CN103113374B - Carbapenem antibiotic and new synthetic process thereof - Google Patents
Carbapenem antibiotic and new synthetic process thereof Download PDFInfo
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- CN103113374B CN103113374B CN201310075659.9A CN201310075659A CN103113374B CN 103113374 B CN103113374 B CN 103113374B CN 201310075659 A CN201310075659 A CN 201310075659A CN 103113374 B CN103113374 B CN 103113374B
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000008569 process Effects 0.000 title claims abstract description 11
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title claims abstract description 7
- 230000003115 biocidal effect Effects 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 238000003786 synthesis reaction Methods 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- -1 1 Beta-methyl carbapenem compound Chemical class 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 150000003568 thioethers Chemical class 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 229960004132 diethyl ether Drugs 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 3
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 108090000204 Dipeptidase 1 Proteins 0.000 abstract description 4
- 102000006635 beta-lactamase Human genes 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000000845 anti-microbial effect Effects 0.000 abstract description 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- YKMONJZIUAOVEM-GDVGLLTNSA-N (5S)-4-methyl-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound CC1C=CN2[C@H]1CC2=O YKMONJZIUAOVEM-GDVGLLTNSA-N 0.000 abstract 1
- 230000000087 stabilizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 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 3
- 229960002260 meropenem Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 229950011346 panipenem Drugs 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002460 imidazoles Chemical class 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
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229930188189 sulfomycin Natural products 0.000 description 1
- 108010051634 sulfomycin Proteins 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- 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
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides carbapenem antibiotic and a new synthetic process thereof. A compound is wide in antibacterial spectrum and high in antimicrobial activity, and is used for stabilizing beta-lactamase; pyrrolidone and a methyl carbapenem nuclear parent which are easily obtained are used as raw materials; and the raw materials are reacted in seven steps to obtain the target compound. Compared with the existing synthetic process, the synthetic method has the advantages of easily available synthetic raw materials, high yield, mild reaction conditions, easiness for control, easiness for operating a separation purifying method, and suitability for large-scale industrial preparation.
Description
Technical field
The present invention relates to a kind of carbapenem compound and new synthetic process thereof, belong to antibiotic medicine field.
Background technology
Carbapenem antibiotic is the class beta-lactam compound that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stablizes β-lactamase, and receives much concern.Its constructional feature is compared with the parent nucleus 6-APA of penicillin, and the sulphur atom of 4 is replaced by carbon, and 2 have double bond, is compounded with the effect of the five-ring of penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.Carbapenem itself has good anti-microbial activity, and also can suppress β-lactamase, therefore, it becomes the focus of Recent study simultaneously.Wherein mesomethylene carbon penem is proved to be has good restraining effect to the β-lactamase of category-A and C class.It is the most important structural modification position of carbapenem compound that 3-position replaces, most kind has the side chain of sulfur-bearing and has the pyrrolidine ring of different substituents in 3-position, some is also containing amino, imino-etc., and typical medicine is as sulfomycin, imipenum, meropenem, panipenem etc.The substituting groups such as 4-position introducing methyl can improve the stability to DHP-I.2-position is connected to hydroxyl usually.
Represent medicine meropenem (meropenem) and within 1994, start listing.Within 2003, included by American Pharmacopeia, this medicine be first can be individually dosed 4-methyl carbapenem antibiotic, it is stronger than imipenum (imipenem) and panipenem (panipenem) 2-8 times to gram negative bacilli vitro antibacterial activity, is more better than cynnematin and Penicillin antibiotics.
In order to overcome the deficiencies in the prior art, on the basis of the carbapenem compound that the present invention has now used clinically, devising series compound of the present invention, and providing the synthesis technique of this series compound, being applicable to a large amount of synthesis.
Summary of the invention
The object of this invention is to provide a kind of such as formula the one 1 Beta-methyl carbapenem compound shown in (I) and synthesis technique thereof, its synthesis general formula as shown in Figure 1.With the easy pyrrolidone that is easy to get and beta-methyl carbapenem parent nucleus for raw material is obtained by reacting target compound through 7 steps, the advantage of this synthesis technique is: adopt the linked reaction of Pd catalysis to build proline(Pro) N position aromatic nucleus skeleton; Adopt the configuration reversal in mesyloxy alkyl process to introduce S and replace position chiral centre; By controlling the pH value of hydrogenation, synthesis final product.Compared with existing synthesis technique, synthetic method synthesis material of the present invention easily obtains, yield is higher, reaction conditions is gentle and easily control, separation purification method easily operate, and is applicable to industrial a large amount of preparation.
The technical solution adopted for the present invention to solve the technical problems is:
The invention provides a kind of 1 Beta-methyl carbapenem compound, its general structure as shown in (I),
R can be positioned at 3 or 4 of aromatic nucleus, is respectively methoxyl group, oxyethyl group, isopropoxy.
