublets,11H).
实施例14
用与实施例12中所述相似的方法进行脱保护和氢化,所不同的是使用(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-烯丙氧羰基-6-氨基甲酰基苯基氨基甲酰基)-1-(4-硝基苄氧羰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸对硝基苄基酯。氢化后,将水层冻干,得到(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸。
Nmr(DMSO-d6+acetic acid-d4):δ 1.3-1.38(2xd,6H);2.0-2.11(m,1H);2.85-2.96(m,1H);3.09(dd,1H);3.37(dd,1H);3.53(quintet,1H);3.79(dd,1H);3.94(t,1H);4.16(t,1H);4.33(dd,1H);4.43(t,1H);7.87(dd,1H);7.97(d,1H);9.12(d,1H).
Ms(+ve FAB):541(Na salt),563(di-Na salt).
所用原料如下制备:
在-10℃下用草酰氯(2.63ml)、DMF(2.55ml)和N-甲基吗啉(7.95ml)使硝基对苯二甲酸(6.33g)于二氯甲烷(75ml)和THF(15ml)中转化为单酰氯。1小时后除去溶剂,不用进一步纯化,将该产物溶于烯丙醇(20ml)和THF(10ml)并在室温下搅拌过夜。脱除溶剂并将残留物分配在EtOAc和NaHCO水溶液之间。酸化该NaHCO3溶液并用EtOAc提取,得到产物,4-烯丙氧羰基-2-硝基苯甲酸(6.8g)。
Nmr(CDCl3):δ 4.89(d,2H);5.31-5.49(m,2H);5.95-6.15(m,1H);7.94(d,1H);8.36(dd,1H);8.54(d,1H).
不用纯化,通过上述方法将该酸转化成酰氯,将其溶于0℃的THF(100ml)中。将氨气鼓泡进该溶液直至反应完成。将该溶液分配在EtOAc和水之间,有机馏分的产物在硅胶上进行纯化,用二氯甲烷然后用EtOAc进行洗脱。用与实施例12中相似的方法用SnCl2还原含有少量杂质的产物(4g),得到4-烯丙氧羰基-2-氨基苯甲酰胺。
Nmr(DMSO-d6):δ 4.79(d,2H);5.22-5.46(m,2H);5.91-6.13(m,1H);7.02(dd,1H);7.37(d,1H);7.61(d,1H).
通过将(2S,4S)-4-乙酰硫基-1-(4-硝基苄氧羰基)-2-羧基吡咯烷(1.58g)悬浮于二氯甲烷(25ml)中而将其转化为酰氯并加入草酰氯(1.52ml)。加入几滴DMF。2小时后蒸发溶剂,在氩气氛下将溶于二氯甲烷(10ml)中的该酰氯加入4-烯丙氧羰基-2-氨基苯甲酰胺(0.52g)于0℃的含有N-甲基吗啉(0.38ml)的THF(10ml)和二氯甲烷(5ml)中的溶液。将该反应混合物放置过夜并分配在二氯甲烷和HCl稀水溶液之间。二氯甲烷级分用水、盐水洗涤并干燥。通过硅胶层析进行纯化,用增加浓度的EtOAc的二氯甲烷溶液洗脱,得到(2S,4S)-4-乙酰硫基-1-(4-硝基苄氧羰基)-2-(3-烯丙氧羰基-6-氨基甲酰基苯基氨基甲酰基)吡咯烷(0.84g)。
Nmr(CDCl3):δ 2.25(quintet,1H);2.29(s,3H);2.83(m,1H);3.53(dd,1H);4.02(quintet,1H);4.2(dd,1H);4.49(dd,1H);4.85(d,2H);5.23-5.46(m,2H);5.97-6.13(m,1H);7.31-7.5(broad,2H);7.57(d,1H);7.75(dd,1H);7.81-7.95(broad,2H);9.27(d,1H).
用与实施例2中所述相似的方法由上述硫基乙酸酯生成硫醇。
按实施例12中所述的方法使(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸4-硝基苄基酯和(2S,4S)-1-(4-硝基苄氧羰基)-2-(2-氨基甲酰基-5-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫醇于乙腈(20ml)中的溶液进行反应,得到(1R,5R,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-烯丙氧基-3-羧基-6-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸4-硝基苄基酯,为黄色泡沫体(1.24g)。
Nmr1.23-1.35(m,6H);2.2-2.38(m,1H);2.77-2.93(m,1H);3.27(dd,1H);3.28-3.42(m,1H);3.65-3.92(m,2H);4.17-4.35(m,3H);4.53(t,1H);4.83(d,2H);4.92-5.44(m,6H);5.93-6.11(m,1H);6.22-6.58(broad,2H);7.35-8.23(complex pattern of doublets and double doublets,10H);9.20(d,1H).
实施例15
用与实施例2中所述相似的方法进行脱保护和纯化(最终产物的层析在HP20SS柱上进行),所不同的是使用(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(2-二甲氨基羰基-3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。将层析柱所得的合适的水级分冻干,得到(1R,5S,6S,8R,2′S,4′S)-2-(2-(2-二甲氨基羰基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸。
Nmr(DMSO-d6+acetic acid-d4,mixture of rotamers):δ 1.17(d,6H);1.75(m,2H);2.65,2.72(2xs,overlapping m,4H);3.00,3.01(2xs,overlapping m,4H);3.17(dd,1H);3.41(quintet,1H);3.55(m,2H);3.96(m,2H);4.15(dd,1H);7.43(t,1H);7.68(m,1H);8.20-8.40(2xd,1H).
所用原料如下制备:
用实施例1中对于形成3-烯丙氧基-5-氨基苯甲酸烯丙基酯所述相似的方法将2-二甲氨基羰基-3-硝基苯甲酸(1g)转化为烯丙基酯,得到2-二甲氨基羰基-3-硝基苯甲酸烯丙基酯(0.88g)。
Nmr(DMSO-d6):δ 2.45(s,3H);2.97(s,3H);4.79(dd,2H);5.28-5.47(m,2H);5.9-6.1(m,1H);7.81(t,1H);8.28-8.4(dq,2H).
Ms(CI):279(MH)+
用与实施例1中所述的还原相似的方法用SnCl2还原烯丙基酯(0.44g),得到2-二甲氨基羰基-3-氨基苯甲酸烯丙基酯(0.41g),为清的红色油状物。
Nmr(CDCl3):δ 2.24(s,3H);3.06(s,3H);3.64(broad,2H);4.68(dd,2H);5.17-5.37(m,2H);5.82-6.02(m,1H);6.83(dd,1H);7.09-6.85(m,1H);7.37(dd,1H).
Ms(CI):249(MH)+
用与实施例12中所述的EEDQ方法类似的方法使2-二甲氨基羰基-3-氨基苯甲酸烯丙基酯(0.39g,1.4mM)与(2S,4S)-4-乙酰硫基-1-烯丙氧羰基-2-羧基吡咯烷(0.42g,1.54mM)缩合,得到(2S,4S)-1-烯丙氧羰基-2-(2-二甲氨基羰基-3-烯丙氧羰基苯基氨基甲酰基吡咯烷-4-基硫基乙酸酯(0.84g)。
Nmr(CDCl3,mixture of rotamers):δ 2.32(s,3H);2.38(br m,part obscured,1H);2.38(br m,part obscured,1H);2.74,2.76(2xs overlapping br m,4H);3.11,3.14(2xs,3H);3.36-3.45(m,1H);3.98-4.14(m,2H);4.50(dd,1H);4.56-4.79(m,4H);5.16-5.44(m,4H);5.93-6.06(m,2H);7.45(t,1H);7.81-7.86(m,1H);8.33-8.41(2xd,1H);8.60(br,1H).
Ms(CI):504(MH)+
用与实施例12中所述相似的方法由上述硫基乙酸酯生成硫醇。
用与实施例1中“被护的碳代青霉烯的制备”步骤中所述相似的方法使(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸烯丙基酯(0.73g,1.47mM)和(2S,4S)-1-(烯丙氧羰基)-2-(2-二甲氨基羰基-3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫醇于乙腈(12ml)中的溶液反应,得到(1R,5R,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(2-二甲氨基羰基-3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯,为白色固体(0.63g)。
Nmr(CDCl3,mixture of rotamers):δ 1.24(d,3H);1.35(2xd,3H);1.98(br,1H);2.34(br,1H);2.73(s,3H);3.11,3.13(2xs,3H);3.22-3.46(m,3H);3.66-3.85(m,1H);4.00-4.26(m,3H);4.50(t,1H);4.62-4.80(m,6H);5.08-5.46(m,6H);5.83-6.06(m,3H);7.46(td,1H);7.86(d,1H);8.29(m,1H);8.55(br,1H).
Ms(CI):711(MH)+
实施例16
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钾盐
向(1R,5S,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸4-烯丙基酯(0.4g,0.53mmol)于DMF(20ml)中的溶液中加入Meldrum酸(0.2g,1.39mmol)和四(三苯基膦)钯(40mg,0.035mmol)。该反应混合物在室温下搅拌1小时。在室温下将1M磷酸钾缓冲液(20ml)和锌粉(0.5g)的溶液加入该溶液,1小时后,该反应混合物用硅藻土过滤并用固体碳酸钾将滤液的pH调至7.5。过滤该溶液,减压浓缩,所得残留物通过反相层析进行纯化(Nucleosil C18),用水作为洗脱剂,冻干后得到标题化合物(78mg,28%)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.15(d,3H);1.17(d,3H);1.74(m,1H);2.06(s,3H);2.66(m,1H);2.84(m,1H);3.20(dd,1H);3.40(m,2H);3.70(m,1H);3.97(m,2H);4.16(dd,1H);7.92(s,1H);7.94(s,1H);8.19(s,1H).
