CN111233921A - Novel compound and method for synthesizing fosfomycin impurity D by using same - Google Patents
Novel compound and method for synthesizing fosfomycin impurity D by using same Download PDFInfo
- Publication number
- CN111233921A CN111233921A CN201811436852.XA CN201811436852A CN111233921A CN 111233921 A CN111233921 A CN 111233921A CN 201811436852 A CN201811436852 A CN 201811436852A CN 111233921 A CN111233921 A CN 111233921A
- Authority
- CN
- China
- Prior art keywords
- compound
- base
- solvent
- synthesis
- sodium
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 135
- RDPFAWYPVPIZPV-UHFFFAOYSA-N [2-[[2-[2-amino-3-hydroxy-2-(hydroxymethyl)propoxy]-1-hydroxypropyl]-hydroxyphosphoryl]oxy-1-hydroxypropyl]phosphonic acid Chemical compound OCC(N)(CO)COC(C)C(O)P(O)(=O)OC(C)C(O)P(O)(O)=O RDPFAWYPVPIZPV-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 9
- 238000001308 synthesis method Methods 0.000 claims abstract 8
- 238000006243 chemical reaction Methods 0.000 claims description 109
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 108
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 106
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 80
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 72
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- 230000015572 biosynthetic process Effects 0.000 claims description 56
- 238000003786 synthesis reaction Methods 0.000 claims description 56
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 40
- 239000003960 organic solvent Substances 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 37
- -1 phosphate compound Chemical class 0.000 claims description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000002585 base Substances 0.000 claims description 27
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 23
- 235000011181 potassium carbonates Nutrition 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 21
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 16
- 150000007529 inorganic bases Chemical class 0.000 claims description 16
- 150000007530 organic bases Chemical class 0.000 claims description 16
- 239000012312 sodium hydride Substances 0.000 claims description 16
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 16
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 11
- 235000011056 potassium acetate Nutrition 0.000 claims description 11
- 239000011736 potassium bicarbonate Substances 0.000 claims description 11
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 11
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 11
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001632 sodium acetate Substances 0.000 claims description 11
- 235000017281 sodium acetate Nutrition 0.000 claims description 11
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- HFTQXLCZRCQAAX-UHFFFAOYSA-N 2-bromo-1,1-dimethoxypropane Chemical compound COC(OC)C(C)Br HFTQXLCZRCQAAX-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000012074 organic phase Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- 239000000047 product Substances 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 14
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 8
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 229960000308 fosfomycin Drugs 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 208000003455 anaphylaxis Diseases 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 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 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UFDULEKOJAEIRI-UHFFFAOYSA-N (2-acetyloxy-3-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(I)=C1OC(C)=O UFDULEKOJAEIRI-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- OLQJQHSAWMFDJE-UHFFFAOYSA-N 2-(hydroxymethyl)-2-nitropropane-1,3-diol Chemical compound OCC(CO)(CO)[N+]([O-])=O OLQJQHSAWMFDJE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000192125 Firmicutes Species 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention relates to a novel compound formula (VI), a synthesis method of the novel compound formula (VI) and a method for synthesizing a fosfomycin impurity D by using the novel compound formula (VI). The novel compound has the formula (VI) as shown below:
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel compound and a method for synthesizing a fosfomycin impurity D by using the same.
Background
With the continuous emergence of multi-drug-resistant bacteria, pan-drug-resistant bacteria and even full-drug-resistant bacteria infection, the infection lacks new effective antibacterial drugs, and clinicians pay close attention to some classical 'old' antibacterial drugs, such as fosfomycin and the like. Phosphomycin is a natural, small-molecular broad-spectrum antibiotic, and has good antibacterial effect on various gram-negative and gram-positive bacteria.
The clinical adverse reactions of fosfomycin are mostly reported as anaphylactic shock and death caused by anaphylactic shock, high molecular impurities (polymers) existing in antibiotics can cause anaphylactic reactions, other impurities such as process impurities or degradation products and the like can also cause adverse reactions, and if the impurities are not strictly controlled, serious toxic and side effects can be generated on a human body, so that the research on fosfomycin impurities has great significance on the quality control of medicines and the medication safety of people.
The fosfomycin impurity A and the fosfomycin impurity B are required to be controlled within 0.3% in European pharmacopoeia and United states pharmacopoeia, the fosfomycin impurity C and the fosfomycin impurity D are required to be controlled within 0.1% in European pharmacopoeia and United states pharmacopoeia, and the respective structural formulas are respectively as follows:
through literature search, reports about synthesizing the fosfomycin impurity D are not found, and therefore, the method for synthesizing the fosfomycin impurity D has important significance for preparing the impurity standard substance and controlling the quality of the fosfomycin product.
Disclosure of Invention
The invention aims to obtain a novel compound, the structural formula of which is shown as a formula VI:
wherein R is nitro, NHR1Or NR1R2；
Further, R1Is an amino protecting group, R2Is an amino protecting group;
further, R1Is an alkoxycarbonyl amino-protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl methoxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl or ethoxycarbonyl; r1Is an acyl amino protecting group such as phthaloyl, p-toluenesulfonyl or trifluoroacetyl; r1Is alkyl amino protecting group, such as trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl; r2Is an alkoxycarbonyl amino-protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl methoxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl or ethoxycarbonyl; r2Is an acyl amino protecting group such as phthaloyl, p-toluenesulfonyl or trifluoroacetyl; r2Is alkyl amino protecting group, such as trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl;
preferably, R1Is an alkoxycarbonyl amino-protecting group such as benzyloxycarbonyl, t-butyloxycarbonyl, fluorenyl-methoxycarbonyl; r1Is acyl amino protecting group, such as p-toluenesulfonyl and trifluoroacetyl; r1Is an alkyl amino protecting group, such as 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl; r2Is alkyl amino protecting group, such as trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl;
more preferably, R1Is an alkoxycarbonyl amino-protecting group, such as benzyloxycarbonyl, tert-butoxycarbonyl; r1Is an alkyl amino protecting group, such as 2, 4-dimethoxybenzyl, p-methoxybenzyl or benzyl; r2Is benzyl, 2, 4-dimethoxybenzyl or p-methoxybenzyl.
