CN86106583A - 抗菌素的制备方法 - Google Patents
抗菌素的制备方法 Download PDFInfo
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- CN86106583A CN86106583A CN198686106583A CN86106583A CN86106583A CN 86106583 A CN86106583 A CN 86106583A CN 198686106583 A CN198686106583 A CN 198686106583A CN 86106583 A CN86106583 A CN 86106583A CN 86106583 A CN86106583 A CN 86106583A
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- 238000002360 preparation method Methods 0.000 title claims description 20
- 230000003115 biocidal effect Effects 0.000 title description 2
- -1 pivaloyl oxygen methyl esters Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000000126 substance Substances 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 31
- 239000002253 acid Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000001301 oxygen Substances 0.000 abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 abstract description 20
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 abstract description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- 239000000047 product Substances 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000003431 oxalo group Chemical group 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 229920001821 foam rubber Polymers 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 4
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 2
- DUNKKIRUWZSMPT-RXMQYKEDSA-N (5r)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CS[C@@H]2CC(=O)N12 DUNKKIRUWZSMPT-RXMQYKEDSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 150000007944 thiolates Chemical class 0.000 description 2
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- OJFLAJPKXKIQAC-UHFFFAOYSA-M 2-oxo-2-phenylmethoxyacetate;tetrabutylazanium Chemical compound [O-]C(=O)C(=O)OCC1=CC=CC=C1.CCCC[N+](CCCC)(CCCC)CCCC OJFLAJPKXKIQAC-UHFFFAOYSA-M 0.000 description 1
- VYLDBYOSHBXGNF-UHFFFAOYSA-N 2-oxo-2-phenylmethoxyacetic acid Chemical compound OC(=O)C(=O)OCC1=CC=CC=C1 VYLDBYOSHBXGNF-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 125000002217 penem group Chemical group 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