Numbering is that respective compound adds-1 to-6, specifically sees embodiment.
The invention provides the synthesis technique such as formula 1 Beta-methyl carbapenem compound shown in (I), its synthesis general formula is shown below,
Reactions steps is:
1) compound 1 is first with TIPS protection, obtains compound 2;
2) compound 2 and fragrant bromo-derivative 3 obtain compound 4 through linked reaction;
3) compound 4 remove silicon ether protection after, 4 hydroxyl methylsulfonyls are activated, then with thioacetic acid nak response, build thioether, through hydrolysis obtain key intermediate 7.
4) compound 7 and carbapenem parent nucleus 8 reacting generating compound 9 in the presence of base;
5) compound 9 removes PNB protecting group, obtains target product 10.
In synthesis technique provided by the invention, step 2) in:
The solvent of linked reaction can be selected from toluene, tetrahydrofuran (THF), methylene dichloride any one;
The catalyzer of linked reaction can be selected from Pd (dba) Cl
2, Pd (PPh
3)
4, PdCl
2(dppf), Pd (OAc)
2any one;
The alkali of linked reaction can select any one of triethylamine, pyridine, N dimethylamine yl pyridines, salt of wormwood, cesium carbonate.
In synthesis technique provided by the invention, step 3) in:
The reaction conditions of methylsulfonyl activation is: drip methylsulfonyl chloride under frozen water cooling, and control temperature, at 0 ~ 10 DEG C, is preferably 8 DEG C;
The reaction solvent building thioether is 1: 1 ~ 3: 1 mixing by volume of DMF/ toluene, and temperature of reaction is 60 ~ 80 DEG C; Being preferably DMF/ volume of toluene ratio is 1: 1, and temperature of reaction is 70 DEG C;
The purifying process of key intermediate 7 is completed by conventional silica gel column chromatography, and eluent is that petrol ether/ethyl acetate mixes by 3: 1 to 6: 1 volume ratio, and being preferably petrol ether/ethyl acetate volume ratio is 4: 1.
In synthesis technique provided by the invention, step 5) in:
The pH value of hydrogenation is 6.0-7.2, is preferably 7.0;
The purifying process of target product 10 adds acetone soln in the filtrate after washed with diethylether, and rear ethanol/water or isopropanol/water, in different volumes ratio recrystallization, are preferably ethanol/water volume ratio 3: 1.
Accompanying drawing explanation
Fig. 1 is the synthesis general formula of carbapenem compound.
Embodiment
The preparation of embodiment 1, compound 10-1 (R is methoxyl group)
1, the preparation of compound 2
Be dissolved in 500mL methylene dichloride by 20.2g compound 1 and 40.8g imidazoles, icy salt solution is cooled to 0 DEG C once, drips 42.4g TIPSCl, and keep thermotonus 2 hours, rise to room temperature, stirring is spent the night.Reaction solution uses the saturated NaHCO3 of 300mL and saturated common salt water washing successively, anhydrous sodium sulfate drying, filters, and be evaporated to and dryly obtain 50.3g white solid, yield 97.7, crude product is directly used in next step.
2, the preparation of compound 4
By the compound 3-1 of step preparation on 25.7g, 1.3g Pd (dba) Cl
2with 57.9g CsCO
3under nitrogen protection, be dissolved in 500mL THF, add 20.6g compound 3-l, stirred at ambient temperature 3 hours.By in reaction solution impouring 300mL saturated ammonium chloride solution, dichloromethane extraction (300mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry.Crude product column chromatography purification, petrol ether/ethyl acetate (12/1, v/v) is washed, and obtains 10.5g colorless oil compounds 4-1, yield 28.9%.
3, the preparation of compound 5-1
7.23g compound 4-1 is dissolved in 200mL THF, under frozen water cooling, drips the THF solution of the TBAF of 50mL1.0Mol/L, react 2 hours under room temperature.By in reaction solution impouring 200mL saturated sodium bicarbonate solution, dichloromethane extraction (200mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry.Crude product column chromatography purification, petrol ether/ethyl acetate (2/1, v/v) is washed, and obtains 3.7g colorless oil compounds 7-1, yield 89.4%.
4, the preparation of compound 6-1
Be dissolved in 150mL methylene dichloride by 2.07g compound 5-1 and 3.3g triethylamine, frozen water cooling is lower drips 1.4g methylsulfonyl chloride, and control temperature, below 10 DEG C, drips and finishes, rise to stirred overnight at room temperature.By in reaction solution impouring 100mL saturated sodium bicarbonate solution, dichloromethane extraction (100mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry, is directly used in next step reaction.