More preferably, the compound of formula vi is specifically:
another object of the present invention is to provide a synthetic method for preparing a novel compound of formula VI, which employs the following technical scheme: the compound I is subjected to hydroxyl protection and substitution reaction to prepare a compound III, the compound III is subjected to reduction reaction to obtain a compound IV, the compound IV is subjected to oxidation reaction to obtain a compound V, and the compound V is reacted with dibenzyl phosphite to obtain a compound VI. The specific synthetic route is as follows:
specifically, the synthesis of the novel compound of formula VI comprises the following steps:
(1) synthesis of Compound II
Under the alkaline condition, in an organic solvent, reacting a compound I with benzyl bromide to obtain a compound II, wherein the reaction formula is as follows:
wherein the organic solvent is one or more of N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone and N, N-dimethylacetamide, and preferably is N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile and 1, 4-dioxane. The dosage of the organic solvent is the dosage of conventional chemical reaction, and the volume mass ratio of the organic solvent to the compound I is 5-20 mL/g.
In the invention, the alkali can be inorganic alkali and/or organic alkali, the inorganic alkali is one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic alkali is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the alkali is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine. The molar ratio of the base to the compound I is (1:1) - (3:1), and the molar ratio of the compound I to the bromobenzyl is (1:2) - (1: 2.5).
(2) And synthesizing the Compound III
Reacting the compound II with ethyl 2-bromopropionate in an organic solvent under an alkaline condition to obtain a compound III, wherein the reaction formula is as follows:
wherein the organic solvent is one or more of N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone and N, N-dimethylacetamide, and preferably is N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile and 1, 4-dioxane. The dosage of the organic solvent is the dosage of the conventional chemical reaction, and the volume-mass ratio of the organic solvent to the compound II is 5-20 mL/g.
The base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine. The molar ratio of the base to the compound II is (1:1) - (3:1), and the molar ratio of the compound II to the ethyl 2-bromopropionate is (1:1) - (1: 1.3).
(3) Synthesis of Compound IV
Reducing the compound III in an organic solvent by a reducing agent to generate alcohol, wherein the reaction formula is as follows:
wherein the organic solvent is an ether solvent, an alcohol solvent or a hydrocarbon solvent, preferably an ether solvent, and the ether solvent is one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether; the dosage of the organic solvent is the dosage of the conventional chemical reaction, and the volume-mass ratio of the organic solvent to the compound III is 5-20 mL/g. The reducing agent is metal hydride such as Lithium Aluminum Hydride (LAH), sodium borohydride-ZnCl2Sodium borohydride, potassium borohydride and the like, and the molar ratio of the reducing agent to the compound III is (0.9:1) - (3: 1).
(4) Synthesis of Compound V
And (3) carrying out oxidation reaction on the compound IV to obtain a compound V, wherein the reaction formula is as follows:
wherein the solvent is one or more of dichloromethane, hexane, acetonitrile and dimethyl sulfoxide (DMSO); preferably dichloromethane or dimethyl sulfoxide (DMSO); the dosage of the organic solvent is the dosage of the conventional chemical reaction, and the volume-mass ratio of the organic solvent to the compound IV is 5-20 mL/g. The oxidant is active MnO2Oxygen ammonium salt, higher iodide(ii) a Preferably active MnO2Or higher iodides, such as diacetoxyiodobenzene (Diacetoxyiodo) benzene (DIB), 2-iodoxybenzoic acid (IBX) and Dess-martin oxidant Dess-Martinperiodinane (DMP). The molar ratio of the oxidant to the compound IV is (1:1) - (1.5: 1).
(5) Synthesis of Compound VI
Reacting the compound V with dibenzyl phosphite in the presence of a solvent and alkali to obtain a compound VI, wherein the reaction formula is as follows:
wherein the organic solvent is one or more of dichloromethane, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone and N, N-dimethylacetamide, and preferably dichloromethane. The dosage of the organic solvent is the dosage of conventional chemical reaction, and the volume-to-mass ratio of the organic solvent to the compound V is 5-20 mL/g.
The base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of morpholine, triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium carbonate, potassium carbonate, N-diisopropylethylamine or triethylamine. The molar ratio of the alkali to the compound V is (1:1) - (3:1), and the molar ratio of the compound V to the dibenzylphosphite is (1:1) - (1: 1.2).
The invention also relates to the application of the compound VI in synthesizing the fosfomycin impurity D.
The invention uses a compound of formula I as an initial raw material to synthesize a key intermediate compound VI, the intermediate is subjected to substitution reaction and phosphate hydrolysis to prepare a compound VIII, the compound VIII is then reacted with 2-bromo-1, 1-dimethoxypropane to prepare a phosphate compound IX, the compound IX is hydrolyzed under an acidic condition to obtain an aldehyde compound X, the compound X and dibenzyl phosphite react in the presence of a solvent and alkali to obtain a compound XI, and the compound XI is subjected to nitro reduction or amino deprotection and hydroxyl deprotection to prepare a fosfomycin impurity D, wherein the reaction formula is as follows:
or
Another object of the present invention is to provide a method for synthesizing fosfomycin impurity D, comprising the steps of:
(1) and synthesis of Compound VII
Under the alkaline condition, in an organic solvent, a compound VI reacts with benzyl bromide to prepare a compound VII, and the following reaction formula is shown:
wherein the organic solvent is one or more of N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone and N, N-dimethylacetamide, and preferably is N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile and 1, 4-dioxane. The dosage of the organic solvent is the dosage of the conventional chemical reaction, and the volume mass ratio of the organic solvent to the compound VI is 5-20 mL/g.
In the invention, the alkali can be inorganic alkali and/or organic alkali, the inorganic alkali is one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic alkali is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the alkali is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine. The molar ratio of the base to the compound VI is (1:1) - (3:1), and the molar ratio of the compound VI to the bromobenzyl is (1:1) - (1: 1.5).