3R,4R-4-乙酸基-3-[1R-1-(甲硅烷氧基)乙基]-2-氮杂环丁烷酮转化成抗菌的5R,6S-6(1R-1-羟乙基)-2-(1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸和医药上可接受的盐及其特戊酰氧甲酯的方法和中间产品。
Description
本发明涉及一种制备5R,6S-6-(1R-1-羟乙基)-2-(1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸,其化学式为
或者制备一种在医药上可接受的阳离子盐或是它的特戊酰氧甲酯的改进的方法及其中间产品。尤其是盐或酯,为非对映异构体近似1∶1的混合物,混合物中penem2-取代基是(顺式-1-氧代-3-硫醇烷基硫代),即硫醇烷环取代基是彼止成比例的顺式。在欧洲专利申请130025的说明书中,首次叙述了这些化合物,该申请案进一步公开了用这些化合物作为抗菌剂的方法。
在欧洲专利130025中公开的合成方法是非常通用的,很容易做到各种各样类似物的合成。然而,对于个别的化合物,尤其是上述顺式化合物及其特戊酰氧甲酯,一种更直接的包括较少化学步骤的合成是非常合乎需要的。
对上述化学式(Ⅰ)化合物的一种引人注意的前体是3R,4R-4-乙酸基-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-氮杂环丁烷酮,其化学式为
从6-氨基-青霉烷酸有效地制备出化合物,例如采用Leanza等人在《四面体》39卷2505~2513页(1983)中提出的方法。在设计合成的第一阶段,Leanza等人提出的氮杂环丁烷酮被转化为新的化合物,其化学式为
然而,这种化合物对其后提出的与酰基氯的反应无效,因为酰基氯优先与产生无用产品的硫羟烷亚砜基起反应。但是,意外地以酰基氟代替酰基氯,导致对氮的选择酰化作用,预先形成无法利用的化合物,其化学式(Ⅲb)示于下文。这样,对于下文所示化学式(Ⅲa)的原料产生一种有用的东西,并且通过进一步转化,提供更有价值的下述化学式(Ⅱ)的中间产品。虽然上述二甲基-叔-丁基甲硅烷基羟基保护基是最佳的,当然其它的甲硅烷基羟基保护基也可代用。
因此,本发明针对如下化学式的化合物:
X是氢或氯;
其中,R3含义同上
R2是氢或一般的甲硅烷基羟基保护基(最好是二甲基-叔-丁基硅烷基)。但当R3是特戊酰氧甲基时,R2必须不是氢;
其中,R1是一般的甲硅烷基羟基保护基(最好是二甲基-叔-丁基甲硅烷基),R是氢或
其中,R3定义同上。
本发明还包括制备化学式(Ⅲb)化合物的方法
其中,R1和R3含义如上所述。该方法包括下述化学式的化合物
与化学式
的一个酰基氟的酰化作用。该作用在0~80℃时,在有叔胺存在和在反应惰性溶剂中进行,较低的温度例如-20~-70℃为最佳。该工艺过程还包括把产品(Ⅲb)通过化学式(Ⅱ)化合物转化到上述化学式(Ⅰ)化合物的常规方法。
最后,当R3是特戊酰氧甲基时,本发明的目标便是,用氟亚磺酸钾为试剂,把相应的酰基氯转化为酰基氟的方法。
“反应惰性溶剂”用来表示一种溶剂,这种溶剂不与试剂、中间产品或产品相互作用。对所需产品的产率有不利影响。
本发明也包括上述化学式(Ⅱ)的化合物转化为上述化学式(Ⅰ)的化合物或者它在医药上可接受的阳离子盐的方法,化学式(Ⅱ)中R2是氢,R3不是特戊酰氧甲基。
熟悉本技术领域的人员将知道苄基或对-硝基苄基脂可以代替上述烯丙基或2-氯烯丙基酯,于是,通过一般氢解过程,最终可除去保护基。
在本合成方法的第一阶段,外消旋顺式-或反式-3-(乙酰硫代)硫醇烷1-氧化物在反应惰性溶剂如异丙醇中,于绝对无水条件下通过碱金属醇盐如甲醇钠的作用转化成硫醇盐。转化过程最好在低温(例如
-5°~-45℃)下进行,以-20~-30℃为最佳。保持相同的无水
和低温的条件,硫醇盐(C)与二硫化碳反应,生成下述化学式的盐。
该盐接着与具有如上述化学式A的氮杂环丁烷酮反应,一般在稍高温度(例如-20~20℃),最好在-5~+5℃下生成上述化学式(Ⅲa)的化合物。每一种由此产生的顺式和反应产品皆由一对近似等量的非对映异构体组成。
然后,化学式(Ⅲa)的化合物与化学式(Ⅳ)的酰基氟在一般所述的条件和以上概述的条件下进行反应,最佳的初始温度为-45~-60℃,最大提高到-15~-25℃。理想的反应惰性溶剂是二氯甲烷,理想的叔胺是N,N-二异丙基乙烷。
