CN101007816A - Improved Biapenem preparation method - Google Patents
Improved Biapenem preparation method Download PDFInfo
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- CN101007816A CN101007816A CN 200610038044 CN200610038044A CN101007816A CN 101007816 A CN101007816 A CN 101007816A CN 200610038044 CN200610038044 CN 200610038044 CN 200610038044 A CN200610038044 A CN 200610038044A CN 101007816 A CN101007816 A CN 101007816A
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- dihydro
- triazole
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- pyrazolo
- biapenem
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- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 title claims abstract description 20
- 229960003169 biapenem Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 9
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 6
- PRWQCRRRNHMOGS-UHFFFAOYSA-N CS(=O)(=O)O.CS(=O)(=O)O.C1N=CN2N1CC(C2)SSC2CN1N(CN=C1)C2 Chemical compound CS(=O)(=O)O.CS(=O)(=O)O.C1N=CN2N1CC(C2)SSC2CN1N(CN=C1)C2 PRWQCRRRNHMOGS-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- TUCWRDCGELFJHN-UHFFFAOYSA-N methanesulfonate 1H-1,2,4-triazol-4-ium Chemical compound CS(=O)(=O)O.N1N=CN=C1 TUCWRDCGELFJHN-UHFFFAOYSA-N 0.000 claims description 4
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 150000003016 phosphoric acids Chemical class 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 239000002594 sorbent Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 239000003610 charcoal Substances 0.000 claims 1
- 230000001143 conditioned effect Effects 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 abstract 4
- 229950002475 mesilate Drugs 0.000 abstract 4
- 239000012467 final product Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 229940098779 methanesulfonic acid Drugs 0.000 abstract 1
- 238000001556 precipitation Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 235000019365 chlortetracycline Nutrition 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SDJHDRMYZQFJJO-UHFFFAOYSA-N ethanethioic s-acid;potassium Chemical compound [K].CC(S)=O SDJHDRMYZQFJJO-UHFFFAOYSA-N 0.000 description 2
- -1 ethyl formyl Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 2
- 229960002260 meropenem Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- FTMZGRHBYHVTTN-UHFFFAOYSA-N 1,5,6,7-tetrahydropyrazolo[1,2-a][1,2,4]triazole Chemical class C1N=CN2CCCN21 FTMZGRHBYHVTTN-UHFFFAOYSA-N 0.000 description 1
- NRSQCGUTOPAURA-UHFFFAOYSA-N 1,5,6,7-tetrahydropyrazolo[1,2-a][1,2,4]triazole-6-thiol Chemical compound C1N=CN2CC(S)CN21 NRSQCGUTOPAURA-UHFFFAOYSA-N 0.000 description 1
- YKMONJZIUAOVEM-WDSKDSINSA-N 1beta-methylcarbapenem Chemical compound C[C@H]1C=CN2C(=O)C[C@@H]12 YKMONJZIUAOVEM-WDSKDSINSA-N 0.000 description 1
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UIIXOFPRKPPCBR-UHFFFAOYSA-N 4-bromopyrazolidine-1,2-dicarbaldehyde Chemical compound BrC1CN(C=O)N(C=O)C1 UIIXOFPRKPPCBR-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- XSVQKTDPCLNSPD-UHFFFAOYSA-N C=CC.[Br] Chemical compound C=CC.[Br] XSVQKTDPCLNSPD-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 208000036209 Intraabdominal Infections Diseases 0.000 description 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229950011346 panipenem Drugs 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Abstract
The invention relates to a method for preparing biapenem. It comprises: carrying out salt precipitation with bi (6, 7- dihydro- 5H- pyrazole [1. 2a][1.2.4] triazole onium salt- 6- group ) dithioether bichloride and methanesulfonic acid, then getting the mesilate of 6, 7- dihydro- 5H- pyrazole [1. 2a][1.2.4] triazole onium salt- 6- group ) dithioether bichloride (side-chain mesilate)without column chromatography. The final product biapenem can be produced with mesilate which is produced by using side-chain mesilate and doublecyclic parent nucleus without column chromatography. The invention is characterized by reduced cost, temperate reaction condition, and suitability for industrial and large- scale production.