(2) Synthesis of Compound VIII
Hydrolyzing the compound VII in a protic solvent under an alkaline condition to obtain a compound VIII, wherein the reaction formula is as follows:
wherein the protic solvent is one or more of an alcohol solvent, N, N-Dimethylformamide (DMF) and N, N-dimethylacetamide, preferably an alcohol solvent, and more preferably methanol or ethanol. The dosage of the organic solvent is the dosage of conventional chemical reaction, and the volume mass ratio of the organic solvent to the compound VII is 5-20 mL/g.
The base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium hydroxide or potassium hydroxide. The molar ratio of the alkali to the compound VII is (2:1) - (3: 1).
(3) Synthesis of Compound IX
Reacting the compound VIII with 2-bromo-1, 1-dimethoxypropane in an organic solvent under alkaline conditions to prepare a phosphate compound IX, wherein the reaction formula is as follows:
wherein the organic solvent is one or more of N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone and N, N-dimethylacetamide, and preferably is N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile and 1, 4-dioxane. The dosage of the organic solvent is the dosage of conventional chemical reaction, and the volume-mass ratio of the organic solvent to the compound VIII is 5-20 mL/g.
In the invention, the alkali can be inorganic alkali and/or organic alkali, the inorganic alkali is one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic alkali is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the alkali is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine. The molar ratio of the base to the compound VIII is (1:1) - (3:1), and the molar ratio of the compound VIII to the 2-bromo-1, 1-dimethoxypropane is (1:1) - (1: 1.3).
(4) Synthesis of Compound X
Hydrolyzing the compound IX under acidic conditions to obtain an aldehyde compound X, which is shown in the following reaction formula:
wherein the solvent is one or more of methanol, ethanol, Tetrahydrofuran (THF), dichloromethane, acetonitrile, 1, 4-dioxane, diethyl ether, acetone, acetic acid and water, preferably a mixed solvent of Tetrahydrofuran (THF), acetone, 1, 4-dioxane and water. The dosage of the solvent is the dosage of conventional chemical reaction, and the volume mass ratio of the solvent to the compound IX is 5-20 mL/g.
The acid can be inorganic acid and/or organic acid, the inorganic acid is hydrochloric acid, the organic acid is formic acid or p-toluenesulfonic acid, and the molar ratio of the acid to the compound IX is (1:1) - (1: 3).
(5) Synthesis of Compound XI
Reacting a compound X with dibenzylphosphite in the presence of a solvent and a base to obtain a compound XI, wherein the compound XI is shown as the following reaction formula:
wherein the organic solvent is one or more of dichloromethane, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone and N, N-dimethylacetamide, and preferably dichloromethane. The dosage of the organic solvent is the dosage of the conventional chemical reaction, and the volume-mass ratio of the organic solvent to the compound X is 5-20 mL/g.
The base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of morpholine, triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium carbonate, potassium carbonate, N-diisopropylethylamine or triethylamine. The molar ratio of the base to the compound X is (1:1) - (3:1), and the molar ratio of the compound X to dibenzylphosphite is (1:1) - (1: 1.2).
(6) Synthesis of Compound D
Dissolving a compound XI in a solvent, adding 10% Pd/C, completely reacting under the pressure of hydrogen, filtering, concentrating, and crystallizing to obtain a fosfomycin impurity D. The solvent is an alcohol solvent and/or water, preferably a methanol solvent, an ethanol solvent, a mixed solvent of methanol and water or a mixed solvent of ethanol and water, the dosage of the solvent is the dosage of conventional chemical reaction, and the volume-to-mass ratio of the solvent to the compound XI is 5-20 mL/g. The reaction formula is shown as follows:
or
(6) Synthesis of Compound XII
Dissolving the compound XI in dichloromethane, adding trifluoroacetic acid, and reacting completely at room temperature to prepare the compound XII, wherein the reaction formula is shown as follows:
(7) synthesis of Compound D
Deprotection of hydroxyl group of compound XII can obtain fosfomycin impurity D, which has the following reaction formula:
the solvent is an alcohol solvent and/or water, preferably a methanol solvent, an ethanol solvent, a mixed solvent of methanol and water or a mixed solvent of ethanol and water, the dosage of the solvent is the dosage of conventional chemical reaction, and the volume-to-mass ratio of the solvent to the compound XI is 5-20 mL/g.
The invention has the beneficial effects that the novel compound can be used for synthesizing the fosfomycin impurity D, and provides a reference substance meeting the requirements for quality control of fosfomycin products.
Detailed Description
Example 1
(1) Synthesis of Compound II
Dissolving 302.0g of trihydroxymethyl nitromethane (2.0mol) in 1.5L of anhydrous N, N-Dimethylformamide (DMF), cooling to 10 ℃ after complete dissolution, adding 176.0g of sodium hydride (with the content of 60 percent and 4.4mol) in batches, controlling the temperature to be-5 ℃, reacting for 1 hour after the addition, slowly dropwise adding 752.4g of benzyl bromide (4.4mol), and reacting at room temperature overnight after the addition. The reaction solution was poured into 6L of saturated ammonium chloride solution, stirred for 30 minutes, extracted with ethyl acetate (5L × 3 times), the organic phases were combined, washed with 5L of water, 5L of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified (EA: PE = 0-35%) to obtain 406.3g of the product with a yield of 61.3%.
(2) And synthesizing the Compound III
331.4g of compound II (1.0mol) are dissolved in 3.3L tetrahydrofuran, cooled to 10 ℃, 48.0g of sodium hydride (content 60%, 1.2mol) are added in portions, after the addition is finished, the mixture is refluxed for 1 hour, cooled to room temperature, 235.3g of ethyl 2-bromopropionate (1.3mol) are added dropwise, after the addition is finished, the reaction is carried out for 2 hours until the reaction is finished, the reaction solution is poured into 3L of saturated ammonium chloride solution, stirred for 20 minutes, ethyl acetate is added for extraction (2L x 3 times), the organic phases are combined, the organic phases are washed with 1L of water, 1L of saturated common salt solution is washed, dried by anhydrous sodium sulfate, filtered and concentrated, and the product is obtained by 308.5g and the yield is 71.5% after purification (EA: PE = 0-10%).