在本合成的第二阶段中,化学式(Ⅱ)的化合物是在反应惰性溶剂(例如无乙醇氯仿)中,由三烷基亚磷酸酯(例如三乙基亚磷酸酯)对化学式(Ⅲb)化合物的作用所形成。而化学式(Ⅱ)含有完整的penem环系,式中R2是一个甲硅烷基保护基。对温度要求不严格,但一般在室温以上,例如40~80℃之间,当氯仿是溶剂时,可方便地达到回流温度。
在最后或次末阶段,用标准方法除去甲硅烷基保护基,例如在二甲基-叔-丁基甲硅烷基的情况下,则通过乙酸和四丁铵氟化物在无水四氢呋喃中的作用,以生成物的特戊酰氧甲酯形式或化学式(Ⅱ)的形式(其中R2是氢),生成化学式(Ⅰ)的化合物。
最后,当R3是烯丙基或2-氯烯丙基时,酯被水解,以酸或生成物在医药上可接受的阳离子盐形式生成所要求的化学式(Ⅰ)的penem。通常应用无水条件来避免降解β-内酰胺,最佳条件是在有三苯膦和四(三苯膦)钯(例如,前者大约为0.15摩尔当量,后者大约为0.075摩尔当量)的催化量的情况下,在无水反应惰性溶剂中(例如二氯甲烷和(或)乙酸乙酯),采用1~1.1摩尔当量的亲油羧酸碱金属盐(例如2-乙基己酸钠)。尽管温度要求不严格,但反应仍适宜在室温下进行。
所需的酰基氟(Ⅳ)由相应的酰基氯即以前用于该目的的试剂制备,或由无水氟化铯制取(通常在室温或接近室温时进行,而初始与试剂化合是在较低温度例如0~-30℃),或是由氟亚磺酸钾制取(FSO2K,通常在较热的温度例如45~85℃时进行)。出乎意料的是当R3是特戊酰氧甲基时,只有此最后一个试剂和条件会得到满意的酰基氟产率。
关于本发明方法所需的起始原料,3R,4R-4-乙酸基-3-〔1R-1-(甲硅烷氧基)乙基〕-2-氮杂环丁烷酮可根据上面引证的Leanza等人的方法容易得到。按照上面引证的欧洲专利申请的方法,每种外消旋顺式-和反式-3-(乙酰硫代)硫醇烷1-氧化物是可以得到的。根据Afonso等人在《美国化学学会杂志》104卷6138~6139页(1982)提出的方法,烯丙基乙二酸一酰基氯化物是可以得到的。根据下文详述的方法,2-氯烯丙基乙二酸一酰基氯化物可从2-氯烯丙基醇和草酰氯中得到。特戊酰氧甲基乙二酸一酰基氯化物可通过一系列步骤从草酸的苄基半酯和氯甲基特戊酸酯中制得,这也在下文中详述。
用例解的方法列举的下述实施例,但不能认作对本发明的限制,在本发明范围和精神内对本发明进行多方面的改变是允许的。
实施例1
3S,4R-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4-〔顺式-1-氧代-3-硫醇烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
配有机械搅拌器、滴液漏斗和低温温度计的经火焰干燥的三颈瓶,在氮气气氛下,装有外消旋顺式-3-(乙酰基硫代)硫醇烷1-氧化物(4.26克,23.9毫摩尔)和90毫升异丙醇。该反应被冷却到液温-20℃时,甲醇钠(1.18克,21.9毫摩尔)以一次添加。在-20~-25℃搅拌90分钟,然后升温到-10℃。该反应再被冷却到-30℃,并且逐滴加入溶于30毫升异丙醇的二硫化碳溶液(7.96克,104毫摩尔)历时超过半小时,然后在-25~-30℃搅拌40分钟。逐滴地加进溶于54毫升异丙醇的3R,4R-4-乙酸基-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-氮杂环丁烷酮的溶液(6克,20.9毫摩尔,Leanza等人在《四面体》39卷,2505~2513页(1983)提出〕超过30分钟,该反应在-20℃时搅拌30分钟,接着升温到0℃,并且在0~1℃搅拌90分钟。用150毫升饱和氯化铵溶液使该反应骤冷,然后添加200毫升乙酸乙酯,将该混合物转移到分液漏斗,同时加进150毫升盐水。有机相被分离而水相用添加的200毫升乙酸乙酯萃取,所合并的乙酸乙酯萃取物用100毫升一份的盐水洗涤两次。有机相被冷却到5℃并用硫酸镁干燥,然后过滤并在真空下浓缩,得到粘性油。该油与50毫升一份的二氯甲烷共沸四次,在高真空下泵送,得出包括两个化学名称的非对映异构体混合物的黄色泡沫体8.32克(90.5%)。
将上述泡沫胶试样与异丙基醚搅拌两小时,藉此制得分析试样。黄色固体经过滤后干燥。其熔点为85~89℃(分解)。
分析C16H29O3NS4Si:
计算值:C,43.69%;H,6.65%;N,3.19%。
实测值:C,43.41%;H,6.38%;N,3.06%。
红外线(KBr)/厘米1770
