CN115232168A - Preparation method of fosfomycin methoxyl ring-opening impurity - Google Patents
Preparation method of fosfomycin methoxyl ring-opening impurity Download PDFInfo
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- CN115232168A CN115232168A CN202210930494.8A CN202210930494A CN115232168A CN 115232168 A CN115232168 A CN 115232168A CN 202210930494 A CN202210930494 A CN 202210930494A CN 115232168 A CN115232168 A CN 115232168A
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- fosfomycin
- phosphite
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- methoxyl
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- 229960000308 fosfomycin Drugs 0.000 title claims abstract description 35
- 239000012535 impurity Substances 0.000 title claims abstract description 25
- 238000007142 ring opening reaction Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 9
- HZVKHMQXJYFYRF-UHFFFAOYSA-N 2-methoxypropanal Chemical compound COC(C)C=O HZVKHMQXJYFYRF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- YTTFFPATQICAQN-UHFFFAOYSA-N 2-methoxypropan-1-ol Chemical compound COC(C)CO YTTFFPATQICAQN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000007800 oxidant agent Substances 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- -1 (1-hydroxy-2-methoxypropyl) phosphonic acid Chemical compound 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 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 12
- 239000002904 solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 6
- UFDULEKOJAEIRI-UHFFFAOYSA-N (2-acetyloxy-3-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(I)=C1OC(C)=O UFDULEKOJAEIRI-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 claims description 2
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 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
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 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 claims description 2
- BVXOPEOQUQWRHQ-UHFFFAOYSA-N dibutyl phosphite Chemical compound CCCCOP([O-])OCCCC BVXOPEOQUQWRHQ-UHFFFAOYSA-N 0.000 claims description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 2
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 claims description 2
- KUMNEOGIHFCNQW-UHFFFAOYSA-N diphenyl phosphite Chemical compound C=1C=CC=CC=1OP([O-])OC1=CC=CC=C1 KUMNEOGIHFCNQW-UHFFFAOYSA-N 0.000 claims description 2
- NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 2
- 238000001308 synthesis method Methods 0.000 claims 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 abstract description 12
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 150000008301 phosphite esters Chemical class 0.000 abstract 1
- 238000005809 transesterification reaction Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- YMZJBJPWTXJQMR-MUWMCQJSSA-L calcium;[(2s,3r)-3-methyloxiran-2-yl]-dioxido-oxo-$l^{5}-phosphane Chemical compound [Ca+2].C[C@H]1O[C@H]1P([O-])([O-])=O YMZJBJPWTXJQMR-MUWMCQJSSA-L 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- QZIQJIKUVJMTDG-OTUWWBTESA-L disodium;[(2s,3r)-3-methyloxiran-2-yl]-dioxido-oxo-$l^{5}-phosphane Chemical class [Na+].[Na+].C[C@H]1O[C@H]1P([O-])([O-])=O QZIQJIKUVJMTDG-OTUWWBTESA-L 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960001806 fosfomycin trometamol salt Drugs 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic 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)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- 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)
Abstract
The invention belongs to the technical field of medicine production, and particularly relates to a preparation method of fosfomycin methoxyl open-loop impurities. The method comprises the steps of taking 2-methoxy-1-propanol as an initial raw material, oxidizing the initial raw material into aldehyde by using a proper oxidant, namely 2-methoxypropionaldehyde, reacting the obtained 2-methoxypropionaldehyde with a phosphite ester reagent, and finally performing a transesterification reaction to obtain a final target product, namely the fosfomycin methoxy ring-opening impurity. The method for synthesizing the fosfomycin methoxyl open-loop impurities has the advantages of simple process route, convenient operation and mild experimental conditions, and the synthesized fosfomycin methoxyl open-loop impurities can be used as reference substances for detecting related substances in fosfomycin related varieties and related preparations thereof and can be used for quality control of the fosfomycin related varieties and the related preparations thereof.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of fosfomycin methoxyl open-loop impurities.