所用原料如下制备:
将(2S,4S)-4-乙酰硫基-2-羧基-1-(4-硝基苄氧羰基)吡咯烷(1g,1.8mmol)和EEDQ(0.53g,3mmol)于氯仿(70ml)中的溶液在室温下搅拌1小时。然后将3-乙酰氨基-5-氨基苯甲酸(0.53g,2.7mmol)和二异丙基乙胺(0.7ml,4mmol)加入该反应混合物,将其在室温下搅拌2小时。蒸发溶剂后,粗化合物通过在HP20SS上层析进行纯化,用甲醇/水(80∶20)作为洗脱剂。部分蒸发溶剂,冷冻干燥,得到(2S,4S)-(4-硝基苄氧羰基)-2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯(1g,67%)。
将(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯溶于甲醇(60ml)和水(20ml)的混合物中,并用1M NaOH水溶液将该溶液的pH调至11。在室温下30分钟后,该反应混合物用甲醇中和,蒸发并通过在HP20SS上层析进行纯化,用甲醇/水(80∶20)作为洗脱剂。蒸发并冷冻干燥,得到(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫醇(0.68g,74%)。
Nmr(DMSOd6+acetic acid-d4):δ 2.05(m,1H);2.75(m,1H);3.20-3.80(m,2H);4.00(m,1H);4.42(m,1H);5.40(br s,2H);7.45-8.30(m,7H).
向(1R,5S,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯基磷酰氧基碳代青霉烯-3-甲酸4-硝基苄基酯(0.6g,1.2mmol)于DMF(12ml)中的溶液中顺序加入二异丙基乙胺(0.6ml,3.4mmol)、(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫醇(0.6g,1.2mmol)、三正丁基膦(0.6ml,2.4mmol)和水(0.1ml,5.5mmol)。将该反应混合物在4℃下搅拌过夜,蒸发至干,所得残留物通过在HP20SS树脂上层析进行纯化,用乙腈/水(40∶60)作为洗脱剂。蒸发并冷冻干燥,得到(1R,5R,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯(0.8g,88%)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.15(d,3H);1.17(d,3H);2.05(s,3H);2.17(m,1H);2.81(m,1H);3.26(dd,1H);3.36(td,1H);4.56-4.74(m,2H);5.02-5.73(m,4H);5.91(m,1H);7.47(d,1H);7.68(d,1H);7.85-7.99(m,3H);8.20-8.29(m,2H).
实施例17
(1R,5S,6S,8R,2′S,4′S)-2-(2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钾盐
用与实施例16类似的方法由(1R,5S,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸-4-烯丙基酯(二异丙基乙胺盐)制备标题化合物。
Nmr(DMSO-d6+acetic acid-d4):δ 1.14(d,3H);1.16(d,3H);1.75(m,1H);2.07(s,3H);2.73(m,1H);2.96(dd,1H);3.21(dd,1H);3.39(m,1H);3.54(dd,1H);3.78(m,1H);3.96(m,1H);4.08(t,1H);4.18(dd,1H);7.69(dd,1H);8.18(d,1H);8.42(d,1H).
MS(+ve FAB):571(MH)+,(K salt)
所用原料如下制备:
用与实施例16类似的方法由2-乙酰氨基-5-氨基苯甲酸制备(2S,4S)-1-(4-硝基苄氧羰基)-2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.95(m,1H);2.12(s,3H);2.34(s,3H);2.77(m,1H);3.32(m,1H);3.93-4.50(m,3H);5.04-5.32(m,2H);7.47-8.42(m,7H).
用与实施例16类似的方法由(2S,4S)-1-(4-硝基苄氧羰基)-2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯制备(2S,4S)-1-(4-硝基苄氧羰基)-2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫醇。
用与实施例16类似的方法由(2S,4S)-1-(4-硝基苄氧羰基)-2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫醇和(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸烯丙基酯制备(1R,5R,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(4-乙酰氨基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯(二异丙基乙胺盐)。
Nmr(CDCl3)δ:1.14-1.80(m,23H);2.17(s,3H);2.67(m,1H);3.00-3.30(m,3H);3.35-3.90(m,4H);3.90-4.40(m,3H);4.40-4.75(m,3H);5.00-5.75(m,4H);5.70-6.10(m,1H);7.38-8.65(m,7H).
实施例18
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钾盐
用与实施例16类似的方法由(1R,5S,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯制备标题化合物。
Nmr(DMSOd6+acetic acid-d4):δ 1.16(d,3H);1.17(d,3H);1.74(m,1H);2.64(m,1H);2.81(dd,1H);3.01(s,3H);3.20(m,1H);3.40(m,2H);3.68(m,1H);3.96(m,2H);4.17(dd,1H);7.54(s,1H);7.82(s,1H);8.00(s,1H).
MS(+Ve FAB):单钾盐607(M+H)+;二钾盐645(M+H)+。
所用原料如下制备:
用与实施例16类似的方法由3-氨基-5-甲磺酰氨基苯甲酸制备(2S,4S)-1-(4-(硝基苄氧羰基)-2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(DMSO-d6+acetic acid-d4):δ 2.00(m,1H);2.30(s,3H);2.84(m,1H);2.95(s,3H);3.20-3.51(m,1H);3.83-4.20(m,2H);4.30-4.58(m,1H);5.20(m,2H);7.48-8.22(m,7H).
用与实施例16类似的方法由(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯制备(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫醇。
Nmr(DMSO-d6+acetic acid-d4):δ 2.10(m,1H);2.78(m,1H);2.99(s,3H);3.43(m,1H);3.68(m,1H);4.05(m,1H);4.42(m,1H);5.13-5.32(m,3H);7.50-8.82(m,7H).
用与实施例16类似的方法由(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫醇和(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸烯丙基酯制备(1R,5S,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,3H);1.22(d,3H);1.96(m,1H);2.83(m,1H);3.00(s,3H);2.26-3.57(m,3H);3.87-4.28(m,4H);4.42-4.76(m,3H);5.08-5.42(m,4H);5.92(m,1H);7.22-8.22(m,7H).
实施例19
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐
向(1R,5S,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸-4-硝基苄基酯(0.5g,0.56mmol)于DMF(5ml)和水(5ml)中的搅拌的溶液中加入1M磷酸钠缓冲液(5ml),然后加入锌粉(1g)。将该反应混合物搅拌1小时并通过加碳酸氢钠的饱和水溶液将该溶液的pH调至8。用硅藻土过滤后,浓缩滤液,通过制备色谱(Nucleosil C-18)进行纯化,用水作为洗脱剂。将所需级分浓缩和冷冻干燥,得到标题化合物(44mg,12%)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.15(d,3H);1.16(d,3H);1.78(m,1H);2.73(m,1H);2.92(m,1H);3.21(dd,1H);3.40(m,1H);3.48(m,1H);3.75(m,1H);3.97(m,1H);4.03(m,1H);4.18(m,1H);7.93(s,1H);8.11(s,1H);8.29(s,1H).
MS(-ve FAB):单钠盐576(M-H)-;二钠盐598(M-H)-
所用原料如下制备:
用与实施例16类似的方法由3-氨基-5-磺基苯甲酸制备(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.97(m,1H);2.30(s,3H);2.80(m,1H);3.37(m,1H);3.86-4.15(m,2H);4.46(m,1H);5.05-5.28(m,2H);7.46-9.25(m,7H).
用与实施例16类似的方法由(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯制备(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫醇。
Nmr(DMSO-d6+acetic acid-d4):δ 1.25(d,3H);1.27(d,3H);2.07(m,1H);2.70(m,1H);3.4(m,1H);3.67(m,1H);3.99(m,1H);4.49(m,1H);5.07-5.30(m,2H);7.47-8.40(m,7H).
用与实施例1类似的方法由(2S,4S)-1-(4-硝基苄氧羰基)-2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫醇和(1R,5R,6S,8R)-6-(1-羟基乙基)-1-甲基-2-二苯磷酰氧基碳代青霉烯-3-甲酸4-硝基苄基酯制备(1R,5S,6S,8R,2′S,4′S)-2-(1-(4-硝基苄氧羰基)-2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸4-硝基苄基酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,3H);1.21(d,3H);1.96(m,1H);2.77(m,1H);3.18-3.47(m,2H);3.66-4.90(m,6H);5.04-5.50(m,4H);7.30-8.35(m,11H).
实施例20
(5S,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)碳代青霉烯-3-甲酸,二钠盐
在室温下,向(5R,6S,8R,4′S)-2-(1-烯丙氧羰基)-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)碳代青霉烯-3-甲酸烯丙基酯(0.185g,0.296mmol)于CH2Cl2(4ml)中的搅拌的溶液中顺序加入N-甲基苯胺(0.190g,1.776mmol)、水(4ml)、碳酸氢钠(100mg)和四(三苯基膦)钯(34mg,0.029mmol)。10分钟后,分离出水相并注在C18制备HLPC柱上,得到标题化合物(43mg,27%)。
Nmr(DMSO-d6+acetic acid-d4):1.16(d,3H);1.81(m,1H);2.64(m,1H);2.84(m,1H);3.26(m,3H);3.4(m,1H);3.67(m,1H);3.94(m,2H);4.12(m,1H);7.42(t,1H);7.65(d,1H);7.83(d,1H);8.27(s,1H).
用与实施例1中所述类似的方法,通过使实施例4中所述的(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-硫醇与(5R,6S,8R)-6-(1-羟基乙基)-2-二苯磷酰氧基碳代青霉烯-3-甲酸烯丙基酯(EP-A-126780和EP-A-208889)反应制备原料(5R,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)碳代青霉烯-3-甲酸烯丙基酯,产率为67%。
实施例21
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐
在氩气氛下,向(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯(358mg,0.54mM)和2,2-二甲基-1,3-二噁烷-4,6-二酮(388mg,2.7mM)于DMF(8ml)和THF(4ml)的混合物中的溶液中加入四(三苯基膦)钯(62mg,0.054mM)。在氩气氛及无光的条件下将该溶液搅拌1.75小时,并蒸除溶剂。将残留物溶于THF(6ml)和DMF(2ml)的混合物中,加入2-乙基己酸钠(295mg,1.77mM)于THF(4ml)中的溶液,接着加入乙醚(20ml)。离心分离所得沉淀物,除去上层清液。通过使该产物悬浮于THF(4ml)和乙醚(10ml)的混合物中然后悬浮于乙醚(20ml)中接着离心分离将其洗涤两次。将粗产物溶于水(20ml)中并用NaHCO3将pH调至7.4。过滤后,该溶液在HP20SS树脂上进行层析,合并适当的级分,得到标题产物(206mg,70%)。
Nmr(DMSO-d6+acetic acid-d4):δ 1.17(d,6H);1.95(m,part obscured,1H);2.83(m,1H);3.09(dd,1H);3.25(dd,1H);3.41(quintet,1H);3.64(dd,1H);3.88(quintet,1H);4.02(quintet,1H);4.22(dd,1H);4.31(t,1H);8.00(s,1H);8.28(t,1H);8.46(t,1H).