1H-核磁共振(CDCl3)δ(ppm):0.072(S,3H,CH3Si),0.077(S,3H,CH3Si),0.877(S,9H,叔-丁基),1.21(d,J=6.1Hz,3H,CH3),2.74~3.24(m,6H,3CH2),3.78(m,1H,CHS),4.29(dd,J=6.1、3.7Hz,1H,CH),4.55(m,1H,CHO),5.65(m,1H,CHS),6.65(bs,1H,NH)。
实施例2
3S,4R-N-〔(2-氯烯丙基氧基)草酰〕-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4〔顺式-1-氧代-3-硫醇烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
配备有滴液漏斗和低温温度计的经火焰干燥的三颈烧瓶,在氮气气氛下,装有上述实施例的产品(52.2克,118.7毫摩尔)和975毫升脱水二氯甲烷(通过中性的氧化铝)。该反应冷却到液温-50~-55℃,逐滴地加进2-氯烯丙基乙二酸一酰基氟化物(24.7克,148.4毫摩尔)超过20分钟,在-50~-55℃另搅拌10分钟。逐滴加进16.1克(124.6毫摩尔)N,N-二异丙基乙胺超过65分钟。在-50~-55℃搅拌75分钟。该反应可升温到-20℃,然后用900毫升水使它缓慢地冷却。有机相被分离,并用另外的900毫升水和900毫升盐水洗涤。用硫酸镁干燥有机相,过滤后真空浓缩,得到65.6克(94%)两个非对映异构体混合物的黄色泡沫胶。
1H-核磁共振(CDCl3)δ(ppm):0.33(S,3H,CH3Si),.095(S,3H,CH3Si),0.86(S,9H,叔-丁基),1.24(d,J=6.4Hz,3H,CH3),2.75~3.77(m,7H,硫醇烷),4.43(m,1H,CH),4.66(m,1H,CHO),4.84(S,2H,CH2),5.47(d,1H,乙烯基CH),5.56(d,1H,乙烯基CH),6.7和6.74(2d,J=3.7Hz,1H,NCHS)。
红外线(KBr)/厘米1820,1762,1708。
实施例3
2-氯烯丙基5R,6S-6-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸盐
配备有冷凝器和平衡附加漏斗的经火焰干燥的三颈烧瓶,在氮气气氛下,装有上述实施例的产品(15.6克,26.6毫摩尔)和800毫升无乙醇氯仿。该反应被加热到和缓的回流,于是在70毫升无乙醇氯仿中逐滴加进亚磷酸三乙酯(9.3克,56毫摩尔)历时超过8小时。再经8小时加热到有和缓的回流,然后冷却到室温,用真空浓缩。剩余物与冷的异丙醚搅拌后过滤及干燥,得到6.23克(43%)两个非对映异构体混合物近于纯白色固体,熔点为138~140℃。
分析:C21H32O5NS3ClSi
计算值:C,46.86%;H,5.99%;N,2.60%;S,17.87%;
实测值:C,46.71%;H,5.94%;N,2.46%;S,17.73%;
1H-核磁共振(CDCl3)δ(ppm):0.064(S,6H,2CH3Si),0.87(S,9H,叔-丁基),1.24(d,J=6.4Hz,3H,CH3),2.70~4.05(m,8H,CHCO,硫醇烷),4.25(m,1H,CH),4.74(q,JAB=14.1Hz,2H,CH2),5.38(d,J=0.5Hz,1H,CHS),5.66(m,2H,乙烯基CH2)。
红外线(KBr)/厘米1784。
实施例4
2-氯烯丙基5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫醇烷基硫代-2-penem-3-羧酸盐
配备有温度计和两个附加漏斗的经火焰干燥的三颈瓶,在氮气气氛下,装有上述实施例的产品(22.7克,42毫摩尔)和65毫升脱水四氢呋喃。该反应被冷却到液温5℃,并且逐滴加进25.2克(420毫摩尔)冰醋酸,需时超过15分钟,保持其液温5℃。在四氢呋喃(1M,126毫升)中一滴滴地加进四丁基氟化铵,需时1小时以上,保持液温5℃。该反应可以缓慢地升温至室温,并在室温下搅拌16小时。注入2000毫升冰冻水,用1000毫升乙酸乙酯萃取三次。合并的有机相萃取物用650毫升水洗涤三次、650毫升饱和碳酸氢钠洗涤两次以及用650毫升盐水洗涤两次,然后用用硫酸钠干燥,过滤后进行真空浓缩,得出14.4克(79%)两个非对映异构体混合物的黄色固体。把部分试样加入乙酸乙酯中研磨而制得标准试样,熔点为145~149℃(分解)。
1H-核磁共振(DMSO-d6)δ(ppm):1.17(d,J=6.8Hz,3H,CH3),2.38~4.04(m,9H,CHCO,CHO,硫醇烷),4.78(q,JAB=14.1Hz,2H,CH2),5.25(d,J=4.4Hz 1H,0H),5.48(S,1H,CHS),5.76(d,2H,乙烯基CH2)。