(3) Synthesis of Compound IV
258.6g of Compound III (0.6mol) are dissolved in 2.6L of tetrahydrofuran, 29.5g of sodium borohydride (0.78mol) are added in portions and, after the addition, reflux is carried out for 2 hours. Cooling to room temperature, pouring the reaction solution into 1.3L saturated ammonium chloride solution, stirring for 30 minutes, adding ethyl acetate for extraction (1L multiplied by 3 times), combining organic phases, washing the organic phases with 1L of water, washing the organic phases with 1L of saturated saline solution, drying the organic phases with anhydrous sodium sulfate, filtering and concentrating to obtain 220.1g of a product with the yield of 94.2%.
(4) Synthesis of Compound V
210.1g of compound IV (0.54mol) are dissolved in 2L of dichloromethane, 69.6g of manganese dioxide (0.8mol) are added, the mixture is heated under reflux for 4 hours, the reaction is cooled to room temperature completely, the mixture is filtered, and the filtrate is concentrated to dryness to obtain 195.0g of product with a yield of 93.3%.
(5) Synthesis of Compound VI
193.5g of compound V (0.5mol) are dissolved in 2L of dichloromethane, cooled to 10 ℃, added with 157.2g of dibenzyl phosphite (0.6mol), added with 101.0g of triethylamine (1.0mol), reacted at room temperature overnight after the addition, poured into 2L of water, stirred for 10 minutes, stood for layering, the organic phase separated, the aqueous phase extracted with dichloromethane (1L x 2 times), combined with the organic phase, washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column (EA: PE =5% -50%) to obtain 220.0g of a product with a yield of 67.7%.
Example 2
(1) Synthesis of Compound II
Dissolving 100.0g of compound I (0.45mol) in 600mL of N, N-Dimethylformamide (DMF), cooling to 0 ℃ after complete dissolution, adding 48.0g of sodium hydroxide (1.2mol), reacting at 0 ℃ for 2 hours after complete addition, slowly dropwise adding 180.0g of benzyl bromide (1.05mol), reacting at 0 ℃ for 5 minutes, heating to 10 ℃ for reaction for 2 hours, and reacting completely. Pouring the reaction solution into 2L of saturated ammonium chloride solution, stirring for 30 minutes, extracting with dichloromethane (1L multiplied by 3 times), combining organic phases, washing the organic phases with 1L of water, washing with 1L of saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding 500mL of petroleum ether, crystallizing, filtering, drying to obtain 119.9g of a product, and obtaining the yield of 66.3%.
(2) And synthesizing the Compound III
100.5g of the compound II (0.25mol) was dissolved in 1L of Tetrahydrofuran (THF), 11.2g of sodium hydride (content: 60%, 0.28mol) was added thereto, the temperature was controlled to 0 ℃ or lower, and after the addition, the reaction was carried out for 1 hour, 45.2g of ethyl 2-bromopropionate (0.25mol) was added dropwise thereto, and after the addition, the reaction was carried out for 2 hours, and the reaction was completed by TLC. The reaction solution was poured into 150mL of a saturated ammonium chloride solution, stirred for 30 minutes, extracted with ethyl acetate (500mL × 3 times), the organic phases were combined, washed with 500mL of water, 500mL of a saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (EA: PE =0-30%) to obtain 109.9g of a product with a yield of 87.6%.
(3) Synthesis of Compound IV
100.4g of compound III (0.20mol) are dissolved in 800mL of tetrahydrofuran, 9.9g of sodium borohydride (0.26mol) are added in portions, and after the addition is finished, the reaction is refluxed for 2 hours and is detected to be complete by TLC. After cooling to room temperature, the reaction mixture was poured into 500mL of saturated ammonium chloride solution, stirred for 30 minutes, extracted with ethyl acetate (500 mL. times.3 times), and the organic phases were combined, washed with 1L of water, 1L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 90.0g of a product with a yield of 97.8%.
(4) Synthesis of Compound V
78.2g of the compound IV (0.17mol) are dissolved in 800mL of dichloromethane, 22.2 g of manganese dioxide (0.26mol) are added, the mixture is heated under reflux for 4 hours, the reaction is cooled to room temperature completely, the mixture is filtered, and the filtrate is concentrated to dryness to obtain 74.0g of a product with the yield of 95.0%.
(5) Synthesis of Compound VI
73.3g of the compound V (0.16mol) is dissolved in 600mL of dichloromethane, 49.8g of dibenzyl phosphite (0.19mol) is added, 35.4g of triethylamine (0.35mol) is added dropwise, reaction is carried out at room temperature overnight after the addition, 300mL of water is added into the reaction solution, stirring is carried out for 10 minutes, standing is carried out for layering, an organic phase is separated, an aqueous phase is extracted by dichloromethane (300mL multiplied by 2 times), the organic phases are combined, washed by 400mL of saturated saline solution, dried by anhydrous sodium sulfate and concentrated, and the product is subjected to column chromatography (EA: PE =5% -50%) to obtain 68.0g of the product with the yield of 59.0%.
Example 3
(1) Synthesis of Compound II
99.2g of the compound I (0.47mol) is dissolved in 1L of Tetrahydrofuran (THF), cooled to 0 ℃ after complete dissolution, 98.0g of potassium carbonate (0.71mol) is added, after the addition, reaction is carried out at 0 ℃ for 10 minutes, 188.1g of benzyl bromide (1.1mol) is slowly added dropwise, after the addition, reaction is carried out at 0 ℃ for 5 minutes, then the temperature is raised to 10 ℃ for reaction for 2 hours, and the reaction is complete by TLC detection. Pouring the reaction solution into 1L of saturated ammonium chloride solution, stirring for 30 minutes, extracting with dichloromethane (500mL multiplied by 3 times), combining organic phases, washing the organic phases with 1L of water, washing with 1L of saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding 500mL of petroleum ether, crystallizing, filtering, drying to obtain 125.3g of a product, and obtaining the yield of 68.0%.