Ms(+ve FAB):523(MH)+,(Na salt)
所用原料如下制备:
3-氰基-5-硝基苯甲酸
将3-氨基-5-硝基苯甲酸(3.64g,20mM)溶于浓盐酸(20ml),用水(75ml)稀释,冷至0℃,用30分钟加到NaNO2(1.38g,20mM)于水(10ml)中的溶液中。用饱和Na2CO3溶液将pH调至6.2。将CuSO4·5H2O(10g,42mM)于水(40ml)中以及KCN(10g,154mM)于水(20ml)中的混合物加热至65℃,用15分钟加入重氮盐溶液,并将该混合物回流40分钟。冷却后,用2M盐酸酸化,有机相用乙酸乙酯(2×200ml)提取。合并的提取液用NaH2PO4水溶液、水、盐水洗涤,并用Na2SO4干燥。蒸发,得到3-氰基-5-硝基苯甲酸(3.6g,94%)。
Nmr(DMSO-d6):δ 8.69(t,1H);8.80(t,1H);8.97(t,1H).
Ms(-ve FAB):191(M-H)-
Ir(nujol):v2220cm-1
基本上按实施例1中的方法使3-氰基-5-硝基苯甲酸烯丙基化,所不同的是,层析纯化使用石油/乙酸乙酯(5∶1)的混合物,得到3-氰基-5-硝基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 4.91(dt,2H);5.39-5.53(m,2H);5.99-6.19(m,1H);8.78(t,1H);8.81(t,1H);9.04(t,1H).
Ms(+ve FAB):202M+;232(M+NH4)+;
(均为通过氨还原的氨基化合物)
用实施例1的方法还原上述硝基化合物,得到3-氨基-5-氰基苯甲酸烯丙基酯,m.p.112-113℃。
Nmr(DMSO-d6):δ 4.79(dt,2H);5.25-5.45(m,2H);5.94-6.13(m overlapping br,1H);7.10(t,1H);7.37(t,1H);7.48(t,1H).
Ms(+ve FAB):202M+;232(M+NH4)+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,用二氯甲烷/乙酸乙酯(19∶1~9∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.59(br,2H);3.38(dd,1H);3.97-4.17(m,2H);4.56(t,1H);4.69(d,2H);4.84(d,2H);5.26-5.48(m,4H);5.85-6.14(m,2H);8.03(br s,1H);8.18(t,1H);8.29(br s,1H);9.69(br,1H).
Ms(+ve FAB):458(MH)+;480(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫醇。
Nmr(CDCl3):δ 1.90(d,1H);2.52(br,1H);2.65(br,1H);3.34-3.52(m,2H);4.07(dd,1H);4.54(t,1H);4.69(d,2H);4.84(d,2H);5.27-5.47(m,4H);5.87-6.11(m,2H);8.01(s,1H);8.21(t,1H);8.28(s,1H);9.56(br,1H).
如实施例1所述使上述硫醇与碳代青霉烯磷酸酯缩合,通过层析进行纯化,用二氯甲烷/乙酸乙酯(3∶2至2∶3)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.27(d,3H);1.35(d,3H);2.67(v br,2H);3.21-3.33(overlapping m,2H);3.53(br,1H);3.83(quintet,1H);3.93(dd,1H);4.20-4.31(overlapping m,2H);4.54(t,1H);4.63-4.86(m,6H);5.21-5.47(m,6H);5.82-6.11(m overlapping br,3H);8.05(t,1H);8.33(br s,1H);8.37(br s,1H);9.35(br,1H).
Ms(+ve FAB):665(MH)+;687(M+Na)+
实施例22
用实施例21的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.17(d,3H);1.18(d,3H);1.83(m,part obscured,1H);2.76(quintet,1H);2.98(dd,1H);3.22(dd,1H);3.39(quintet,1H);3.56(dd,1H);3.81(s overlapping m,4H);4.00(quintet,1H);4.15,4.18(t overlapping dd,2H);7.22(t,1H);7.58(t,1H);7.84(t,1H).
Ms(-ve FAB):505(M-H)-,(Na salt)
所用原料如下制备:
基本上按实施例1的烯丙基化步骤使3-羟基-5-硝基苯甲酸甲基化,所不同的是用硫酸二甲酯代替烯丙基溴,不必进行层析纯化,得到3-甲氧基-5-硝基苯甲酸甲酯。
Nmr(CDCl3):δ 3.94(s,3H);3.97(s,3H);7.87(t,1H);7.90(t,1H);8.44(t,1H).
将上述酯(3.45g,16mM)溶于THF(100ml),用1M NaOH(25ml)处理,在室温下搅拌5小时。脱除溶剂后,所得残留物用水(50ml)处理,用2M硫酸酸化并用乙酸乙酯(3×60ml)提取。合并的有机提取液用NaH2PO4水溶液、盐水洗涤,用MgSO4干燥。蒸发,得到3-甲氧基-5-硝基苯甲酸,将其基本上如实施例1中所述进行烯丙基化,所不同的是层析纯化使用石油/乙酸乙酯(6∶1)的混合物,得到3-甲氧基-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.95(s,3H);4.87(dt,2H);5.31-5.48(m,2H);5.95-6.15(m,1H);7.89(t,1H);7.92(t,1H);8.46(t,1H).
Ms(CI):237M+;255(M+NH4)+
用实施例1的方法还原上述硝基化合物,得到3-氨基-5-甲氧基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 3.72(s,3H);4.50(v br,2H);4.75(dt,2H);5.25-5.43(m,2H);5.95-6.11(m,1H);6.47(t,1H);6.75(t,1H);6.93(t,1H).
Ms(CI):208(MH)+
如实施例1所述使上述胺与脯氨酸缩合,通过层析进行纯化,用石油/乙酸乙酯(5∶2~2∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.59(br,2H);3.38(dd,1H);3.85(s,3H);4.02(quintet,1H);4.15(dd,1H);4.55(t,1H);4.68(d,2H);4.81(d,2H);5.22-5.46(m,4H);5.83-6.13(m,2H);7.35(t,1H);7.58(br s,1H);7.64(t,1H);9.12(br,1H).
Ms(+ve FAB):463(MH)+;485(M+Na)+
如实施例1所述使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,用二氯甲烷/乙酸乙酯(60∶40至45∶55)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.25(d,3H);1.37(d,3H);2.64(v br,2H);3.21-3.33(overlapping m,2H);3.48(br,1H);3.80(quintet,1H);3.85(s,3H);4.01(dd,1H);4.19-4.29(overlapping m,2H);4.53(t,1H);4.62-4.83(m,6H);5.20-5.45(m,6H);5.84-6.11(m overlapping br,3H);7.25(t,1H);7.63(m,2H);8.90(br,1H).
Ms(+ve FAB):670(MH)+;692(M+Na)+
实施例23
用实施例21的方法以亚砜中心的非对映异构体的混合物形式制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2-甲亚磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.18(d,6H);1.87(m,part obscured,1H);2.64-2.91,2.82,2.84(m overlpping 2x s,5H);3.21(dd,1H);3.40(quintet,1H);3.52(dd,1H);3.71(quintet,1H);4.01(quintet,1H);4.01(m,1H);4.18(dd,1H);7.83(t,1H);7.94(td,1H);8.45(d,1H).
Ms(+ve FAB):560(MH)+,(Na salt);582(MH)+,(Na2salt)
所用原料如下制备
4-甲亚磺酰基-3-硝基苯甲酸
将4-甲硫基-3-硝基苯甲酸(4.36g,20mM)溶于乙酸(200ml),在室温下用H2O2(2.5ml,30%,22mM)处理。在室温下搅拌4天后,用偏亚硫酸氢钠分解过量的过氧化物,蒸发溶剂。所得残留物通过在硅胶上层析进行纯化,用甲醇洗脱,得到4-甲亚磺酰基-3-硝基苯甲酸(4.1g,89%),m.p.238-239℃。
Nmr(DMSO-d6):δ 2.90(s,3H);8.29(d,1H);8.56(dd,1H);8.68(d,1H).
Ms(-ve FAB):229(M-H)-
基本上如实施例1所述使上述酸烯丙基化,所不同的是不必进行层析纯化,得到4-甲亚磺酰基-3-硝基苯甲酸烯丙基酯,m.p.119-121℃。
Nmr(DMSO-d6):δ 2.91(s,3H);4.91(dt,2H);5.29-5.50(m,2H);5.99-6.18(m,1H);8.34(d,1H);8.61(dd,1H);8.69(d,1H).
用实施例1的方法还原上述硝基化合物,得到3-氨基-4-甲亚磺酰基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 2.92(s,3H);4.82(dt,2H);5.17(br,2H);5.28-5.46(m,2H);5.96-6.11(m,1H);7.30(dd,1H);7.41(m,2H).
Ms(EI):223(M-O)+;239M+
如实施例1所述使上述胺与脯氨酸缩合,通过层析进行纯化,用己烷/乙酸乙酯(3∶2至1∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲亚磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(DMSO-d6at 100°):δ 1.98(m,1H);2.32(s,3H);2.73(s,3H);2.86(m,part obscured,1H);3.36(m,1H);3.91-4.10(overlapping m,2H);4.48(dd,1H);4.53(m,2H);4.86(d,2H);5.11-5.49(m,4H);5.80-5.97(m,1H);6.01-6.15(m,1H);8.09(s,2H);8.35(s,1H).
Ms(+ve FAB):495(MH)+
如实施例1所述使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由乙酸乙酯至乙酸乙酯/异丙醇(98∶2)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲亚磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(DMSO-d6,mixture of rotamers):δ 1.18(d,6H);1.99(br,1H);2.80(soverlapping m,5H);3.25(solvent overlapping m,2H);3.54(m,1H);3.90-4.18(m,3H);4.15(dd,1H);4.55(m,4H);4.85(d,2H);5.06(d,1H);5.14-5.46(m,6H);5.79-6.13(m,3H);7.80-8.05(m,2H);8.12(m,1H);10.10(m,1H).
Ms(+ve FAB):702(MH)+
实施例24
用实施例21的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.16(d,3H);1.18(d,3H);1.75(quintet,1H);2.63(m,1H);2.79(dd,1H);3.20(s overlapping m,4H);3.38(m,2H);3.64(quintet,1H);3.95(m,2H);4.14(dd,1H);8.09(t,1H);8.44(m,2H).