红外线(KBr)/厘米1769。
分析C15H18O5NS3Cl
计算值:C,42.49%;H,4.28%;N,3.31%。
实测值:C,42.79%;H,4.39%;N,3.28%。
实施例5
钠5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸盐
包在铝箔中的经火焰干燥的烧瓶,在氩气气氛下,将上述实施例的产品(18.2克,43毫摩尔)加入400毫升脱气二氯甲烷、三苯膦(1.69克,6.5毫摩尔)、2-乙基己酸钠(在乙酸乙脂中60毫升,0.82M,49毫摩尔)和四(三苯膦)钯(3.69克,3.2毫摩尔)中。该反应在室温下搅拌70分钟,补加350毫克四(三苯膦)钯,在室温下再搅拌25分钟。脱气乙酸乙酯(275毫升)加于该反应超过6分钟。该反应在室温下搅拌30分钟后过滤,固体迅速地被风干,然后用180毫升丙酮调30分钟,使其成浆状,再过滤和干燥,得到15.3克(97%)两个非对映异构体混合物的黄色固体产品,相当于欧洲专利申请130025第20页实施例2的顺式-1-氧代-3-硫醇烷基异构体。
用同样方法,下文实施例9的产品可转化成相同产率的同样标题的产品。
实施例6
5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸
上述实施例的钠盐(1克)溶解在10毫升水中,用3毫升丁醇萃取三次,再用3毫升乙酸乙酯萃取两次。水相与750毫克活性炭在0~5℃下搅拌45分钟,然后过滤。滤液用3毫升丁醇萃取三次,再用3毫升乙酸乙酯萃取两次。水相与750毫克活性炭在0~5℃下搅拌90分钟,然后进行过滤和冻干,得出696毫克浅褐式固体。该固体溶解在1.2毫升水中,被冷却到0~5℃,用1N盐酸酸化成pH2.6,在0~5℃下搅拌45分钟后进行过滤,用少量水洗涤,再干燥,得出374毫克两个非对映异构体混合物的白色固体,熔点178~181℃(分解)。
红外线(KBr)/厘米1778,1745
1H-核磁共振(DMSO-d6)δ(ppm):1.16(d,J=5.6Hz,3H,CH3),2.38~4.00(m,9H,CHCO,CHO,硫醇烷),5.25(bs,1H,OH),5.72(S,1H,CHS)。
分析C12H15O5NS3
计算值:C,41.24%;H,4.33%;N,4.01%。
实测值:C,41.32%;H,4.24%;N,3.82%。
实施例7
3S,4R-N-(烯丙基氧基草酰)-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4-〔顺式-1-氧代-3-硫醇烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
除了使反应混合物保持在-50℃3.5小时,以及在冷却之前不升温到-20℃以外,其它采取实施例2的步骤,使实施例1的标题产品(1.00克,0.00227摩尔)与烯丙基乙二酸一酰基氟化物(0.37克,0.00283摩尔)反应,得到本标题产品为1.19克黄色粘性油状物。
1H-核磁共振(CDCl3)300MHzδ:0.04(S,3H),0.10(S,3H),0.86(S,9H),1.24(d,3H,J=6.3Hz),2.74(m,3H),2.84(m,1H),3.17(m,1H),3.58(m,1H),3.79(dd,1H,J=8.8,14.7Hz),4.40(m,1H),4.79(d,2H,J=5.9Hz),5.32(dd,1H,J=1,10.5Hz),5.40(dd,1H,J=1,17.2Hz),5.94(ddt,1H,J=5.9,10.5,17.2Hz),6.70和6.72(2d,1H,J=3.5Jz)。
实施例8
烯丙基5R,6S-6-〔1R-1-(二甲基-叔-丁基甲硅烷基氧基)乙基〕-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸盐
采用实施例3的步骤,使上述实施例的产品(1.19克,0.00216摩尔)转化成本标题产品,取0.73克此产品用戊烷研碎而不用异丙醚。通过硅胶色谱法,用乙酸乙酯作为洗脱液进一步纯化0.415克本产品。薄层色谱法比移值为0.3(乙酸乙酯)。
1H-核磁共振(CDCl3)300MHzδ:0.08(S,6H),0.88(S,9H),1.25(d,3H,J=6.3Hz),2.6~2.9(m,4H),3.13(m,1H),3.64(m,1H),3.70和3.72(2dd,1H,J=1.5,4.7Hz),3.84和3.97(2dd,1H,J=8.4,14.2Hz),4.24(m,1H),4.70(m,2H),5.24(dd,1H,J=1.3,10.5Hz),5.40(dd,1H,J=1.3,17.1Hz),5.63和5.65(2d,1H,J=1.5Hz),5.93(ddt,1H,J=5.6,10.5,17.1Hz)。