(2) And synthesizing the Compound III
98.0g of the compound II (0.25mol) is dissolved in 1L N, N-Dimethylformamide (DMF), 40.0g of sodium hydroxide (1.0mol) is added, the temperature is controlled within 50 ℃, the reaction is carried out for 1 hour after the addition is finished, 58.5g of ethyl 2-bromopropionate (0.33mol) is added dropwise, the reaction is carried out for 2 hours after the addition is finished, and the reaction is detected to be complete by TLC. The reaction solution was poured into 150mL of a saturated ammonium chloride solution, stirred for 30 minutes, extracted with ethyl acetate (500mL × 3 times), the organic phases were combined, washed with 1L of water, 1L of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (EA: PE =0-15%) to obtain 107.0g of a product with a yield of 87.0%.
(3) Synthesis of Compound IV
98.4g of Compound III (0.20mol) are dissolved in 500mL of 1, 4-dioxane, cooled to 0 ℃ under argon, 6.8g of tetralin aluminum (0.18mol) are added in portions, and after the addition, the reaction is carried out for 1 hour at 0 ℃ and the reaction is detected to be complete by TLC. The reaction mixture was diluted with 500mL of ethyl acetate, quenched with a mixture of ice and water, stirred for 30 minutes, filtered, the filter cake was washed with 300mL of ethyl acetate, the filtrates were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 82.5g of product in 91.8% yield.
(4) Synthesis of Compound V
Dissolving 45.0g of compound IV (0.1mol) in 500mL of dichloromethane, stirring for 10 minutes under the protection of argon, adding 50.9g of dess-martin oxidant (DMP, 0.12mol) at 0 ℃, heating to room temperature, continuing stirring for 2 hours, adding 500mL of a mixed solution of saturated sodium bicarbonate and sodium thiosulfate in a volume ratio of 1:1 into the reaction solution when the reaction is completely cooled to 0 ℃, filtering, extracting the filtrate with dichloromethane (200mL multiplied by 2 times), drying with anhydrous sodium sulfate, concentrating to dryness to obtain 41.9g of a product, wherein the yield is 93.6%.
(5) Synthesis of Compound VI
42.6g of Compound V (0.095mol) is dissolved in 500mL of dichloromethane, cooled to 10 ℃, 31.4g of dibenzyl phosphite (0.12mol) is added, 17.9g of potassium carbonate (0.13mol) is slowly added, after the addition, the reaction solution is reacted at room temperature overnight, the reaction solution is poured into 500mL of water, stirred for 10 minutes, kept stand for layering, an organic phase is separated, an aqueous phase is extracted with dichloromethane (500 mL. times.2), the organic phases are combined, washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column (EA: PE =5% -40%) to obtain 47.0g of a product with a yield of 69.7%.
Example 4
(1) Synthesis of Compound II
Dissolving 99.3g of compound I (0.33mol) in 1L of acetonitrile, cooling to 0 ℃ after complete dissolution, adding 101.0g of triethylamine (1mol), reacting for 10 minutes at 0 ℃ after complete addition, slowly dropwise adding 136.8g of benzyl bromide (0.8mol), reacting for 5 minutes at 0 ℃, heating to 50 ℃ for overnight reaction, pouring the reaction solution into 100mL of saturated ammonium chloride solution for stirring for 30 minutes after complete reaction, extracting ethylene glycol dimethyl ether (500mL multiplied by 3 times), combining organic phases, washing the organic phases with 300mL of water, washing with 500mL of saturated salt solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding 500mL of petroleum ether, crystallizing, filtering, and drying to obtain 103.4g of a product with the yield of 65.0%.
(2) And synthesizing the Compound III
Dissolving 101.2g of compound II (0.21mol) in 1L of Tetrahydrofuran (THF), adding 40.0g of sodium hydroxide (1.0mol), controlling the temperature within 50 ℃, reacting for 1 hour after the addition is finished, dropwise adding 45.2g of ethyl 2-bromopropionate (0.25mol), reacting for 2 hours after the addition is finished, pouring the reaction solution into 300mL of saturated ammonium chloride solution until the reaction is finished, stirring for 30 minutes, extracting with ethyl acetate (500mL multiplied by 3 times), combining organic phases, washing the organic phases with 1L of water, washing with 1L of saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating, and passing through a column (EA: PE =0-20%) to obtain 105.1g of a product with the yield of 86.0%.
(3) Synthesis of Compound IV
Dissolving 59.8g of zinc chloride (0.44mol) in 800mL of anhydrous ethylene glycol dimethyl ether, cooling to 0 ℃, protecting with nitrogen, adding 8.4g of sodium borohydride (0.22mol), stirring for 30 minutes at room temperature after the addition is finished, then cooling to 0-5 ℃, adding 98.9g of compound III (0.17mol) into the mixed solution, slowly heating to 50-60 ℃ after the addition is finished, reacting overnight, adding an ice-water mixture into the reaction solution after the reaction is finished, stirring for 3 hours, extracting with dichloromethane (250mL multiplied by 3 times), combining organic phases, washing and filtering the organic phases with 200mL of water, washing with 200mL of saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 87.9g of a product with the yield of 95.8%.
(4) Synthesis of Compound V
54.0g of compound IV (0.1mol) is dissolved in 300mL of dimethyl sulfoxide (DMSO), 30.8g of 2-iodoxybenzoic acid (IBX) (0.11mol) is added under the protection of argon at the temperature of 0 ℃, the mixture is stirred for 10 minutes, the temperature is raised to room temperature, the stirring is continued for 4 hours until the reaction is completed, 300mL of water is added into the reaction solution, the filtration is carried out, the filtrate is extracted by dichloromethane (300mL multiplied by 3 times), the organic phases are combined, the mixture is washed by sodium bicarbonate and then is washed by saturated saline, and the mixture is dried by anhydrous sodium sulfate and concentrated to obtain 50.0g of a product, wherein the yield is 93.0%.