Ms(-ve FAB):574(M-H)-,(Na salt)
所用原料如下制备:
3-甲硫基-5-硝基苯甲酸
将3-氨基-5-硝基苯甲酸(1.82g,10mM)溶于浓硫酸(1.9ml),用水(10ml)稀释,并冷至5℃。加入NaNO2(0.7g,10mM)于水(3ml)中的溶液并将该混合物搅拌30分钟。在3℃下将重氮盐的冷溶液加入甲硫基铜(Ⅰ)的淤浆中,并将该混合物搅拌45分钟。有机相用乙酸乙酯(5×60ml)提取,合并的有机层用NaH2PO4水溶液、水、盐水洗涤,用Na2SO4干燥。蒸发,得到3-甲硫基-5-硝基苯甲酸(1.77g,83%)。
Nmr(DMSO-d6):δ 2.63(s,3H);8.10(t,1H);8.21(t,1H);8.32(t,1H);13.68(br,1H).
Ms(-ve FAB):213(M-H)-
基本上如实施例1所述使上述酸烯丙基化,所不同的是层析洗脱剂是石油/乙酸乙酯(6∶1)的混合物,得到3-甲硫基-5-硝基苯甲酸烯丙基酯。
(CDCl3):δ 2.60(s,3H);4.87(dt,2H);5.32-5.49(m,2H);5.93-6.07(m,1H);8.20(m,2H);8.57(t,1H).
Ms(EI):253M+
3-甲磺酰基-5-硝基苯甲酸烯丙基酯
将3-甲硫基-5-硝基苯甲酸烯丙基酯(1.12g,4.4mM)溶于甲醇(30ml)并冷至2℃。缓慢加入“过氧单过硫酸钾”(2KHSO5·KHSO4·K2SO4,8.13g,13.2mM)于水(25ml)中的溶液,连续搅拌4小时。该混合物用水(60ml)稀释并用乙酸乙酯(3×100ml)提取。合并的有机提取液用水、盐水洗涤,用Na2SO4干燥。粗产物通过硅胶层析进行纯化,用石油/乙酸乙酯(3∶1至2∶1)进行梯度洗脱,得到3-甲磺酰基-5-硝基苯甲酸烯丙基酯(0.74g,59%)。
Nmr(DMSO-d6):δ 3.44(s,3H);4.94(dt,2H);5.32-5.53(m,2H);6.01-6.25(m,1H);8.78(t,1H);8.89(t,1H);8.91(t,1H).
用实施例1的方法还原上述硝基化合物,得到3-氨基-5-甲磺酰基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 3.15(s,3H);4.80(dt,2H);5.26-5.47(m,2H);5.95-6.15(m overlapping br,3H);7.29(t,1H);7.47(t,1H);7.51(t,1H).
如实施例1所述使上述胺与脯氨酸缩合,通过层析进行纯化,用己烷/乙酸乙酯(2∶1至1∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.34(s,3H);2.48(m,1H);2.62(m,1H);3.17(s,3H);3.41(dd,1H);4.03(quintet,1H);4.15(dd,1H);4.58(dd,1H);4.71(d,2H);4.84(dt,2H);5.27-5.47(m,4H);5.88-6.14(m,2H);8.23(br s,2H);8.37(t,1H);9.69(br,1H).
Ms(+ve FAB):511(MH)+;533(M+Na)+
如实施例1所述使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,用二氯甲烷/乙酸乙酯(55∶45至20∶80)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.36(d,3H);2.54(br,1H);2.66(br,1H);3.12(s,3H);3.19-3.22(overlapping m,2H);3.54(br,1H);3.87(quintet,1H);3.94(dd,1H);4.25,4.29(quintet overlapping dd,2H);4.55(t,1H);4.65-4.80(m,4H);4.85(d,2H);5.20-5.46(m,6H);5.86-6.12(m overlapping br,3H);8.31(br,1H);8.43(br,1H);8.52(br,1H);9.40(br,1H).
Ms(+ve FAB):718(MH)+;740(M+Na)+
实施例25
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-三氟甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐
Nmr(DMSO-d6+acetic acid-d4):δ 1.16(d,6H);1.92(m,part obscured,1H);2.77(m,part obscured,1H);3.00(dd,1H);3.21(dd,1H);3.37(quintet,1H);3.59(quintet,1H);3.80(quintet,1H);3.97(quintet,1H);4.20(m,2H);7.91(br s,1H);8.27(br s,1H);8.44(br s,1H).
Ms(-ve FAB):542(M-H)-,(acid);564(M-H)-,(Na salt)
所用原料如下制备:
基本上如实施例1所述使3-硝基-5-三氟甲基苯甲酸烯丙基化,所不同的是所得产物的纯度足以直接使用而不必进行层析,得到3-硝基-5-三氟甲基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 4.91(dt,2H);5.30-5.51(m,2H);5.99-6.20(m,1H);8.58(br s,1H);8.77(br s,1H);8.84(t,1H).
Ms(CI):275M+;293(M+NH4)+
用实施例2的方法还原上述硝基化合物,得到3-氨基-5-三氟甲基苯甲酸烯丙酯,其纯度足以直接使用而不必进行层析。
Nmr(DMSO-d6):δ 4.78(dt,2H);5.24-5.43(m,2H);5.93-6.13(m,1H);7.08(t,1H);7.27(br s,1H);7.44(t,1H).
Ms(CI):245M+;263(M+NH4)+
按实施例1所述使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(9∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-三氟甲基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯
Nmr(CDCl3):δ 2.33(s,3H);2.59(m,2H);3.39(dd,1H);4.04(quintet,1H);4.14(dd,1H);4.58(t,1H);4.62(dt,2H);4.85(dt,2H);5.23-5.48(m,4H);5.84-6.15(m,2H);8.03(br s,1H);8.23(br s,2H);9.60(br,1H).
Ms(+ve FAB):501(MH)+;523(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯/二氯甲烷(9∶1)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-三氟甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.21(d,6H);2.05(br,1H);2.85(br,1H);3.29(dd,1H);3.44(dd,1H);3.51(quintet,1H);3.93(br,1H);4.05-4.18(m,2H);4.27(dd,1H);4.43-4.71(overlapping m,5H);4.85(d,2H);5.16-5.46(m,6H);5.70-6.16(m,3H);7.94(br s,1H);8.37(br s,1H);8.53(br s,1H).
Ms(+ve FAB):708(MH)+;730(M+Na)+
实施例26
用实施例1的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,6H);1.93(m,part obscured,1H);2.86(quintet,1H);3.02(dd,1H);3.26(dd,1H);3.44(quintet,1H);3.68(dd,1H);3.84(quintet,1H);3.95(s,3H);4.03(quintet,1H);4.22(dd,1H);4.34(t,1H);7.13(d,1H);7.78(dd,1H);8.25(d,1H).
Ms(+ve FAB):528(MH)+,(Na salt);550(MH)+,(Na2salt)
所用原料如下制备:
基本上按实施例1的方法使4-甲氧基-3-硝基苯甲酸烯丙基化,所不同的是该产物的纯度足以直接使用而不必层析,得到3-硝基-4-甲氧基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.03(s,3H);4.83(dt,2H);5.29-5.46(m,2H);5.93-6.14(m,1H);7.14(d,1H);8.24(dd,1H);8.52(d,1H).
Ms(CI):237M+;255(M+NH4)+
用实施例2的方法还原上述硝基化合物,得到3-氨基-4-甲氧基苯甲酸烯丙基酯,其纯度足以直接使用而不必层析。
Nmr(CDCl3):δ 3.72(br,2H);3.90(s,3H);4.77(dt,2H);5.24-5.43(m,2H);5.95-6.10(m,1H);6.79(d,1H);7.41(d,1H);7.50(dd,1H).
Ms(CI):208(MH)+
如实施例4所述使上述胺与脯氨酸缩合,所不同的是所得产物通过硅胶层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(4∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.51(br,1H);2.66(br,1H);3.41(dd,1H);3.93(s,3H);4.01(quintet,1H);4.17(dd,1H);4.55(t,1H);4.64(d,2H);4.80(dt,2H);5.18-5.44(m,4H);5.81-6.14(m overlapping br,2H);6.91(d,1H);7.84(dd,1H);8.90(br,1H);9.01(d,1H).
Ms(+ve FAB):463(MH)+;485(M+Na)+
如实施例1所述使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯
Nmr(CDCl3):δ 1.23(d,3H);1.36(d,3H);2.52(br,1H);2.66(br,1H);3.22(dd,1H);3.28(quintet,1H);3.44(dd,1H);3.83(quintet,1H);3.93(s,3H);4.09(m,1H);4.19-4.31(overlapping m,2H);4.53(t,1H);4.65(m,4H);4.81(d,2H);5.19-5.45(m,6H);5.83-6.11(m,3H);6.91(d,1H);7.83(dd,1H);8.79(br,1H);9.04(d,1H).
Ms(+ve FAB):670(MH)+;692(M+Na)+
实施例27
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.17(d,6H);1.83(m,part obscured,1H);2.75(quintet,1H);2.97(dd,1H);3.23(dd,1H);3.40(quintet,1H);3.56(dd,1H);3.82(s+m,4H);3.99(quintet,1H);4.12(t,1H);4.19(dd,1H);7.09(d,1H);7.75(dd,1H);7.95(d,1H).
Ms(+ve FAB):528(MH)+,(Na salt);550(MH)+,(Na2salt)
所用原料如下制备:
基本上按实施例1中所述使2-甲氧基-5-硝基苯甲酸烯丙基化,所不同的是所得产物的纯度足以直接使用而不必进行层析,得到2-甲氧基-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.03(s,3H);4.85(dt,2H);5.30-5.49(m,2H);5.95-6.14(m,1H);7.08(d,1H);8.48(dd,1H);8.72(d,1H).
Ms(CI):238(MH)+;255(M+NH4)+
用实施例2的方法还原上述硝基化合物,得到5-氨基-2-甲氧基苯甲酸烯丙基酯,其纯度足以直接使用而不必进行层析。
Nmr(CDCl3):δ 3.39(br,2H);3.83(s,3H);4.80(dt,2H);5.23-5.47(m,2H);5.94-6.13(m,1H);6.83(d,2H);7.18(t,1H).