实施例9
烯丙基5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3羧酸盐
采用实施例4的步骤,使上述实施例的产品(200毫克,0.397毫摩尔)转化成本标题产品。通过硅胶色谱法,用CH3OH∶乙酸乙酯为1∶19的洗脱液纯化1.33毫克本产品。
1H-核磁共振(CDCl3)300MHz:1.36(d,3H,J=6.2Hz),2.46和2.51(2brd,1H),2.6~2.9(m,4H),3.14(m,1H),3.6~3.8(m,2H),3.81和3.93(2dd,1H,J=8,14Hz,4.23(m,1H),4.66(dd,1H,J=5.6,13Hz),4.77(dd,1H,J=5.6,13Hz),5.25(d,1H,J=10.5Hz),5.41(d,1H,J=17.1Hz),5.67和5.70(2S,1H),5.94(ddt,1H,J=5.6,10.5,17.1)。
红外线(KBr)/厘米3233,1767,1681,1495,1316,1201,1124。
实施例10
3S,4R-N-特戊酰氧甲基氧草酰)-3-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-4-〔顺式-1-氧代-3-硫醇烷基硫代(硫代羰基)硫代〕-2-氮杂环丁烷酮
将实施例1的产品(4.65克,0.0106摩尔)溶解在21.1毫升脱水二氯甲烷中,并冷却到-30℃。加入特戊酰氧甲基草酰氟化物(4.36克,0.0211摩尔),使该混合物冷却到-50℃,通过注射器加进N,N-二异丙基乙胺(1.63克,2.21毫升,0.0127摩尔)需时5分钟以上。在此期间,该反应因化学反应放热而温升至-35℃,35分钟后在-35~-50℃,先用125毫升脱水二氯甲烷,再用185毫升水稀释该混合物。二氯甲烷层被分离,用185毫升淡水洗涤一次,然后用硫酸钠干燥,除去干燥剂后,得到本标题产品7.06克,虽有酰基氟污染,但对于下一步骤来说纯度是足够的。薄层色谱法比移值为0.3(乙酸乙酯)。
1H-核磁共振(CDCl3,90MHz)δ(ppm):0.04(S,3H),0.10(S,3H),0.88(S,9H),1.21和1.2~1.6(S和m,12H),2.6~3.4(m,5H),3.6~4(M,2H),4.4~4.8(m,2H),5.85(S,2H),7.2(m,1H)。
实施例11
特戊酰氧甲基5R,6S-6-〔1R-1-(二甲基-叔-丁基甲硅烷氧基)乙基〕-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸盐
采用实施例3的步骤,使上述实施例的产品(6.98克粗制品,6.52克纯品,0.0104摩尔)转化成粗制品的本标题的产品(11.8克)。未经滴定,在480毫升正己烷和90毫升二氯甲烷中,提取而进一步提纯,用300毫升水洗涤四次,然后用硫酸钠干燥,分离之即得黄色的油(8.71克),仍有亚磷酸三乙酯的气味。使亚磷酸三乙酯自乙酸乙酯(12毫升,用于溶解)和正己烷(165毫升到浊点,在三小时持续迟滞期间需300多毫升)中结晶,由此析出纯净的本标题产品2.50克。薄层色谱法比移值为0.15(乙酸乙酯)。
1H-核磁共振(CDCl3)δ(ppm):0.1(S,6H),0.9(S,9H),1.2(m,12H),2.4~4.5(m,9H),5.7(dd,1H),5.9(q,2H)。
实施例12
特戊酰氧甲基5R,6S-6-(1R-1-羟乙基)-2-(顺式-1-氧代-3-硫醇烷基硫代)-2-penem-3-羧酸盐
采用实施例4的步骤使上述实施例的产品(1.88克,3.25毫摩尔)转化成本标题产品,先用500毫升乙酸乙酯稀释该反应混合物,然后用150毫升盐水洗涤三次,用硫酸钠干燥并分离,藉此达到初步分离。由此形成的剩余物用200毫升乙酸乙酯再溶解,用150毫升水洗涤两次,每次都添加足够的盐水以破坏乳状液,所合并的含水萃取剂则用乙酸乙酯回洗,并且与原来的有机相合并。用硫酸钠干燥此有机相混合体,再剥离成泡沫胶1.66克,泡沫胶从乙酸乙酯和乙醚结晶析出而得到纯净的本标题产品1.34克。
红外线(KBr)2.96,5.60,5.69,5.91和6.75微米。
1H-核磁共振(CDCl3,250MHz)δ(ppm):1.23(S,9H),1.35(d,3H),2.5(bc,1H),2.6~2.9(C,4H),3.16(m,1H),3.62~4.0(C,3H),4.25(m,1H),5.7和5.72(2d,1H),5.88(q,2H)。