6, the preparation of compound 7-1
The compound 7-1 upper step prepared is dissolved in the mixing solutions of 100mL DMF/ toluene (1/1, v/v), adds 1.25g AcSK, is heated to 70 DEG C, stirs 6 hours.Be cooled to room temperature, add 80mL saturated ammonium chloride solution, use 100mL diluted ethyl acetate, separate organic phase, aqueous phase extracts 2 times by 100mL ethyl acetate again, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain pale yellow oil.
Pale yellow oil is dissolved in 80mL methyl alcohol, adds the sodium hydroxide solution of 10g10%, reflux 2 hours.Be cooled to room temperature, by reaction solution impouring 80mL saturated sodium bicarbonate solution, dichloromethane extraction (80mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry.Column chromatography purification, petrol ether/ethyl acetate (4/1, v/v) is washed, and obtains 1.0g colorless oil 7-1, yield 45.0% (two steps merge).
6, the preparation of compound 9-1
0.61g compound 8 is dissolved in 20mL acetonitrile, under nitrogen protection, adds the acetonitrile solution that 0.23g ethyl diisopropyl amine and 10mL are dissolved with 0.23g compound 7-1 successively, room temperature for overnight.Reaction solution 50mL diluted ethyl acetate, 30mL saturated sodium bicarbonate solution washs, and merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry, obtains pale yellow oil.Column chromatography purification, petrol ether/ethyl acetate (8/1, v/v) is washed, and obtains 0.31g colorless oil 9-1, yield 53.3%.
7, the preparation of compound 10-1
3.1g compound 9-1 is dissolved in 100mL pH be 7.0 phosphoric acid buffer and THF (1/1, v/v) mixing solutions in, add 0.3g Pd/C, the H of 50psi
2under pressure, react 6 hours.Filter, washed with diethylether twice, adds acetone soln 50mL in filtrate, separates out faint yellow solid, with ethanol/water (3/1, v/v) recrystallization, obtains faint yellow solid 0.54g, yield 22.0%.
Claims (5)
1. a synthesis technique for 1 Beta-methyl carbapenem compound, the general structure of this compounds is as shown in (I):
In formula: R
13 or 4 of aromatic nucleus can be positioned at, be selected from methoxyl group, oxyethyl group, isopropoxy;
It is characterized in that, its synthesis general formula is shown below, and comprises the following steps:
1) compound 1 is first with TIPS protection, obtains compound 2;
2) compound 2 and the coupling of fragrant bromo-derivative 3 obtain compound 4;
3) compound 4 remove silicon ether protection after, 4 hydroxyl methylsulfonyls are activated, then with thioacetic acid nak response, build thioether, through hydrolysis obtain compound 7;
4) compound 7 and carbapenem parent nucleus 8 reacting generating compound 9 in the presence of base;
5) compound 9 removes PNB protecting group, obtains compound 10;
Wherein, described step 2) in:
The solvent of described linked reaction can be selected from toluene, tetrahydrofuran (THF), methylene dichloride any one;
The catalyzer of described linked reaction can be selected from Pd (dba) Cl
2, Pd (PPh
3)
4, PdCl
2(dppf), Pd (OAc)
2any one;
The alkali of described linked reaction can select any one of triethylamine, pyridine, N dimethylamine yl pyridines, salt of wormwood, cesium carbonate.
2. synthesis technique according to claim 1, is characterized in that, described step 3) in:
The reaction conditions of described methylsulfonyl activation is: drip methylsulfonyl chloride under frozen water cooling, control temperature is at 0 ~ 10 DEG C;
The reaction solvent building thioether is 1: 1 ~ 3: 1 mixing by volume of DMF/ toluene, and temperature of reaction is 60 ~ 80 DEG C;
The purifying process of compound 7 is completed by conventional silica gel column chromatography, and eluent is that petrol ether/ethyl acetate mixes by 3: 1 to 6: 1 volume ratio.
3. synthesis technique according to claim 2, is characterized in that, described step 3) in:
The reaction conditions of described methylsulfonyl activation is: drip methylsulfonyl chloride under frozen water cooling, control temperature is at 8 DEG C;
The reaction solvent building thioether is 1: 1 mixing by volume of DMF/ toluene, and temperature of reaction is 70 DEG C;
The purifying process of compound 7 is completed by conventional silica gel column chromatography, and eluent is that petrol ether/ethyl acetate mixes by 4: 1 volume ratios.
4. synthesis technique according to claim 1, is characterized in that, described step 5) in:
The pH value of reaction is 6.0-7.2;
The purifying process of compound 10 adds acetone soln in the filtrate after washed with diethylether, and ethanol/water or isopropanol/water are in different volumes ratio recrystallization.
5. synthesis technique according to claim 4, is characterized in that, described step 5) in:
The pH value of reaction is 7.0;
The purifying process of compound 10 adds acetone soln in the filtrate after washed with diethylether, and ethanol/water is in 3: 1 ratio recrystallizations.
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