Ms(CI):208(MH)+
如实施例4所述使上述胺与脯氨酸缩合,所不同的是所得产物通过硅胶层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(4∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-4-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.58(br,2H);3.39(dd,1H);3.89(s,3H);4.02(quintet,1H);4.13(dd,1H);4.53(t,1H);4.66(dt,2H);4.80(dt,2H);5.23-5.48(m,4H);5.84-6.13(m,2H);6.94(d,1H);7.80(m,2H);8.94(br,1H).
Ms(CI):463(MH)+
按实施例1所述使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯浓缩,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-4-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.25(d,3H);1.36(d,3H);2.65(br,2H);3.25(dd,1H);3.28(quintet,1H);3.47(br,1H);3.79(quintet,1H);3.89(s,3H);4.01(dd,1H);4.18-4.29(overlapping m,2H);4.51(t,1H);4.66(m,4H);4.79(dt,2H);5.19-5.46(m,6H);5.84-6.11(m,3H);6.95(d,1H);7.79-7.87(m,2H);8.70(br,1H).
Ms(+ve FAB):670(MH)+;692(M+Na)+
实施例28
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.18(d,6H);1.85(m,part obscured,1H);2.66-2.86(overlapping m,2H);3.21(dd,1H);3.41(quintet,1H);3.52-3.72(overlapping m,2H);3.82(s,3H);3.99(quintet,1H);4.08(dd,1H);4.17(dd,1H);7.17(t,1H);7.45(dd,1H);8.41(dd,1H).
Ms(+ve FAB):528(MH)+,(Na salt);550(MH)+,(Na2salt)
所用原料如下制备:
基本上按实施例1的烯丙基化步骤使2-羟基-3-硝基苯甲酸甲基化,所不同的是用甲基碘代替烯丙基溴,不必进行层析纯化,得到2-甲氧基-3-硝基苯甲酸甲酯。
Nmr(DMSO-d6):δ 3.88(s,3H);3.90(s,3H);7.44(t,1H);8.04(dd,1H);8.12(dd,1H).
Ms(CI):212(MH)+;229(M+NH4)+
基本上用实施例22的方法使上述酯(3.45g,16mM)水解,所不同的是溶剂是DMSO而不是THF,得到2-甲氧基-3-硝基苯甲酸。
Nmr(DMSO-d6):δ 3.89(s,3H);7.40(t,1H);8.01(dd,1H);8.06(dd,1H).
Ms(CI):215(M+NH4)+
基本上按实施例1中所述使上述硝基酸烯丙基化,所不同的是该产物的纯度足以直接使用而不必进行层析,得到2-甲氧基-3-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.00(s,3H);4.86(dt,2H);5.31-5.50(m,2H);5.96-6.16(m,1H);7.27(d,1H);7.92(dd,1H);8.06(dd,1H).
Ms(CI):238(MH)+;255(M+NH4)+
用实施例1的方法还原上述硝基化合物,得到3-氨基-2-甲氧基苯甲酸烯丙基酯,其纯度足以直接使用而不必进行层析。
Nmr(CDCl3):δ 3.86(s,3H);3.92(br,2H);4.82(dt,2H);5.26-5.49(m,2H);5.96-6.16(m,1H);6.91(dd,1H);7.00(t,1H);7.23(dd,1H).
Ms(CI):208(MH)+;225(M+NH4)+
按实施例4的方法使上述胺与脯氨酸缩合,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.30(s,3H);2.53(br,1H);2.65(br,1H);3.41(dd,1H);3.86(s,3H);4.04(quintet,1H);4.16(dd,1H);4.58(t,1H);4.66(d,2H);4.83(dt,2H);5.20-5.47(m,4H);5.83-6.13(m overlapping br,2H);7.16(t,1H);7.60(dd,1H);8.57(dd,1H);9.15(br,1H).
Ms(+ve FAB):463(MH)+;485(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.35(d,3H);2.53(br,1H);2.68(br,1H);3.24(dd,1H);3.28(quintet,1H);3.43(br,1H);3.80(quintet,1H);3.83(s,3H);4.12(m,1H);4.19-4.29(overlapping m,2H);4.57(t,1H);4.64(m,4H);4.83(d,2H);5.18-5.48(m,6H);5.81-6.14(m,3H);7.17(t,1H);7.61(dd,1H);8.56(dd,1H);9.02(br,1H).
Ms(+ve FAB):670(MH)+;692(M+Na)+
实施例29
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.19(d,6H);1.88(m,part obscured,1H);2.31(s,3H);2.77(dt,1H);2.93(dd,1H);3.22(dd,1H);3.42(quintet,1H);3.57(dd,1H);3.77(quintet,1H);4.01(quintet,1H);4.16(t,1H);4.19(dd,1H);7.35(d,1H);7.69(dd,1H);8.39(d,1H).
Ms(+ve FAB):512(MH)+,(Na salt);534(MH)+,(Na2salt);556(M+Na)+,(Na2salt);
所用原料如下制备:
如实施例1中所述使4-甲基-3-硝基苯甲酸烯丙基化,所不同的是不必进行层析纯化,得到4-甲基-3-硝基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 2.59(s,3H);4.84(dt,2H);5.27-5.47(m,2H);5.96-6.16(m,1H);7.67(d,1H);8.16(dd,1H);8.44(d,1H).
Ms(EI):222(MH)+
用实施例2的方法还原上述硝基化合物,所不同的是溶剂为甲醇,得到3-氨基-4-甲基苯甲酸烯丙基酯,其纯度足以直接使用而不必进行层析。
Nmr(DMSO-d6):δ 2.10(s,3H);4.74(dt,2H);5.15(br,2H);5.22-5.43(m,2H);5.93-6.12(m,1H);7.04(d,1H);7.11(dd,1H);7.28(d,1H).
Ms(CI):192(MH)+;209(M+NH4)+
按实施例4的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(9∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(DMSO-d6,mix of rotamers):δ 1.97(quintet,1H);2.26(s,3H);2.34(s,3H);2.80(br,1H);3.30(br,1H);3.93-4.08(br m,2H);4.53(br,3H);4.80(dt,2H);5.10-5.44(m overlapping br,4H);5.78-6.13(m overlapping br,2H);7.38(d,1H);7.72(dd,1H);7.94(br,0.5H);8.01(br,0.5H);9.61(br,0.5H);9.67(br,0.5H).
Ms(CI):447(MH)+;464(M+NH4)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙酸乙酯(1∶1)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(DMSO-d6+acetic acid-d4,mix of rotamers):δ 1.16(d,3H);1.18(d,3H);1.98(quintet,1H);2.27(s,3H);2.86(br,1H);3.27(dd,1H);3.33(t,1H);3.56(quintet,1H);3.95(quintet,1H);4.02(dd,1H);4.15(quintet,1H);4.27(dd,1H);4.48-4.70(overlapping m,5H);4.80(d,2H);5.10-5.45(moverlapping br,6H);5.81-6.14(m overlapping br,3H);7.38(d,1H);7.75(dd,1H);8.01(br,0.5H);8.07(br,0.5H);9.60(br,1H).
Ms(+ve FAB):654(MH)+;676(M+Na)+
实施例30
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.15(d,3H);1.16(d,3H);1.78(dt,1H);2.48(s,3H);2.60(dt,1H);2.90(dd,1H);3.21(dd,1H);3.39(quintet,1H);3.49(dd,1H);3.73(quintet,1H);3.99(quintet,1H);4.03(t,1H);4.17(dd,1H);7.23(d,1H);7.70(dd,1H);8.12(d,1H).
Ms(+ve FAB):512(MH)+,(Na salt);534(MH)+,(Na2salt);556(M+Na)+,(Na2salt)
所用原料如下制备:
按实施例1中所述使2-甲基-5-硝基苯甲酸烯丙基化,所不同的是不必进行层析纯化,得到2-甲基-5-硝基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 2.65(s,3H);4.84(dt,2H);5.28-5.47(m,2H);5.99-6.18(m,1H);7.65(d,1H);8.31(dd,1H);8.57(d,1H).
Ms(CI):222(MH)+;0.99(M+NH4)+
用实施例2的方法还原上述硝基化合物,所不同的是溶剂为甲醇,得到5-氨基-2-甲基苯甲酸烯丙基酯,其纯度足以直接使用而不必进行层析。
Nmr(DMSO-d6):δ 2.33(s,3H);4.73(dt,2H);5.18(br,2H);5.23-5.44(m,2H);5.93-6.12(m,1H);6.68(dd,1H);6.95(d,1H);7.12(d,1H).
Ms(CI):192(MH)+;209(M+NH4)+
按实施例4的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(9∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基)-2-(3-烯丙氧羰基-4-甲基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(DMSO-d6,mix of rotamers):δ 1.91(br m,1H);2.33(s,3H);2.76(br m,1H);3.28(s overlapping m,4H);4.00(br m,2H);4.38(t,1H);4.51(br,2H);4.78(dt,2H);5.01-5.46(m overlapping br,4H);5.68-6.16(m overlapping br,2H);7.27(d,1H);7.72(dd,1H);8.11(br,0.5H);8.05(br,0.5H);10.17(br,1H).
Ms(+FAB):447(MH)+;469(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙酸乙酯(1∶1)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-4-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(DMSO-d6+acetic acid-d4):δ 1.19(d,6H);1.92(br,part obscured,1H);2.48(s,3H);2.79(br,1H);3.25(dd,1H);3.54(quintet,1H);3.91(br m,1H);4.01(quintet,1H);4.12(dd,1H);4.25(dd,1H);4.45(m,1H);4.50-4.68(m,4H);4.78(dt,2H);5.18-5.45(m,6H);5.70-6.13(m overlapping br,3H);7.25(d,1H);7.76(dd,1H);8.12(br m,1H).