制备方法1
2-氯烯丙基乙二酸一酰基氟化物
〔(2-氯烯丙基氧基)草酰氯〕
CH2=CClCH2O(CO)COF
在干氮下,经火焰干燥的玻璃装置中,把氟化铯(167克,1.1摩尔)装入1升单颈瓶中,并且是在高真空条件下装入,用火焰慢慢地加热,直至固体变得能自由流动,然后冷却到室温。加入从CaH2(183毫升)中蒸馏出的乙腈,该混合物被冷却到液温-20℃。逐滴加进2-氯烯丙基乙二酸一酰基氯化物(183克,1.0摩尔)超过30分钟,缓慢地升温到室温,在室温下搅拌16小时,副产物氟化铯用乙腈洗涤,通过过滤回收。滤液和洗涤液合并移去,残余物在低温下蒸馏从而得到129克(77%)所要求的产品,沸点62~64℃/22毫米。
红外线(CHCl3)/厘米1770,1870
1H-核磁共振(CDCl3)δ(ppm):4.80(S,2H),5.4~5.6(m,2H)。
制备方法2
烯丙基乙二酸一酰基氟化物
〔烯丙基草酰氟化物〕
CH2=CHCH2O(CO)COF
通过上述制备方法,将烯丙基乙二酸一酰基氯化物(252.5克,1.70摩尔)和氟化铯(284克,1.87摩尔)转化成二次蒸馏得到的本标题产品,沸点48~50℃/35毫米;124~126℃(大气压)。
1H-核磁共振(CDCl3)250MHz,δ:4.76(d,2H,J=6Hz),5.28(dd,1H,J=1,7Hz),5.37(dd,1H,J=1,17Hz),5.90(ddt,1H,J=6,11,17Hz)。
13C-核磁共振(CDCl3)63MHz,δ:68.5(t),120.4(t),129.7(d),146.3(d,JC-F=375Hz),153.0(d,JC-C-F=87Hz)。
红外线(neat)1860(C=0),177(C=0),1120/厘米。
制备方法3
2-氯烯丙基乙二酸一酰基氯化物
〔(2-氯烯丙基氧基)草酰氯〕
在氮气气氛下将草酰氯(130毫升,1.49摩尔)放入干燥的三颈瓶中,并冷却到0℃,边搅拌边逐滴加进2-氯烯丙基醇(138克,1.49摩尔)把温度保持在0~2℃,以此方法控制HCl的剧烈逸出。然后才可升温至室温且保持16小时,并蒸馏得本标题产品214克,沸点82~84℃/23毫米。
制备方法4
苄基乙二酸一酰基氯化物
〔(苄基氧基)草酰氯〕
在氮气气氛中,将草酰氯(262毫升)溶于1升无水醚,并加热至回流,在该温度下,添加苄醇207毫千超过70分钟,待回流16小时后将醚蒸出,残余物经减压蒸馏,得到372克(94%)本标题产品,沸点85℃/0.7毫米。
制备方法5
草酸,半苄基酯
将浸于800毫升乙醚中的上例制备的标题产品(180克,0.91摩尔),置于丙酮干冰浴中冷却。当该混合物得以升温至0℃时,将氢氧化铵水溶液(2M,906毫升,0.91摩尔)分批加入,然后该混合物升温至室温,搅拌1小时,同时用95毫升2M氢氧化铵调节pH值至8.5。为分离水相,用400毫升乙醚萃取两次,用500毫升新鲜的乙醚使其分层,冷却至10℃,并且用2M HCl把pH值调节到1.5。有机相和水相被分离,水相用400毫升乙醚萃取两次,把三个酸性有机相加以合并用500毫升盐水洗涤,再用硫酸钠干燥并移去至得到白色固体的标题产品163克。
1H-核磁共振(CDCl3)δ(ppm):5.2(S,1H),6.95(S,2H),7.3(S,5H)。
制备方法6
苄基特戊酰氧甲基草酸
将上例制备的产品(163克,0.91摩尔)溶解于1升氯仿,用碳酸氢钠(76.2克,0.91摩尔)小心地中和(起泡沫)。另外,将1.5升水中的硫酸氢四丁铵(308克,0.91摩尔)与相同量的碳酸氢钠小心地中和。将前一个浆液缓慢地加到后一个溶液中,剧烈地搅拌20分钟,水相被分离,用500毫升新鲜的氯仿洗涤。有机相则合并为一,用硫酸钠干燥,分离之,得到四丁铵苄基草酸478克。将四丁铵苄基草酸溶解在400毫升丙酮中。加进氯甲基特戊酸酯(118毫升,0.82摩尔),在氮气气氛中,于室温下搅拌混合物16小时,蒸出丙酮,剩余物溶解在1升乙酸乙酯中,用500毫升水洗涤四次,用500毫升盐水洗涤一次,然后用硫酸钠干燥,除去硫酸钠,得到油状物的本标题产品201克。薄层色谱法比移值为0.60(乙酸乙酯与正己烷之比为2∶3)。
1H-核磁共振(CDCl,90MHz)δ(ppm):1.21(S,9H),5.2(S,2H),5.8(S,2H),7.3(S,5H)。
制备方法7
草酸,半特戊酰氧甲基酯
将上例制备的标题产品(27.3克,0.093摩尔)和2.8克10%pd/c混合在150毫升乙酸乙酯中,并于4个大气压及室温下,置于Paar氢化装置中氢化1.5小时。通过在硅藻土上的过滤,以回收催化剂。除去滤液,得到油状物的本标题产品19.3克。