(5) Synthesis of Compound VI
Under the protection of nitrogen, 50.0g of compound V (0.093mol) is dissolved in 500mL of dichloromethane, cooled to 10 ℃, 28.8g of dibenzyl phosphite (0.11mol) is added, 24.5g N, N-diisopropylethylamine (0.19mol) is slowly added, after the addition is finished, the reaction solution is reacted at room temperature overnight, the reaction solution is poured into 500mL of water, stirred for 10 minutes, kept stand for layering, an organic phase is separated, an aqueous phase is extracted by dichloromethane (500mL multiplied by 2 times), the organic phases are combined, washed by 500mL of saturated common salt water, dried by anhydrous sodium sulfate and concentrated, and the product is subjected to column chromatography (EA: PE =5% -30%) to obtain 50.1g of product, and the yield is 67.3%.
Example 5 Synthesis of Phosphomycin impurity D
(1) And synthesis of Compound VII
195.0g of compound VI (0.3mol) is dissolved in 3L Tetrahydrofuran (THF), cooled to 0 ℃ after complete dissolution, 82.8g of potassium carbonate (0.6mol) is added, after the addition, the reaction is carried out at 0 ℃ for 10 minutes, 77.0g of benzyl bromide (0.45mol) is slowly dropped, after the addition, the reflux reaction is carried out for 4 hours, and the TLC detection reaction is complete. The reaction solution was poured into 1L of saturated ammonium chloride solution and stirred for 30 minutes, dichloromethane was extracted (500 mL. times.3 times), the organic phases were combined, washed with 1L of water, 1L of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column to give 160.1g of a product with a yield of 72.1%.
(2) Synthesis of Compound VIII
Dissolving 148.0g of compound VII (0.2mol) in 1.5L of methanol, cooling to 5 ℃, dropwise adding 500mL of sodium hydroxide solution (1mol/L), continuing to react for 1 hour after the addition, detecting the reaction completion by TLC, dropwise adding 1mol/L hydrochloric acid into the reaction solution, adjusting the pH to 4, adding dichloromethane for extraction (2L multiplied by 3 times), combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, concentrating, dissolving by using ethyl acetate, adding methyl tert-butyl ether, crystallizing, filtering, and drying to obtain 69.1g of a product, wherein the yield is 61.7%.
(3) Synthesis of Compound IX
56.0g of compound VIII (0.1mol) was dissolved in 0.5L N, N-Dimethylformamide (DMF), and after complete dissolution, 29.0g of cesium carbonate (0.15mol) was added, followed by reaction at 0 ℃ for 20 minutes, and 20.0g of 2-bromo-1, 1-dimethoxypropane (0.11mol) was slowly added dropwise, followed by reaction at 70 ℃ overnight and completion of the reaction by TLC. The reaction mixture was poured into 200mL of water and stirred for 30 minutes, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with 200mL of water, 200mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain 45.0g of a product with a yield of 68.0%.
(4) Synthesis of Compound X
40.0g of Compound IX (0.06mol) was dissolved in 200mL of tetrahydrofuran, 50mL of water was added, 5g of p-toluenesulfonic acid (0.03mol) was added, and after completion of the addition, the reaction was carried out at room temperature for 2 hours and the reaction was completed by TLC. The reaction solution was poured into a saturated sodium bicarbonate solution and stirred for 20 minutes, extracted with ethyl acetate (50mL × 3 times), the organic phases were combined, washed with 50mL of water, 50mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain 31.0g of a product with a yield of 83.9%.
(5) Synthesis of Compound XI
Dissolving 31.0g of compound X (0.05mol) in 300mL of dichloromethane, cooling to 10 ℃, adding 15.7g of dibenzyl phosphite (0.06mol), dropwise adding 10.1g of triethylamine (0.1mol), reacting at room temperature overnight after the addition is finished, adding 150mL of water into the reaction solution, stirring for 10 minutes, standing for layering, separating out an organic phase, extracting an aqueous phase with dichloromethane (150mL multiplied by 2 times), combining the organic phases, washing with 200mL of saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and passing through a column (EA: PE =5% -50%) to obtain 25.0g of a product with the yield of 56.9%.
(6) Synthesis of Compound D
15.0g of compound XI (17mmol) was dissolved in a mixed solution of 200mL of methanol and 100mL of water, 5g of 10% Pd/C hydrogen was added and the mixture was reacted under pressure for 4 hours, and then filtered through celite, the filtrate was concentrated and dissolved in 20mL of methanol, and then 100mL of ethyl acetate was added to crystallize product 5.0g, with a yield of 74.1%.
1H-NMR(500MHz, D2O) 3.64-3.53 (m, 9H), 3.16(s, 1H), 3.04(s, 1H), 1.25-1.21(m, 3H), 1.13-1.03(m, 3H). M/Z=396.1 (M-H)-。
Example 6 Synthesis of Phosphomycin impurity D
(1) And synthesis of Compound VII
213.0g of compound VI (0.3mol) is dissolved in 3.2L N N-Dimethylformamide (DMF), after the complete dissolution, the mixture is cooled to 0 ℃, 12.0g of sodium hydroxide (0.3mol) is added, after the complete addition, the reaction is carried out for 10 minutes at 0 ℃, 51.3g of benzyl bromide (0.3mol) is slowly dropped, after the completion of the addition, the reflux reaction is carried out for 4 hours, and the reaction is detected to be complete by TLC. The reaction solution was poured into 1.1L of saturated ammonium chloride solution and stirred for 30 minutes, extracted with dichloromethane (1L X3 times), the organic phases were combined, washed with 1L of water, 1L of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column to give 175.9g of a product with a yield of 73.3%.
(2) Synthesis of Compound VIII
160.0g of compound VII (0.2mol) is dissolved in 2L of methanol, cooled to 5 ℃, 400mL of potassium hydroxide solution (1mol/L) is added dropwise, the reaction is continued for 2 hours after the addition, TLC detects that the reaction is complete, 1mol/L hydrochloric acid is added dropwise into the reaction solution, the pH is adjusted to 4, dichloromethane is added for extraction (2L multiplied by 3 times), organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, filtered, concentrated, dissolved by ethyl acetate, added with methyl tert-butyl ether, crystallized, filtered and dried to obtain 78.2g of a product, and the yield is 63.1%.