Ms(+ve FAB):654(MH)+;676(M+Na)+
实施例31
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐
在氩气氛下将(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯(3g,4.59mM)和2,2-二甲基-1,3-二噁烷-4,6-二酮(3.97g,27.6mM)溶于DMSO(15ml)和THF(5ml)的混合物中,并加入四(三苯基膦)钯(531mg,0.46mM)。在氩气氛及无光的条件下将该溶液搅拌1小时。加入2-乙基己酸钠(1.53g,9.22mM)于THF(5ml)中的溶液,然后加入THF(250ml)。在氩气层下过滤所得沉淀物以除去水分,用小部分THF(二次)和乙醚顺序洗涤。将粗产物和NaHCO3(1.5g)溶于水(100ml)中,所得溶液在HP20SS树脂上进行层析,由水至水/乙腈(9∶1)进行梯度洗脱。合并适当的级分,冷冻干燥,得到(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.13(d,3H);1.15(d,3H);1.76(dt,1H);2.32(s,3H);2.68(dt,1H);2.87(dd,1H);3.18(dd,1H);3.36(quintet,1H);3.45(dd,1H);3.71(quintet,1H);3.95(quintet,1H);4.02(t,1H);4.14(dd,1H);7.49(s,1H);7.65(s,1H);8.05(s,1H).
Ms(+ve FAB):512(MH)+,(Na salt);534(MH)+,(Na2salt);556(M+Na)+,(Na2salt)
所用原料如下制备:
3-甲基-5-硝基苯甲酸
在搅拌下将3,5-二甲基硝基苯(30g,0.198M)在吡啶(400ml)和水(250ml)的混合物中加热至80℃。用0.75小时分批加入KMnSO4(62.7g,0.396M),并在85~90℃下继续加热1.75小时。该热溶液通过硅藻土过滤,用热水(150ml)洗涤。粉红色滤液用几滴偏亚硫酸氢钠脱色,并蒸发至干。将残留物溶于水(250ml)中,用乙醚(2×90ml)提取。将水层酸化(浓盐酸),用乙酸乙酯(3×120ml)提取。合并的有机提取液用NaHPO溶液、盐水洗涤,用MgSO4干燥。使粗产物通过一个硅胶垫进行洗脱,用乙酸乙酯/二氯甲烷/乙酸(25∶25∶1)的混合物作为洗脱剂,得到3-甲基-5-硝基苯甲酸(14.5g,40%)。
Nmr(DMSO-d6):δ 2.51(s,3H);8.17(s,1H);8.30(t,1H);8.42(t,1H);13.58(br,1H).
Ms(CI):181(MH)+
如实施例1中所述使3-甲基-5-硝基苯甲酸烯丙基化,所不同的是不必进行层析纯化,得到3-甲基-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 2.53(s,3H);4.87(dt,2H);5.31-5.48(m,2H);5.99-6.13(m,1H);8.20(s,1H);8.23(s,1H);8.68(s,1H).
Ms(CI):222(MH)+
用实施例1的方法还原上述硝基化合物,得到5-氨基-3-甲基苯甲酸烯丙基酯,其纯度足以直接使用而不需进行层析。
Nmr(CDCl3):δ 2.30(s,3H);3.46(br,2H);4.78(dt,2H);5.23-5.45(m,2H);5.93-6.12(m,1H);6.68(t,1H);7.17(t,1H);7.27(t,1H).
Ms(CI):192(MH)+;220(M+C2H5)+
按实施例4的方法使上述胺与脯氨酸缩合,用己烷/乙酸乙酯(3∶1)作为洗脱剂通过层析进行纯化,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.39(s,3H);2.58(br,2H);3.29(dd,1H);4.02(quintet,1H);4.13(dd,1H);4.56(t,1H);4.68(dm,2H);4.82(dt,2H);5.23-5.44(m,4H);5.86-6.12(m,2H);7.63(s,1H);7.85(s,1H);7.85(s,1H);9.09(br,1H).
Ms(+FAB):447(MH)+
按实施例1的方法使上述硫基乙酸酯脱烯丙基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,用二氯甲烷/乙酸乙酯(3∶2至2∶3)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.23(d,3H);1.35(d,3H);2.38(s,3H);2.63(br,2H);3.23(dd,1H);3.27(quintet,1H);3.46(br,1H);3.78(quintet,1H);4.00(dd,1H);4.24(overlapping m,2H);4.51(t,1H);4.59-4.63(m,4H);4.79(d,2H);5.17-5.42(m,6H);5.82-6.09(m,3H);7.61(s,1H);7.73(s,1H);7.99(s,1H);8.87(br,1H).
Ms(+ve FAB):654(MH)+
实施例32
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.18(d,6H);1.92(br,part obscured,1H);2.81(m,1H);3.03(dd,1H);3.23(dd,1H);3.41(quintet,1H);3.61(m,1H);3.90(s overlapping m,4H);4.00(quintet,1H);4.21(overlapping m,2H);8.25(t,1H);8.50(m,2H)L.
Ms(+ve FAB):556(MH)+,(Na salt);578(MH)+,(Na2salt)
所用原料如下制备:
如实施例1中所述使3-甲氧羰基-5-硝基苯甲酸烯丙基化,所不同的是不必通过层析进行纯化,得到3-甲氧羰基-5-硝基苯甲酸烯丙基酯。
Nmr(DMSO-d6):δ 3.97(s,3H);4.91(dt,2H);5.31-5.51(m,2H);6.00-6.19(m,1H);8.75(t,1H);8.81(d,2H).
Ms(EI):265M+
用实施例2的方法还原上述硝基化合物,所不同的是溶剂为甲醇,得到3-氨基-5-甲氧羰基苯甲酸烯丙基酯,其纯度足以直接使用而不必进行层析。
Nmr(DMSO-d6):δ 3.79(br,2H);3.92(s,3H);4.82(dt,2H);5.26-5.46(m,2H);5.94-6.14(m,1H);7.53(m,2H);8.07(t,1H).
Ms(CI):236(MH)+;253(M+NH4)+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(9∶1)进行洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.60(br,2H);3.40(dd,1H);3.94(s,3H);4.04(quintet,1H);4.14(dd,1H);4.58(t,1H);4.68(dm,2H);4.85(dt,2H);5.25-5.47(m,4H);5.85-6.16(m,2H);8.36(t,1H);8.43(m,2H);9.40(br,1H).
Ms(+FAB):491(MH)+;513(M+Na)+
在氩气氛下将(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯(1.2g,2.4mM)溶于THF(50ml),加入甲基胺水溶液(33%,w/v,0.51g,5.4mM)。继续搅拌3小时,脱除溶剂。所得残留物用2M盐酸处理并用乙酸乙酯处理。有机溶液用水、盐水、NaHCO水溶液洗涤,用MgSO4干燥。脱除溶剂,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫醇(1.02g,93%)。该硫醇按实施例1的方法不用进一步纯化而直接与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙酸乙酯(1∶1)进梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.37(d,3H);2.64(br,2H);3.26(dd overlapping quintet,2H);3.48(br,1H);3.86(quintet,1H);3.94(s overlapping m,4H);4.25(quintet,1H);4.29(dd,1H);4.56(t,1H);4.69(m,4H);4.86(dm,2H);5.19-5.46(m,6H);5.85-6.13(m,3H);8.46(m,3H);9.18(br,1H).
Ms(+ve FAB):698(MH)+;720(M+Na)+
实施例33
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,6H);1.96(m,part obscured,1H);2.81(m,1H);3.14(dd,1H);3.27(dd,1H);3.43(quintet,1H);3.73(m,1H);3.91(quintet,1H);4.04(quintet,1H);4.23(dd,1H);4.43(t,2H);7.29(t,1H);8.54(t,1H).
Ms(+ve FAB):534(MH)+,(Na salt);556(MH)+,(Na2salt)
所用原料如下制备:
2,4-二氟-5-硝基苯甲酸
将2,4-二氟苯甲酸(5g,0.031M)溶于浓硫酸(30ml)中并冷至0℃。搅拌该混合物,并滴加发烟硝酸(d 1.567g/ml,1.91ml,0.047M),将温度保持低于5℃。搅拌3小时后,将该混合物倒在冰上,有机相用二氯甲烷(2×75ml)提取。合并的有机层用水洗涤,干燥(MgSO4)并蒸发,得到2,4-二氟-5-硝基苯甲酸(3.9g,61%)。
Nmr(DMSO-d6):δ 7.18(t,1H);8.88(t,1H);9.93(br,1H).
Ms(-FAB):202(M-H)-
按实施例1的方法使2,4-二氟-5-硝基苯甲酸烯丙基化,所不同的是反应时间仅为1.5小时,DMF在使用前用IR-120-H离子交换树脂搅拌,不必通过层析进行纯化,得到2,4-二氟-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.88(dt,2H);5.31-5.50(m,2H);5.93-6.13(m,1H);7.13(t,1H);8.80(dd,1H).
Ms(EI):265M+
用实施例2的方法还原上述硝基化合物,所不同的是溶剂为甲醇,得到5-氨基-2,4-二氟苯甲酸烯丙基酯,其纯度足以直接使用而不必进行层析。
Nmr(CDCl3):δ 3.61(br,2H);4.81(dt,2H);5.26-5.48(m,2H);5.92-6.12(m,1H);6.83(t,1H);7.38(dd,1H).
Ms(CI):214(MH)+;231(M+NH4)+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(9∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.63(br,2H);3.39(dd,1H);4.04(quintet,1H);4.14(dd,1H);4.59(t,1H);4.66(dt,2H);4.83(dt,2H);5.22-5.49(m,4H);5.84-6.13(m,2H);6.94(t,1H);8.82(t,1H);9.22(br,1H).
Ms(+FAB):469(MH)+;491(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙酸乙酯(1∶1)进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.25(d,3H);1.38(d,3H);2.62(br,2H);3.24(dd overlapping quintet,2H);3.45(dd,1H);3.88(quintet,1H);4.03(dd,1H);4.25(quintet,1H);4.29(dd,1H);4.57(t,1H);4.68(m,4H);4.82(dm,2H);5.21-5.48(m,6H);5.85-6.10(m,3H);6.94(t,1H);8.85(t,1H);9.12(br,1H).
Ms(+ve FAB):676(MH)+;698(M+Na)+
实施例34
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2,4-二甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,6H);1.95(m,part obscured,1H);2.87(dt,1H);3.08(dd,1H);3.26(dd,1H);3.41(quintet,1H);3.71(dd,1H);3.87(quintet,part obscured,1H);3.91(s,3H);3.96(s,3H);4.03(quintet,1H);4.21(dd,1H);4.39(t,2H);6.76(s,1H);8.44(s,1H).