1H-核磁共振(CDCl3,90MHz)δ(ppm):1.21(S,9H),5.96(S,2H),10.31(S,1H)。
制备方法8
特戊酰氧甲基乙二酸一酰基氯化物
将上例制备方法的标题产品(19.2克,0.094摩尔)溶解于20毫升苯,并分批加入到100毫升苯中的草酰氯(47.7克,33毫升,0.376摩尔)超过20分钟。30分钟后,蒸馏该混合物并蒸馏出残余物(19.2克),以得到本标题产品16.4克。沸点83℃/0.4毫米。
制备方法9
特戊酰氧甲基乙二酸一酰基氟化物
〔(特戊酰氧甲基草酰氟化物〕
(CH3)3C(CO)OCH2O(CO)COF
将氟亚磺酸钾(80%KSO2F,2.40克,含KSO2F为1.92克,0.016摩尔)加到草酰氯(3.50克,0.016摩尔),该混合物在油浴中逐渐加热到60℃,在此温度时,大量的气体开始逸出,移去油浴。一旦反应变弱,油浴就复位,使混合物升温至80℃,保持15分钟后冷却到60℃,在60℃时从油浴中蒸馏出本标题产品1.19克,沸点为52~54℃/0.4毫米。在-50℃时凝固,室温时熔化。
13C-核磁共振:在89Hz和252.6Hz情况下裂解草酸羰基,测得其值为176.6,152.6和151.5,148.1和140.2,81.7,38.8和26.6。
Claims (9)
2、根据权利要求1所述的方法,其中连接在硫醇烷环上的官能团具有顺式相关的立体化学结构。
6、根据权利要求5所述的方法,其中R3是
7、根据权利要求5所述的方法,其中R3是
-CH2-CH=CH2
8、根据权利要求5所述的方法,其中R3是
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US06/877,831 US4739047A (en) | 1985-10-17 | 1986-06-24 | Intermediates for 2-(1-oxo-3-thiolanyl)-2-penem antibiotics |
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YU43956B (en) | 1989-12-31 |
GR3002766T3 (en) | 1993-01-25 |
NO165839B (no) | 1991-01-07 |
ES2029794T3 (es) | 1992-10-01 |
CN86106583B (zh) | 1988-07-06 |
EP0223397B1 (en) | 1991-09-04 |
FI864182A (fi) | 1987-04-18 |
HUT45065A (en) | 1988-05-30 |
FI83654C (fi) | 1991-08-12 |
KR870004039A (ko) | 1987-05-07 |
IL80295A0 (en) | 1987-01-30 |
IE862739L (en) | 1987-04-17 |
NO864125L (no) | 1987-04-21 |
PT83560A (en) | 1986-11-01 |
KR890004559B1 (ko) | 1989-11-15 |
NZ217944A (en) | 1989-06-28 |
PL261891A1 (en) | 1988-08-04 |
NO165839C (no) | 1991-04-17 |
DK495286A (da) | 1987-04-18 |
HU198066B (en) | 1989-07-28 |
IE59260B1 (en) | 1994-01-26 |
ATE66923T1 (de) | 1991-09-15 |
EP0223397A3 (en) | 1988-12-14 |
DE3681255D1 (de) | 1991-10-10 |
PL149240B1 (en) | 1990-01-31 |
PT83560B (pt) | 1989-05-31 |
EG18143A (en) | 1992-08-30 |
NO864125D0 (no) | 1986-10-16 |
EP0223397A2 (en) | 1987-05-27 |
DK495286D0 (da) | 1986-10-16 |
FI864182A0 (fi) | 1986-10-16 |
YU176286A (en) | 1988-02-29 |
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