Description
Technical field
The present invention relates to a kind of improved, cost is low and the preparation method of effective and biapenem that can industrialized production.
Background technology
Carbapenem antibiotic (Carbapenems) belongs to the microbiotic of atypical beta-lactam brand new.Be used for the treatment of severe infections in the institute, multi-drug resistant bacteria infection and polyinfection etc., in recent years China be applied to the clinical Yi Mipeinan that Merck ﹠ Co., Inc. is arranged (Imipenem, Yi Mipeinan), Japan's three common panipenems (Panipenem) and the meropenem (Meropenem) of SUMITOMO CHEMICAL.
Biapenem (Biapenem) is novel 1 Beta-methyl carbapenem antibiotic, this product is 1 beta-methyl carbon penicillenic that the dicyclo triazole is arranged on 2 sulphur, have antimicrobial spectrum widely, Gram-negative, Gram-positive, aerophil and anerobe are all had good germicidal action; Stable to people DHP-I, need not with DHP-I inhibitor drug combination, and stable to β-Nei Xiananmei; Pharmacokinetic property is good, and toxicity is low; Concurrency intra-abdominal infection, lower respiratory infection (comprising bacterial pneumonia) and concurrency urinary tract infection there are good therapeutic action, better tolerance, the untoward reaction rate is low.Can predict the new line medicine that it will become the treatment severe infection.
Biapenem is by the injection carbapenem antibiotic kind of Japanese Lederle company and American Cyanamid Company's exploitation, is united in Japan by Japanese Lederle company and Japanese MingZhi fruit Co., Ltd in March, 2002 and goes on the market.
According to bibliographical information, biapenem synthetic mainly contains following two lines:
1, with the hydrazine hydrate is raw material,, with the acetone reaction, obtains 1-formyl radical-2-isopropylidene diamine again with the ethyl formate condensation.Above-mentioned product carries out alkylated reaction with the propylene bromine, obtains 1-allyl group-1 formyl radical-2-isopropylidene diamine, and product and formic acid reaction obtain 1-allyl group-1; 2-diformyl diamine; this reactant carries out bromo, cyclization, obtains 4-bromo-1,2-diformyl pyrazolidine.Product utilization thioacetic acid potassium mercaptolation, hydrolysis then, oxidation, salify in hydrochloric acid.The gained hydrochloride is with ethyl formyl imide hydrochloride reactant salt, and cyclization obtains two (6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole salt-6-yl) disulfide dihydrochlorides.The dicyclo product obtains side chain for biapenem 6,7-dihydro-6-sulfydryl-5H-pyrazolo [1,2-a] [1,2,4] triazole muriate with the reduction of tributyl phosphorus.This side chain is with bicyclic mother nucleus β-MEPDE condensation, and the last reduction of condensation product obtains target product biapenem (Toshio Kumagai et al., J.Org.Chem., 1998,63:8145～8149).
2, be raw material equally with the hydrazine hydrate, with the epoxy chloropropane cyclization, obtain 4-hydroxyl-1, the 2-pyrazolidine with the PNZ-Cl condensation, is protected amido then.The methylsulfonyl chloride chlorination of protection after product, by thioacetic acid potassium sulfhydrylation, hydrolysis obtains side chain 4-sulfydryl-1 then, two pairs of nitro benzyloxies of 2-acyl group pyrazolidine.Side chain is with parent nucleus β-MEPDE condensation, hydrogenation, and last and ethyl formyl imide hydrochloride reactant salt cyclization obtains the target product biapenem.
Route 1 raw material is easy to get, and reaction conditions is gentle, adopts more.But problems such as it also exists synthetic difficulty big, and polystep reaction needed column chromatography, and yield is low.
Summary of the invention
The present invention passes through by two (6,7-dihydro-5H-pyrazolo [1,2a] [1,2,4] triazole salt-6-yl) disulfide dichloride and methylsulfonic acid the reaction and after obtaining its mesylate, can obtain 6 without column chromatography, 7-dihydro-6-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole mesylate (being the side chain mesylate), and, also need not just can obtain biapenem when hydrogenation prepares the finished product through column chromatography by the condenses that side chain mesylate and bicyclic mother nucleus reaction make, the preparation biapenem needs column chromatography in the solution prior art, yield is low, problem that can not scale operation, and provide cost low, synthetic method efficiently.