Ms(+ve FAB):558(MH)+,(Na salt);580(MH)+,(Na2salt)
所用原料如下制备:
2,4-二甲基-5-硝基苯甲酸
通过在冷却下将钠金属(1.42g,0.062M)溶于甲醇(40ml)中制备甲醇钠溶液。加入2,4-二氟-5-硝基苯甲酸烯丙基酯(5g,0.021M)并将该混合物搅拌2小时。加入NaOH(2g,0.05M)于水(10ml)中的溶液,将该混合物在室温下搅拌16小时。蒸发溶剂,将残留物溶于水(50ml)中,用乙醚(40ml)提取。水层用硫酸酸化,过滤所得的沉淀物并干燥,得到2,4-二甲氧基-5-硝基苯甲酸(4.23g,91%)。
Nmr(CDCl3):δ 4.07(s,3H);4.16(s,3H);6.62(s,1H);8.81(s,1H).
Ms(CI):228(MH)+;245(M+NH4)+
如实施例1中所述使2,4-二甲氧基-5-硝基苯甲酸烯丙基化,所不同的是不必通过层析进行纯化,得到2,4-二甲氧基-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ4.02(s,3H);4.04(s,3H);4.79(dt,2H);5.26-5.46(m,2H);5.93-6.13(m,1H);6.54(s,1H);8.63(s,1H).
Ms(+FAB):268(MH)+;290(M+Na)+
用实施例1的方法还原上述硝基化合物,得到5-氨基-2,4-二甲氧基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.25(br,2H);3.87(s,3H);3.90(s,3H);4.76(dt,2H);5.22-5.46(m,2H);5.93-6.12(m,1H);6.47(s,1H);7.29(s,1H).
Ms(CI):238(MH)+
按实施例4的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(4∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2,4-二甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.32(s,3H);2.49(br,1H);2.64(br,1H);3.40(dd,1H);3.91(s,3H);3.93(s,3H);4.00(quintet,1H);4.17(dd,1H);4.53(t,1H);4.64(d,2H);4.77(dt,2H);5.19-5.46(m,4H);5.80-6.14(m overlapping br,2H);6.49(s,1H);8.69(br,1H);8.81(s,1H).
Ms(+FAB):493(MH)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(5-烯丙氧羰基-2,4-二甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.22(d,3H);1.36(d,3H);2.48(br,1H);2.65(br,1H);3.23(dd,1H);3.28(quintet,1H);3.43(dd,1H);3.80(quintet,1H);3.91(s,3H);3.92(s,3H);4.09(dd,1H);4.24(quintet,1H);4.27(dd,1H);4.51(t,1H);4.66(m,4H);4.77(dt,2H);5.20-5.45(m,6H);5.83-6.11(m overlapping br,3H);6.49(s,1H);8.45(br,1H);8.82(s,1H).
Ms(+ve FAB):700(MH)+
实施例35
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(5-羧基-2-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.17(d,6H);1.83(mpart obscured,1H);2.62-2.79(overlapping m,2H);3.18(dd,1H);3.41(quintet,1H);3.66(quintet,1H);3.98(quintet,1H);4.07(dd,1H);4.17(dd,1H);7.79(m,2H);8.67(s,1H).
Ms(+ve FAB):523(MH)+,(Na salt);545(MH)+,(Na2salt)
所用原料如下制备:
4-氰基-3-硝基苯甲酸
在180℃及氩气氛下将4-氯-3-硝基苯甲酸(5.84g,29mM),氰化铜(5.2g,58mM)、氯化铜(0.96g,9.7mM)和喹啉(6.9ml,58mM)加热3.5小时。冷却后,将该混合物溶于浓盐酸(60ml),用水(80ml)稀释,用乙酸乙酯(3×100ml)提取。合并的有机层用NaH2PO4水溶液、盐水洗涤并用MgSO干燥。粗产物通过硅胶层析进行纯化,用二氯甲烷/乙酸(98∶2)的混合物洗脱,得到4-氰基-3-硝基苯甲酸(2.65g,48%)。
Nmr(DMSO-d6):δ 8.31(d,1H);8.41(dd,1H);8.68(d,1H).
Ms(EI):192M+
基本上如实施例1中所述使上述硝基酸烯丙基化,通过硅胶层析纯化该粗产物,用己烷:乙酸乙酯(6∶1)作为洗脱剂,得到4-氰基-3-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.93(dt,2H);5.37-5.50(m,2H);5.97-6.13(m,1H);8.03(d,1H);8.46(dd,1H);8.94(d,1H).
Ms(CI):221(MH)+;250(M+NH4)+
用实施例1的方法还原上述硝基化合物,得到3-氨基-4-氨基甲酰基苯甲酸烯丙基酯,用乙酸乙酯/汽油重结晶,m.p.149-150℃。
Nmr(DMSO-d6):δ 4.77(dt,2H);5.25-5.43(m,2H);5.96-6.11(m,1H);6.72(br,2H);7.04(dd,1H);7.25(br,1H);7.35(d,1H);7.63(d,1H);7.87(br,1H).
Ms(EI):220M+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,用己烷/乙酸乙酯(1∶1)洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3,mix of rotamers):δ 2.25(quintet,1H);2.28(s,3H);2.82(br,1H);3.52(dd,1H);4.13(t,1H);4.20(br m,1H);4.52(dd,1H);4.61(br,2H);4.85(d,2H);5.01-5.48(m overlapping br,4H);5.66-6.12(m overlapping br,2H);6.55(br,1H);6.89(br,1H);7.64(br m,1H);7.79(br m,1H);9.30(br m,1H);11.68(br,0.5H);12.06(br,0.5H).
Ms(+ve FAB):476(MH)+
(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯
将DMF(0.2ml,2.5mM)溶于乙腈(10ml),冷至-5℃,并用草酰氯(0.2ml,2.3mM)处理。搅拌30分钟后,加入(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯(1g,2.1mM)于乙腈(15ml)中的溶液,接着加入吡啶(0.38ml,4.6mM)。15分钟后,该混合物用乙酸乙酯(200ml)稀释,用盐酸(2M,20ml)、水、NaHCO水溶液和盐水洗涤,并用Na2SO4干燥。粗产物通过层析进纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(5-烯丙氧羰基-2-氰基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯(0.9g,93%)。
Nmr(CDCl3):δ 2.32(s,3H);2.63(br,2H);3.46(dd,1H);4.06(quintet,1H);4.16(dd,1H);4.64(t,1H);4.71(dt,2H);4.85(dt,2H);5.22-5.47(m,4H);5.87-6.14(m,2H);7.67(d,1H);7.87(dd,1H);8.96(d,1H);9.42(br,1H).
Ms(+ve FAB):458(MH)+;480(M+Na)+
按实施例1的方法使上述硫基乙酸乙酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.35(d,3H);2.60(br,2H);3.25(dd overlapping quintet,2H);3.52(br,1H);3.88(quintet,1H);4.02(dd,1H);4.25(quintet,1H);4.28(dd,1H);4.55-4.74(m,5H);4.85(dt,2H);5.18-5.468(m,6H);5.83-6.11(m,3H);7.65(dt,1H);7.87(dd,1H);9.00(br s,1H);9.25(br,1H).
Ms(+ve FAB):665(MH)+;687(M+Na)+
实施例36
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF。
Nmr(DMSO-d6+acetic acid-d4):δ 1.20(d,6H);1.99(dt,1H);2.91(dt,1H);3.26(dd overlapping m,3H);3.42(quintet,1H);3.74(dd,1H);3.96(quintet,1H);4.04(quintet,1H);4.22(dd,1H);4.41(t,1H);7.43(dm,1H);7.81(dd,1H);8.00(t,1H).
Ms(+ve FAB):516(MH)+,(Na salt);538(MH)+,(Na2salt)
所用的原料如下制备:
3-氟-5-硝基苯甲酸
将在氩气氛下的四氟硼酸硝基钠(3.53g,30.2mM)于乙腈(50ml)中的剧烈搅拌的淤浆在冰浴中冷却,分三批加入3-氨基-5-硝基苯甲酸(5.0g,27.5mM)。然后使温度升至室温,并将该混合物搅拌48小时。加入1,2-二氯苯(50ml),减压蒸除该混合物中的乙腈。然后当放气结束时将该混合物加热至170℃保持30分钟。冷却后,将该混合物倒入二氯甲烷(200ml)中,用NaHCO3溶液提取。水相用二氯甲烷反洗后,将其酸化(2M盐酸),有机相用乙酸乙酯(2×100ml)提取。合并的有机层用盐水洗涤并用MgSO4干燥。粗产物通过硅胶层析进行纯化,由二氯甲烷/乙酸(99∶1)至二氯甲烷/异丙醇/乙酸(80∶20∶1)进行梯度洗脱,得到3-氟-5-硝基苯甲酸(3.26g,64%)。
(DMSO-d6):δ 8.14(dm,1H);8.37(dt,1H);8.46(m,1H).
Ms(EI):185M+
3-氟-5-硝基苯甲酸烯丙基酯
将3-氟-5-硝基苯甲酸(3g,16.2mM)、对甲苯磺酸(1.54g,8.1mM)和稀丙醇(50ml)加热回流,使馏出物通过3
分子筛16小时。冷却后,该混合物用三乙胺中和并脱除溶剂。将残留物溶于乙酸乙酯,用2M盐酸、NaHCO3水溶液和盐水洗涤,用Na2SO4干燥。粗产物通过硅胶层析进行纯化,由二氯甲烷至乙酸乙酯/二氯甲烷(3∶1)进行梯度洗脱,得到3-氟-5-硝基苯甲酸烯丙基酯。
Nmr(CDCl3):δ 4.89(dt,2H);5.33-5.49(m,2H);5.95-6.15(m,1H);8.11(m,2H);8.70(t,1H).
Ms(CI):226(MH)+;253(M+C2H5)+
用实施例1的方法还原上述硝基化合物,得到3-氨基-5-氟苯甲酸烯丙基酯。
Nmr(CDCl3):δ 3.89(br,2H);4.79(dt,2H);5.25-5.45(m,2H);5.92-6.12(m,1H);6.54(dt,1H);7.07-7.15(m,2H).
Ms(CI):196(MH)+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(85∶13)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-5-氟苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3):δ 2.33(s,3H);2.59(br,2H);3.48(dd,1H);4.03(quintet,1H);4.13(dd,1H);4.56(t,1H);4.68(dt,2H);4.82(dt,2H);5.25-5.46(m,4H);5.86-6.11(m,2H);6.47(dm,1H);7.72(t,1H);7.87(dt m,1H);9.38(br,1H).