Background
Fosfomycin is a novel broad-spectrum antibiotic, belongs to phosphoric acid derivatives in structure, has a unique chemical structure and is small in molecular weight. It has unique action mechanism, can inhibit early stage of cell wall synthesis, has no cross resistance to other antibiotics, and is mainly used for gram-negative and gram-positive bacterial infection. Currently, there are 4 varieties of fosfomycin, which are fosfomycin sodium salt, fosfomycin calcium salt, fosfomycin trometamol salt and fosfomycin benzylamine salt. Sodium salt and calcium salt are used mostly in Europe, japan and southeast Asia, and the Japanese pharmacopoeia only collects two varieties of fosfomycin sodium salt and fosfomycin calcium salt. In the United states, fosfomycin trometamol dominates and is sold well. At present, foreign manufacturers of fosfomycin mainly comprise Japanese sawei company and Mingzhi fruit company; ma Duoshi, germany; greek, martos; perdufredrick International, USA, etc. Phosphomycin, jointly developed by Merck, USA (merck) and Spanish cepa in 1967. The fosfomycin sodium salt and the fosfomycin calcium salt are marketed in Europe in 1975, and are firstly put into industrial production in Spain, and then the industrial production is started successively in Italy and Germany; the product of Mingmen corporation was marketed in Japan in 1980. Fosfomycin trometamol was marketed in europe in 1988; approved by the U.S. FDA in the united states for marketing in 1996 month 12. The fosfomycin methoxyl ring-opening impurity, namely (1-hydroxy-2-methoxypropyl) phosphonic acid, is an important impurity in fosfomycin related substances. Therefore, the development of the preparation method of the fosfomycin methoxyl open-loop impurity, which is simple and convenient to operate, mild in condition and low in cost, has important significance.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing fosfomycin methoxyl open-loop impurities, which is intended for quality control of fosfomycin related products, and is characterized in that:
starting with 2-methoxy-1-propanol, the aldehyde, i.e., 2-methoxypropionaldehyde, is oxidized in a suitable solvent by a suitable oxidizing agent, including but not limited to pyridinium chlorochromate (PCC), dess-martin oxidizer (DMP), activated manganese dioxide (MnO) 2 ) 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), diacetoxyiodobenzene (DIB) or 2-iodoxybenzoic acid (IBX). The solvent is one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N-dimethylformamide and dimethyl sulfoxidePreferably, methylene chloride.
The resulting 2-methoxypropionaldehyde is reacted with a phosphite reagent including, but not limited to, reagents such as dibenzyl phosphite, dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite, diphenyl phosphite, and the like, preferably dibenzyl phosphite, in the presence of a solvent and a base to provide the corresponding phosphate intermediate. The solvent is one or more of dichloromethane, tetrahydrofuran, toluene, 1,4-dioxane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether and N-methylpyrrolidone, and dichloromethane is preferred; 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, pyridine, morpholine, p-dimethylaminopyridine or N, N-diisopropylethylamine, and the base is preferably sodium carbonate, potassium carbonate or triethylamine.
And carrying out catalytic hydrogenation and de-esterification reaction on the obtained phosphate intermediate to obtain a final target product (1-hydroxy-2-methoxypropyl) phosphonic acid, namely the fosfomycin methoxyl open-loop impurity. The solvent used for catalytic hydrodeesterification 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.
The invention has the advantages of providing the preparation method of the fosfomycin methoxyl open-loop impurities, which has simple and convenient operation, mild conditions, easily obtained raw materials and low cost, and providing the reference substances meeting the requirements for the quality control of the related fosfomycin varieties and the related preparations thereof.
Drawings
FIG. 1 is a scheme showing the synthesis of the fosfomycin methoxy ring-opening impurity.
FIG. 2 is a mass spectrum of fosfomycin methoxy ring-opening impurities.
FIG. 3 is a nuclear magnetic (hydrogen) spectrum of fosfomycin methoxy ring-opening impurities.
FIG. 4 is an HPLC-ELSD picture of fosfomycin methoxy ring-opening impurities.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: a method for synthesizing fosfomycin methoxyl open-loop impurities comprises the following steps:
s1, synthesis of 2-methoxypropionaldehyde: 2-methoxy-1-propanol (5 g,55.5 mmol) was added to 200mL of dichloromethane, celite (23.9 g) was added, PCC (23.9 g,110.9 mmol) was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the temperature was lowered and suction filtration was carried out, the filtrate was distilled, the fractions were collected and dried, and the next reaction was carried out directly.
S2, synthesis of dibenzyl (1-hydroxy-2-methoxypropyl) phosphonate: and (2) cooling the dichloromethane solution of the 2-methoxypropionaldehyde obtained in the last step to 10 ℃, adding dibenzylphosphite (17.4g, 66.4 mmol), adding triethylamine (11.1g, 108.9 mmol), stirring overnight at room temperature, adding water after the reaction is completed, stirring, standing for layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, drying by using anhydrous sodium sulfate, concentrating, purifying and separating by using a silica gel column chromatography to obtain 10.3g of intermediate (1-hydroxy-2-methoxypropyl) dibenzyl phosphonate, wherein the yield is 53.0%.
S3, synthesis of (1-hydroxy-2-methoxypropyl) phosphonic acid: intermediate (1-hydroxy-2-methoxypropyl) phosphonic acid dibenzyl ester (8.0 g,22.8 mmol) is dissolved in methanol (100 mL), 10% Pd/C (0.4 g) is added, hydrogen is replaced and the hydrogen atmosphere is maintained, the reaction is carried out for 2h at room temperature, suction filtration and reduced pressure concentration are carried out, so that fosfomycin methoxyl ring-opening impurity 3.8g is obtained, and the yield is 97.8%.
Example 2: a method for synthesizing fosfomycin methoxyl open-loop impurities comprises the following steps:
s1, synthesis of 2-methoxypropionaldehyde: adding 2-methoxy-1-propanol (3g, 33.3mmol) into 60mL dichloromethane, adding manganese dioxide (4.3g, 49.5mmol), heating and refluxing for 4h, cooling and filtering after the reaction is completed, and directly carrying out the next reaction on the filtrate.