The synthetic biapenem of the present invention may further comprise the steps, and Compound I I can prepare by the method (ToshioKumagai et al., J.Org.Chem., 1998,63:8145～8149) of bibliographical information:
Technical scheme of the present invention is as follows:
The preparation of step 1 pair (6,7-dihydro-5H-pyrazolo [1,2a] [1,2,4] triazole salt-6-yl) disulfide dimethanesulfonate (III)
Two (6,7-dihydro-5H-pyrazolo [1.2a] [1.2.4] triazole salt-6-yl) disulfide dichloride (II) are dissolved in the methyl alcohol, add methylsulfonic acid under the stirring at room, add the acetone crystallization in the residue behind the concentrating under reduced pressure, obtain the off-white color solid;
Step 26, the preparation of 7-dihydro-6-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole mesylate
With the product type white solid in the step 1, promptly two (6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-6-yl) disulfide dimethanesulfonate (III), tetrahydrofuran (THF) and the aqueous solution adds in the reaction flask, the icy salt solution cooling, add tributyl phosphorus and stir, after reaction finished, tetrahydrofuran (THF) was removed in decompression, the aqueous solution ethyl acetate and washed with dichloromethane, the water layer concentrating under reduced pressure, drying obtains the off-white color solid;
Step 3 pair nitrobenzyl (1R, 5S, 6S)-2-[(6,7-dihydro-5H-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole-6-yl) sulfenyl]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbon is for the preparation of mould-2-alkene-3-carboxylicesters mesylate
With the product type white solid in the step 2, promptly 6,7-dihydro-6-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] three n-formyl sarcolysine sulfonate (IV), bicyclic mother nucleus 1 Beta-methyl penem bicyclic mother nucleus are to drip diisopropylethylamine/tetrahydrofuran solution at ambient temperature after MAP (V), MeCN mix, and after the reaction reaction solution are concentrated, remove organic solvent, add CH
2Cl
2, stirring and separate out solid, filtration drying obtains condenses (VI), is faint yellow solid;
Step 4 (1R, 5S, 6S)-and 2-[(6,7-dihydro-5H-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole-6-yl) sulfenyl]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbon is the preparation of biapenem for mould-2-alkene-3-carboxylate salt (I)
Will be to nitrobenzyl (1R, 5S, 6S)-2-[(6,7-dihydro-5H-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] sulfenyl triazole-6-yl)]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbon is for mould-2-alkene-3-carboxylicesters mesylate (VI), the palladium charcoal, propyl carbinol and water mix, regulate pH value with phosphoric acid salt, room temperature, the hydrogen pressure of 5atm stirs down, reaction finishes the back reduzate did not need column chromatography, boiled off most of reaction solvent earlier, added organic solvent (preferred acetone), add water-retaining agent again (as anhydrous magnesium sulfate, anhydrous sodium sulphate etc.) and sorbent material (preferred diatomite, silica gel, gac) to remove moisture content and impurity, stir after-filtration, use the dehydrated alcohol recrystallization, filtration drying.
Detailed Description Of The Invention
Embodiment by explanation the inventive method in the lower section illustrates one preferred embodiment.But it never is used for limiting the scope of the invention.
Preparation biapenem embodiment
The preparation of step 1 pair (6,7-dihydro-5H-pyrazolo [1,2a] [1,2,4] triazole salt-6-yl) disulfide dimethanesulfonate
With 8g two (6,7-dihydro-5H-pyrazolo [1.2a] [1.2.4] triazole salt-6-yl) disulfide dichloride (II) is dissolved in the 20ml methyl alcohol, add the 5ml methylsulfonic acid under the stirring at room, add 7.5ml acetone crystallization in the residue behind the concentrating under reduced pressure, obtain off-white color solid 7.8g.