Ms(+ve FAB):451(MH)+;473(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-5-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3):δ 1.24(d,3H);1.36(d,3H);2.63(br,2H);3.26(dd,1H);3.29(quintet,1H);3.48(br,1H);3.81(quintet,1H);3.97(dd,1H);4.27(dd overlapping m,2H);4.54(t,1H);4.62-4.76(m,4H);4.81(dt,2H);5.20-5.46(m,6H);5.85-6.10(m overlapping br,3H);7.48(dt,1H);7.83(br s,1H);7.88(dt,1H);9.18(br,1H).
Ms(+ve FAB):658(MH)+;680(M+Na)+
实施例37
用实施例2的方法制备(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-N′-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,二钠盐,所不同的是用DMSO代替DMF,所得产物通过在CHP20P柱上层析进行纯化,用水进行洗脱。
Nmr(DMSO-d6+acetic acid-d4,run at 50°):δ 1.12(d,3H);1.18(d,3H);1.67(br,1H);2.13(br,1H);3.02(dd,1H);3.17(dd,1H);3.28(s overlapping m,5H);3.65(br,1H);3.98(quintet overlapping m,2H);4.12(dd,1H);7.58(d,1H);7.91(d,1H);7.98(m,1H).
Ms(+ve FAB):512(MH)+,(Na salt);534(MH)+,(Na2salt)
所用原料如下制备:
3-甲氨基苯甲酸烯丙基酯
将3-氨基苯甲酸烯丙基酯(5g,28.2mM)溶于原甲酸三乙酯(50ml)并加入三氟乙酸(5滴)。将该溶液搅拌并用3
分子筛回流5小时。脱除溶剂,将残留物溶于乙醇(50ml),接着分几批加入乙酸(8.08ml)和氰基硼氢化钠(6.85g,0.108mM)。该混合物在室温下搅拌16小时,脱除溶剂。将残留物溶于乙醚,用水、盐水洗涤,并用MgSO4干燥。粗产物通过硅胶层析进行纯化,由二氯甲烷至二氯甲烷/乙酸乙酯(95∶5)进行梯度洗脱,得到3-甲氨基苯甲酸烯丙基酯(0.93g,17%)。
Nmr(CDCl3):δ 2.88(s,3H);4.81(dt,2H);5.23-5.45(m,2H);5.94-6.13(m,1H);6.83(dd,1H);7.25(dd,1H);7.33(t,1H);7.43(dm,1H).
Ms(CI):192(MH)+
按实施例1的方法使上述胺与脯氨酸缩合,通过层析进行纯化,由二氯甲烷至二氯甲烷/乙醚(4∶1)进行梯度洗脱,得到(2S,4S)-1-烯丙氧羰基-2-(3-烯丙氧羰基-N′-甲基苯基氨基甲酰基)吡咯烷-4-基硫基乙酸酯。
Nmr(CDCl3,mixture of rotamers):δ 1.93(m,1H);2.32(s,3H);2.48(m,part obscured,1H);3.28,3.31(2 x s,3H);3.40(quintet,1H);3.76(m,1H);4.01(m,1H);4.24(m,1H);4.50-4.74(m,2H);4.86(d,2H);5.18-5.48(m,4H);5.84-6.13(m,2H);7.38-7.68(m,2H);7.90-8.11(m,2H).
Ms(+ve FAB):447(MH)+;469(M+Na)+
按实施例1的方法使上述硫基乙酸酯脱乙酰基化并与碳代青霉烯磷酸酯缩合,通过层析进行纯化,由二氯甲烷至乙酸乙酯进行梯度洗脱,得到(1R,5S,6S,8R,2′S,4′S)-2-(1-烯丙氧羰基-2-(3-烯丙氧羰基-N′-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸烯丙基酯。
Nmr(CDCl3,mixture of rotamers):δ 1.20(2 x d,3H);1.34(2 x d,3H);1.87(br,1H);2.30(br,1H);3.29,3.31(2 x s,overlapping m,6H);4.05-4.30(m,4H);4.50-4.81(m,5H);4.96(d,2H);5.20-5.48(m,6H);5.85-6.13(m,3H);7.39-7.68(m,2H);7.91-8.11(m,2H).
Ms(+ve FAB):654(MH)+;676(M+Na)+
Claims (18)
1、式(Ⅰ)的化合物或其可药用的盐或可体内水解的酯,
其中:
R1是1-羟基乙基、1-氟乙基或羟甲基;
R2是氢或C1-4烷基;
R3是氢或C1-4烷基;
R4和R5是相同或不同的,并且选自氢、囟素、氰基、C1-4烷基、硝基、羟基、羧基、C1-4烷氧基、C1-4烷氧羰基、氨基磺酰基、C1-4烷基氨基磺酰基、二C1-4烷基氨基磺酰基、氨基甲酰基、C1-4烷基氨基甲酰基、二C1-4烷基氨基甲酰基、三氟甲基、磺酸、氨基、C1-4烷基氨基、二C1-4烷基氨基、C1-4链烷酰氨基、C1-4链烷酰基(N-C1-4烷基)氨基、C1-4烷磺酰氨基和C1-4烷基S(O)n -,
其中n是0、1或2;
条件是在与-NR3-连接的链的邻位上没有羟基或羧基取代基。
2、根据权利要求1的化合物,其中R1是1-羟基乙基。
3、根据权利要求1或2的化合物,其中R2是氢或甲基。
4、根据权利要求1或2的化合物,其中R2是甲基。
5、根据权利要求1至4任一项的化合物,其中R3是氢。
6、根据权利要求1至5任一项的化合物,它具有式(Ⅳ):
其中R3、R4和R5如前述所定义。
7、根据权利要求6的化合物,其中R4和R5是相同或不同的并选自氢、氟、氯、羟基、羧基、氰基、硝基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、氨基甲酰基、甲基氨基甲酰基、二甲基氨基甲酰基、三氟甲基、磺酸、甲基亚磺酰基、甲基磺酰基、甲磺酰氨基或乙酰氨基。
8、根据权利要求6或7的化合物,其中R4和R5的至少一个是氢。
9、根据权利要求6的化合物,其中R4是氢、羧基、氟、氯、甲基、甲氧基、氰基、磺酸或甲氧羰基,而R5是氢。
10、根据权利要求1的化合物,它是
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-羟基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2,4-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,4-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-羟基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,5-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(2-氨基甲酰基-3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-乙酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲磺酰氨基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氨基甲酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2-二甲氨基羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(5R,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-2-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4,6-二甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-三氟甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4,6-二氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲基亚磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲磺酰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-N′-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,或其可药用的盐。
11、根据权利要求1的化合物,它是
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-甲氧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-甲氧羰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-氰基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氯苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-4-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-6-氟苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,4-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3,5-二羧基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,
(1R,5S,6S,8R,2′S,4′S)-2-(2-(3-羧基-5-磺基苯基氨基甲酰基)吡咯烷-4-基硫基)-6-(1-羟基乙基)-1-甲基碳代青霉烯-3-甲酸,或其可药用的盐。
12、一种药物组合物,它包含根据权利要求1至11任一项的化合物以及可药用的载体。
14、一种权利要求13中所定义的式(Ⅴ)化合物。
15、一种制备权利要求1的化合物或权利要求13中所定义的式(Ⅴ)化合物的方法,它包括:
a)使式(Ⅵ)化合物与式(Ⅶ)化合物反应:
其中R2、R4-R10如权利要求13中所定义,且L是离去基团,或
b)使式(Ⅷ)化合物环化:
其中R2、R4-R10如前所定义,而R11-R13独立地选自C1-6烷氧基、芳氧基、二C1-6烷基氨基和二芳基氨基或R11-R13的任意两个代表邻亚苯二氧基;或R11-R13之一是C1-4烷基、烯丙基、苄基或苯基,而其它两个独立地选自C1-4烷基、三氟甲基或苯基,其中任何苯基可被C1-3烷基或C1-3烷氧基任意取代;
并且任何官能团可被任意保护,以及以下如有必要:
(ⅰ)脱除任何保护基;
(ⅱ)形成可药用的盐;
(ⅲ)酯化形成可体内水解的盐。
16、一种权利要求1中所定义的式(Ⅰ)化合物,为非药用盐形式。
17、一种权利要求15中所定义的式(Ⅶ)或(Ⅷ)化合物。
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CA2099811A1 (en) * | 1992-07-21 | 1994-01-22 | Frederic H. Jung | Antibiotic compounds |
CA2106141A1 (en) * | 1992-09-28 | 1994-03-29 | Michael J. Betts | Antibiotic compounds |
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Cited By (10)
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CN1041633C (zh) * | 1993-03-16 | 1999-01-13 | 美国氰胺公司 | 新颖的2-硫代碳青霉烯 |
CN1067074C (zh) * | 1996-05-28 | 2001-06-13 | 麦克公司 | 碳代青霉烯类抗菌素、组合物及其制备方法 |
CN101367807B (zh) * | 2007-06-28 | 2011-01-12 | 山东轩竹医药科技有限公司 | 被巯基吡咯烷甲酰胺基吡啶取代的培南衍生物 |
CN101362760B (zh) * | 2007-08-07 | 2010-12-15 | 山东轩竹医药科技有限公司 | 1β-甲基碳代青霉烯化合物 |
CN101362761B (zh) * | 2007-08-12 | 2011-05-18 | 山东轩竹医药科技有限公司 | 含有巯基哌啶的碳代青霉烯抗生素 |
WO2012089058A1 (zh) * | 2010-12-31 | 2012-07-05 | 石药集团中奇制药技术(石家庄)有限公司 | 一种厄他培南钠晶型及其制备方法 |
US9012628B2 (en) | 2010-12-31 | 2015-04-21 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. | Crystalline form of ertapenem sodium and preparation method therefor |
CN106565579A (zh) * | 2016-06-26 | 2017-04-19 | 宁夏海诚电化信息科技有限公司 | 一种尔它培南侧链生产工艺 |
CN110698480A (zh) * | 2018-07-09 | 2020-01-17 | 武汉启瑞药业有限公司 | 一种厄他培南中间体的合成及纯化方法 |
CN110698480B (zh) * | 2018-07-09 | 2023-09-08 | 武汉启瑞药业有限公司 | 一种厄他培南中间体的合成及纯化方法 |
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