S2, synthesis of dibenzyl (1-hydroxy-2-methoxypropyl) phosphonate: under the protection of nitrogen, the dichloromethane solution of the 2-methoxypropionaldehyde obtained in the previous step is cooled to 10 ℃, dibenzyl phosphite (11.5g, 43.9 mmol) is added, N-diisopropylethylamine (9.5g, 73.5 mmol) is added, stirring is carried out at room temperature overnight, after complete reaction, water is added, stirring is carried out, standing and layering are carried out, a water layer is extracted by dichloromethane, an organic layer is combined, saturated saline is washed, anhydrous sodium sulfate is dried, concentration is carried out, silica gel column chromatography purification and separation are carried out, 5.3g of intermediate (1-hydroxy-2-methoxypropyl) dibenzyl phosphonate is obtained, and the yield is 41.3%.
S3, synthesis of (1-hydroxy-2-methoxypropyl) phosphonic acid: the intermediate (1-hydroxy-2-methoxypropyl) dibenzyl phosphonate (5.0 g,14.3 mmol) obtained in the previous step was dissolved in methanol (60 mL), 10% Pd/C (0.25 g) was added, hydrogen was substituted and the hydrogen atmosphere was maintained, the reaction was carried out at room temperature for 2h, suction filtration and concentration under reduced pressure to obtain 2.3g of fosfomycin methoxy open-loop impurity in 94.7% yield.
Example 3: a method for synthesizing fosfomycin methoxyl open-loop impurities comprises the following steps:
s1, synthesis of 2-methoxypropionaldehyde: 2-methoxy-1-propanol (3g, 33.3mmol) was added to 60mL of dichloromethane, sodium hydrogencarbonate (14.0g, 167mmol) and DMP (21.2g, 50.0 mmol) were added, and the mixture was stirred at room temperature for 3 hours, after completion of the reaction, the mixture was cooled and filtered, and the filtrate was directly subjected to the next reaction.
S2, synthesis of dibenzyl (1-hydroxy-2-methoxypropyl) phosphonate: and (2) cooling the dichloromethane solution of the 2-methoxypropionaldehyde obtained in the last step to 10 ℃, adding dibenzylphosphite (11.5g, 43.9mmol), adding N, N-diisopropylethylamine (9.5g, 73.5mmol), stirring at room temperature overnight, adding water after the reaction is completed, stirring, standing for layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline water, drying by using anhydrous sodium sulfate, concentrating, and carrying out silica gel column chromatography purification and separation to obtain 6.1g of intermediate (1-hydroxy-2-methoxypropyl) dibenzyl phosphonate, wherein the yield is 52.3%.
S3, synthesis of (1-hydroxy-2-methoxypropyl) phosphonic acid: intermediate (1-hydroxy-2-methoxypropyl) dibenzyl phosphonate (5.5g, 15.7 mmol) was dissolved in methanol (100 mL), 10% Pd/C (0.3 g) was added, hydrogen replaced and the atmosphere maintained at room temperature for 2h, filtered under suction, and concentrated under reduced pressure to give 2.6g of fosfomycin methoxy ring-opened impurity in 97.4% yield.
Claims (6)
1. A method for synthesizing fosfomycin methoxyl open-loop impurities is characterized by comprising the following steps: the method comprises the following operation steps: starting with 2-methoxy-1-propanol, the aldehyde, i.e., 2-methoxypropionaldehyde, is oxidized by a suitable oxidizing agent in a suitable solvent, where the oxidizing agent includes, but is not limited to, pyridinium chlorochromate (PCC), dess-martin (DMP), activated manganese dioxide (MnO) 2 ) 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), diacetoxyiodobenzene (DIB) or 2-iodoxybenzoic acid (IBX).
2. The process according to claim 1, wherein the obtained 2-methoxypropionaldehyde is reacted with a phosphite reagent in the presence of a solvent and a base to obtain the corresponding phosphate intermediate, wherein the phosphite reagent includes, but is not limited to, reagents such as dibenzyl phosphite, dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, dibutyl phosphite, diphenyl phosphite, etc., preferably dibenzyl phosphite.
3. According to the claims 1 and 2, the obtained phosphate intermediate is subjected to catalytic hydrogenation and de-esterification reaction to obtain the final target product (1-hydroxy-2-methoxypropyl) phosphonic acid, namely the fosfomycin methoxy ring-opening impurity.
4. The method of claim 1, wherein the solvent is one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N-dimethylformamide, and dimethylsulfoxide, preferably dichloromethane.
5. The method of claim 2, wherein the solvent is one or more of dichloromethane, tetrahydrofuran, toluene, 1,4-dioxane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, N-methylpyrrolidone, 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 triethylamine, pyridine, morpholine, p-dimethylaminopyridine or N, N-diisopropylethylamine, and the base is preferably sodium carbonate, potassium carbonate or triethylamine.
6. The synthesis method according to claim 3, wherein the solvent used for catalytic hydrodeesterification 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.
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| 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 |
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