Step 26, the preparation of 7-dihydro-6-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole mesylate
With the product type white solid in the step 1, promptly two (6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-6-yl) disulfide dimethanesulfonate (III) 6g, 30ml tetrahydrofuran (THF) and the 30ml aqueous solution add in the reaction flask, icy salt solution is cooled to 0 ℃, add tributyl phosphorus 6.85g then in 0 ℃ of stirring 2 hours, reaction finishes, and tetrahydrofuran (THF) is removed in decompression, the aqueous solution is washed twice with ethyl acetate and methylene dichloride, the water layer concentrating under reduced pressure, Vanadium Pentoxide in FLAKES vacuum-drying obtains off-white color solid 1.9g.
Step 3 pair nitrobenzyl (1R, 5S, 6S)-2-[(6,7-dihydro-5H-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole-6-yl) sulfenyl]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbon is for the preparation of mould-2-alkene-3-carboxylicesters mesylate
With (IV) 1.5g, 1 Beta-methyl penem bicyclic mother nucleus bicyclic mother nucleus (V) is Dropwise 5 ml diisopropylethylamine/5ml tetrahydrofuran solution at ambient temperature after MAP 3.3g, 20ml MeCN mix, react after 3-4 hour reaction solution is concentrated, remove organic solvent, add 25mlCH
2Cl
2, stirring and separate out solid, filtration drying obtains condenses VI, is faint yellow solid 2.1g.
Step 4 (1R, 5S, 6S)-and 2-[(6,7-dihydro-5H-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole-6-yl) sulfenyl]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbon is the preparation of biapenem for mould-2-alkene-3-carboxylate salt (I)
With 1.5g (VI), 0.3g 10%Pd-C, 30ml propyl carbinol and 30ml water mix the back and regulate pH 4.5～5.5 with Sodium phosphate dibasic, stir 1 hour under the hydrogen pressure of room temperature, 5atm then.Remove by filter catalyzer, and regulate pH once more 4.5～5.5, concentrating under reduced pressure adds 20ml acetone to about 5ml volume, adds anhydrous magnesium sulfate, diatomite.Stirred 2 hours, and filtered, boil off acetone, use the dehydrated alcohol recrystallization, filtration drying gets biapenem 0.52g.
Claims (4)
1. the method for biapenem shown in the preparation formula I is made of the following step:
Formula I
Step 1 is dissolved in two (6,7-dihydro-5H-pyrazolo [1.2a] [1.2.4] triazole salt-6-yl) disulfide dichloride in the methyl alcohol, adds methylsulfonic acid under the stirring at room, adds the acetone crystallization in the residue behind the concentrating under reduced pressure, obtains the off-white color solid;
Step 2, with the off-white color solid product in the step 1, promptly two (6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole-6-yl) disulfide dimethanesulfonate, tetrahydrofuran (THF) and the aqueous solution add in the reaction flask, the icy salt solution cooling, adding tributyl phosphorus stirs, remove impurity after reaction finishes, the concentrating under reduced pressure drying obtains the off-white color solid;
Step 3, with the off-white color solid product in the step 2, promptly 6,7-dihydro-6-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] triazole mesylate, 1 Beta-methyl penem bicyclic mother nucleus are to drip diisopropylethylamine/tetrahydrofuran solution at ambient temperature after MAP, MeCN mix, after the reaction reaction solution is concentrated, remove organic solvent, add CH
2Cl
2, stirring and separate out solid, filtration drying obtains faint yellow solid;
Step 4, will be to nitrobenzyl (1R, 5S, 6S)-2-[(6,7-dihydro-5H-sulfydryl-5H-pyrazolo [1,2a] [1,2,4] sulfenyl triazole-6-yl)]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbon is dissolved in the mixed solvent of propyl carbinol and water for mould-2-alkene-3-carboxylicesters mesylate, adding the palladium catalyst charcoal, is slightly acidic with the pH value of phosphoric acid salt conditioned reaction solution, room temperature, the hydrogen pressure of 5atm is reaction down, product is boiled off most of reaction solvent, add organic solvent, add water-retaining agent and sorbent material again, stir after-filtration to remove moisture content and impurity, use the dehydrated alcohol recrystallization, filtration drying.
2. according to the process of claim 1 wherein that the phosphoric acid salt in the step 4 is Sodium phosphate dibasic.
3. according to the process of claim 1 wherein that the organic solvent that adds in the step 4 is an acetone.
4. according to the process of claim 1 wherein that sorbent material is diatomite or silica gel or gac in the step 4.
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