(3) Synthesis of Compound IX
62.0g of compound VIII (0.1mol) is dissolved in 0.6L of Tetrahydrofuran (THF), after complete dissolution, 4.0g of sodium hydride (content: 60%, 0.1mol) is added, after complete addition, reaction is carried out at 0 ℃ for 40 minutes, 18.3g of 2-bromo-1, 1-dimethoxypropane (0.1mol) is slowly added dropwise, after complete addition, the reaction is carried out overnight, and the reaction is complete as detected by TLC. The reaction solution was poured into 200mL of a saturated ammonium chloride solution and stirred for 30 minutes, extracted with ethyl acetate (500 mL. times.3 times), the organic phases were combined, washed with 300mL of water, 300mL of a saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain 50.3g of a product with a yield of 69.7%.
(4) Synthesis of Compound X
43.3g of the compound IX (0.06mol) are dissolved in 200mL of acetone, 50mL of water are added, 2.8g of formic acid (0.06mol) are added, and after the addition is complete, the reaction is carried out at room temperature for 4 hours and the reaction is checked by TLC. The reaction solution was poured into a saturated sodium bicarbonate solution and stirred for 20 minutes, extracted with ethyl acetate (50mL × 3 times), the organic phases were combined, washed with 50mL of water, 50mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain 34.7g of a product with a yield of 85.6%.
(5) Synthesis of Compound XI
Dissolving 33.8g of compound X (0.05mol) in 400mL of dichloromethane, cooling to 10 ℃, adding 13.1g of dibenzyl phosphite (0.05mol), dropwise adding 15.2g of triethylamine (0.15mol), reacting at room temperature overnight after the addition is finished, adding 200mL of water into the reaction solution, stirring for 10 minutes, standing for layering, separating out an organic phase, extracting an aqueous phase with dichloromethane (150mL multiplied by 2 times), combining the organic phases, washing with 200mL of saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and passing through a column (EA: PE =5% -50%) to obtain 27.5g of a product with the yield of 58.6%.
(6) Synthesis of Compound D
18.8g of the compound XI (20mmol) was dissolved in a mixed solution of 200mL of ethanol and 100mL of water, 10g of 10% Pd/C hydrogen was added and the mixture was reacted under pressure for 4 hours, and then filtered through celite, the filtrate was concentrated and dissolved in 30mL of methanol, and then 150mL of ethyl acetate was added to crystallize the compound XI to give 6.1g, which was a 76.4% yield product.
1H-NMR(500MHz, D2O) 3.64-3.53 (m, 9H), 3.16(s, 1H), 3.04(s, 1H), 1.25-1.21(m, 3H), 1.13-1.03(m, 3H). M/Z=396.1 (M-H)-。
Claims (10)
1. The application of the compound VI in synthesizing the fosfomycin impurity D is as follows:
2. a method for synthesizing fosfomycin impurity D comprises the following steps:
(1) and synthesis of Compound VII
Under the alkaline condition, in an organic solvent, a compound VI reacts with benzyl bromide to prepare a compound VII, and the following reaction formula is shown:
(2) synthesis of Compound VIII
Hydrolyzing the compound VII in a protic solvent under an alkaline condition to obtain a compound VIII, wherein the reaction formula is as follows:
(3) synthesis of Compound IX
Reacting the compound VIII with 2-bromo-1, 1-dimethoxypropane in an organic solvent under alkaline conditions to prepare a phosphate compound IX, wherein the reaction formula is as follows:
(4) synthesis of Compound X
Hydrolyzing the compound IX under acidic conditions to obtain an aldehyde compound X, which is shown in the following reaction formula:
(5) synthesis of Compound XI
Reacting a compound X with dibenzylphosphite in the presence of a solvent and a base to obtain a compound XI, wherein the compound XI is shown as the following reaction formula:
(6) synthesis of Compound D
Dissolving a compound XI in a solvent, adding 10% Pd/C, completely reacting under the pressure of hydrogen, filtering, concentrating and crystallizing to obtain a fosfomycin impurity D, wherein the reaction formula is as follows:
3. a method for synthesizing fosfomycin impurity D comprises the following steps:
(1) and synthesis of Compound VII
Under the alkaline condition, in an organic solvent, a compound VI reacts with benzyl bromide to prepare a compound VII, and the following reaction formula is shown:
(2) synthesis of Compound VIII
Hydrolyzing the compound VII in a protic solvent under an alkaline condition to obtain a compound VIII, wherein the reaction formula is as follows:
(3) synthesis of Compound IX
Reacting the compound VIII with 2-bromo-1, 1-dimethoxypropane in an organic solvent under alkaline conditions to prepare a phosphate compound IX, wherein the reaction formula is as follows:
(4) synthesis of Compound X
Hydrolyzing the compound IX under acidic conditions to obtain an aldehyde compound X, which is shown in the following reaction formula:
(5) synthesis of Compound XI
Reacting a compound X with dibenzylphosphite in the presence of a solvent and a base to obtain a compound XI, wherein the compound XI is shown as the following reaction formula:
(6) synthesis of Compound XII
Dissolving the compound XI in dichloromethane, adding trifluoroacetic acid, and reacting completely at room temperature to prepare the compound XII, wherein the reaction formula is shown as follows:
(7) synthesis of Compound D
Deprotection of hydroxyl group of compound XII can obtain fosfomycin impurity D, which has the following reaction formula:
4. the synthesis method according to claim 2 or 3, wherein the organic solvent in step (1) is one or more of N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone, N-dimethylacetamide, preferably N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, 1, 4-dioxane; the base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine; the molar ratio of the base to the compound VI is (1:1) - (3:1), and the molar ratio of the compound VI to the bromobenzyl is (1:1) - (1: 1.5).
5. The synthesis method according to claim 2 or 3, wherein the protic solvent in step (2) is one or more of an alcoholic solvent, N, N-Dimethylformamide (DMF), and N, N-dimethylacetamide, preferably an alcoholic solvent, more preferably methanol or ethanol; the base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium hydroxide or potassium hydroxide; the molar ratio of the alkali to the compound VII is (2:1) - (3: 1).
6. The synthesis method according to claim 2 or 3, wherein the organic solvent in step (3) is one or more of N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone, N-dimethylacetamide, preferably N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, 1, 4-dioxane; the base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine; the molar ratio of the base to the compound VIII is (1:1) - (3:1), and the molar ratio of the compound VIII to the 2-bromo-1, 1-dimethoxypropane is (1:1) - (1: 1.3).
7. The synthesis method according to claim 2 or 3, wherein the solvent in step (4) is one or more of methanol, ethanol, Tetrahydrofuran (THF), dichloromethane, acetonitrile, 1, 4-dioxane, diethyl ether, acetone, acetic acid and water, preferably a mixed solvent of Tetrahydrofuran (THF), acetone and 1, 4-dioxane and water; the acid can be inorganic acid and/or organic acid, the inorganic acid is hydrochloric acid, the organic acid is formic acid or p-toluenesulfonic acid, and the molar ratio of the acid to the compound IX is (1:1) - (1: 3).
8. The synthesis method according to claim 2 or 3, wherein the organic solvent in step (5) is one or more of dichloromethane, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), toluene, 1, 4-dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone, and N, N-dimethylacetamide, preferably dichloromethane; the base can be inorganic base and/or organic base, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, the organic base is one or more of morpholine, triethylamine, p-dimethylaminopyridine, pyridine or N, N-diisopropylethylamine, and the base is preferably sodium carbonate, potassium carbonate, N-diisopropylethylamine or triethylamine; the molar ratio of the base to the compound X is (1:1) - (3:1), and the molar ratio of the compound X to dibenzylphosphite is (1:1) - (1: 1.2).
9. The synthesis method according to claim 2, wherein the solvent in step (6) is an alcohol solvent and/or water, preferably methanol, ethanol, a mixed solvent of methanol and water, or a mixed solvent of ethanol and water.
10. The synthesis method according to claim 3, wherein the solvent in step (7) is an alcohol solvent and/or water, preferably methanol, ethanol, a mixed solvent of methanol and water, or a mixed solvent of ethanol and water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811436852.XA CN111233921A (en) | 2018-11-28 | 2018-11-28 | Novel compound and method for synthesizing fosfomycin impurity D by using same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811436852.XA CN111233921A (en) | 2018-11-28 | 2018-11-28 | Novel compound and method for synthesizing fosfomycin impurity D by using same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111233921A true CN111233921A (en) | 2020-06-05 |
Family
ID=70875739
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811436852.XA Pending CN111233921A (en) | 2018-11-28 | 2018-11-28 | Novel compound and method for synthesizing fosfomycin impurity D by using same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233921A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117964661A (en) * | 2024-04-01 | 2024-05-03 | 深圳创元生物医药科技有限公司 | Preparation method of fosfomycin genotoxic impurity C |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2345591A1 (en) * | 2009-03-10 | 2010-09-27 | Labiana Pharmaceuticals, S.L. | Procedure for the preparation of phosphomycin trometamol. (Machine-translation by Google Translate, not legally binding) |
-
2018
- 2018-11-28 CN CN201811436852.XA patent/CN111233921A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2345591A1 (en) * | 2009-03-10 | 2010-09-27 | Labiana Pharmaceuticals, S.L. | Procedure for the preparation of phosphomycin trometamol. (Machine-translation by Google Translate, not legally binding) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117964661A (en) * | 2024-04-01 | 2024-05-03 | 深圳创元生物医药科技有限公司 | Preparation method of fosfomycin genotoxic impurity C |
| CN117964661B (en) * | 2024-04-01 | 2024-06-07 | 深圳创元生物医药科技有限公司 | Preparation method of fosfomycin genotoxic impurity C |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI338003B (en) | Process for the manufacture of organic compounds | |
| CN110498770B (en) | Method for preparing intermediate of oxaagolide | |
| JP5921235B2 (en) | 3-Hydroxy-6H-benzo [c] chromen-6-one derivative and method for producing the same | |
| CN114478690B (en) | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane derivative | |
| CN111675692A (en) | Synthetic method of ozenoxacin | |
| CN111320552A (en) | Preparation method of enzalutamide intermediate | |
| CN110498771B (en) | Method for preparing intermediate of pergolide | |
| CN111233921A (en) | Novel compound and method for synthesizing fosfomycin impurity D by using same | |
| EP4015519A1 (en) | Method of preparing asenapine | |
| CN110759870B (en) | Synthesis method of oxalagogri intermediate | |
| KR100674522B1 (en) | Process for Preparation of Spirofluorenols | |
| JP2004506043A (en) | Method for producing cilostazol | |
| CN111233922A (en) | Novel compound and method for synthesizing fosfomycin impurity B by using same | |
| CN108084145B (en) | Ticagrelor intermediate and preparation method thereof | |
| CN113717197B (en) | Preparation method and application of antituberculosis drug Pretomoid | |
| WO2019239202A1 (en) | Novel & improved synthesis of antipsychotic drug | |
| WO2018133533A1 (en) | Montelukast sodium intermediate, preparation method and application thereof | |
| CN110950886A (en) | Method for synthesizing 1-methyl-imidazole-2-methyl formate derivative | |
| CN110372572A (en) | A kind of synthetic method of 4,4- difluoropiperdin -1- formyl chloride | |
| CN111187197B (en) | Synthesis method of Tezacaftor intermediate | |
| CN114736186B (en) | Method for synthesizing Violet Luo Zhongjian body from tert-butyl carbamate | |
| CN114621109B (en) | Synthesis method of apatamide and intermediate thereof | |
| CN107325092B (en) | Novel preparation process of azithromycin | |
| JP2894366B2 (en) | Method for producing deacetylcolchicine | |
| CA3223714A1 (en) | Process for the preparation of a cyp11a1 inhibitor and intermediates thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200605 |
|
| WD01 | Invention patent application deemed withdrawn after publication |