CN103910748B - The preparation method of temocillin sodium - Google Patents
The preparation method of temocillin sodium Download PDFInfo
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- CN103910748B CN103910748B CN201410170590.2A CN201410170590A CN103910748B CN 103910748 B CN103910748 B CN 103910748B CN 201410170590 A CN201410170590 A CN 201410170590A CN 103910748 B CN103910748 B CN 103910748B
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- Prior art keywords
- sodium
- ticarcillin
- temocillin
- preparation
- methoxyl group
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- KBBLJDDYBLDMOU-UHFFFAOYSA-N tert-butyl n-[(2-oxo-1,3-oxazolidin-5-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1CNC(=O)O1 KBBLJDDYBLDMOU-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 claims abstract description 45
- 229960004659 ticarcillin Drugs 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- -1 methoxyl group Chemical group 0.000 claims abstract description 21
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 230000000977 initiatory effect Effects 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 6
- 239000002585 base Substances 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002140 halogenating effect Effects 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000012805 post-processing Methods 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 8
- 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 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- IODUDVQDMKBOJC-UHFFFAOYSA-N tert-butyl hypobromite Chemical compound CC(C)(C)OBr IODUDVQDMKBOJC-UHFFFAOYSA-N 0.000 claims description 3
- SFWFCZUSPDXUPN-UHFFFAOYSA-N tert-butyl hypoiodite Chemical compound CC(C)(C)OI SFWFCZUSPDXUPN-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 229960004075 ticarcillin disodium Drugs 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 5
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 description 4
- 229960001114 temocillin Drugs 0.000 description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- GLXCXYZWVRLFFY-UHFFFAOYSA-N CO.[Li] Chemical compound CO.[Li] GLXCXYZWVRLFFY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- AMJQWGIYCROUQF-UHFFFAOYSA-N calcium;methanolate Chemical compound [Ca+2].[O-]C.[O-]C AMJQWGIYCROUQF-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- WIDKTXGNSOORHA-CJHXQPGBSA-N n,n'-dibenzylethane-1,2-diamine;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;tetrahydrate Chemical class O.O.O.O.C=1C=CC=CC=1CNCCNCC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 WIDKTXGNSOORHA-CJHXQPGBSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- MRGCZDWBFFUEES-CWBCWDDISA-L temocillin disodium Chemical compound [Na+].[Na+].N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C(C([O-])=O)C=1C=CSC=1 MRGCZDWBFFUEES-CWBCWDDISA-L 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the synthetic field of medicine, specifically disclose a kind of preparation method of temocillin sodium, it is characterized in that adopting ticarcillin sodium is initiation material, directly under methoxyl group alkali condition, generates temocillin sodium with ticarcillin sodium, reduce reactions steps, improved yield. Raw material of the present invention is easy to get, and does not need high-pressure hydrogenation deprotection base, little to device dependence, is conducive to produce amplify; Course of reaction toxicity is low, little to ambient influnence, and reaction scheme is short, and yield is high, greatly reduces cost, and product purity is greater than 95%, and yield is greater than 55%, generates through single step reaction, can directly obtain temocillin sodium without refining.
Description
Technical field
The invention belongs to compound preparation field, be specifically related to a kind of preparation method of temocillin sodium.
Technical background
Temocillin sodium (TemocillinSodium, commodity are called Temopen, CAS registration number 61545-06-0) chemistryTitle: (2S, 5R, 6S)-6-[(carboxyl-3-thiophene acetyl) amino]-6-methoxyl group-3,3-dimethyl-7-oxo-4-sulphurAssorted-1-azabicyclo [3.2.0] heptane-2-carboxylic acid disodium salt, its chemical structural formula is as follows:
Temocillin Na Shi Beecham drugmaker (now merging into SmithKlineBeecham drugmaker) research and developmentA PCs for the resistance to beta-lactamase of New-type long-acting, goes on the market as far back as Germany for 1984. The conduct of temocillin sodiumSemi-synthetic broad-spectrum antibiotic, does not orally absorb; Stable to beta-lactamase, to Gram-negative bacteria sensitivity, to enterococcus, haemolysisProperty streptococcus isoreactivity is higher but to pseudomonas aeruginosa poor activity, is used for the treatment of urinary tract due to sensitive bacteria, skin and soft tissueInfect etc.
Temocillin sodium, as a kind of beta-lactam antibiotic, is 6 methoxyl group penicillin of the first, existing preparation roadLine is all to launch centered by the framework of its 6 methoxyl groups, and the preparation method under prior art condition is divided into followingMethod.
The disclosed syntheti c route of patent GB1538052, taking 6-aminopenicillanic acid benzyl ester as raw material, by by 6-β positionAmino is converted into after isocyano group, introduces methyl mercapto, then at HgCl in 6-α position2Effect under, 6-α position is by methoxy substitution,Again by making temocillin sodium with 3-thiophene malonyl-chlorine acidylate and the hydrogenation debenzylation of side chain benzyl protection. This workSkill route is long, and yield is low, uses the toxic reagents such as phosphorus pentachloride, phosgene, mercury chloride, and final step adopts the reduction of palladium hydrocarbonize de-Except protecting group, be unfavorable for industrial amplification production.
The disclosed route of preparing temocillin sodium of patent GB1578748, to protect to methyl-benzyl or to nitrobenzylProtecting Ticarcillin is raw material, and after processing with phosphorus pentachloride, side chain is converted into stable ketenes imine structure, then adds through chlorineBecome and lithium methoxide processing, introduce methoxyl group in 6-α position, then make temocillin sodium through hydro-reduction. With Article 1 route oneSample. Step is longer, and raw materials used Ticarcillin dibenzyl ester is not common commercially available product.
(synthesizing of PCs temocillin disodium, the Chinese Journal of New Drugs such as the Li Miao of China Medicine University, Zhou XiangThe 19th the 22nd phase of volume in 2010) one article of route of preparing temocillin sodium has been proposed, taking ticarcillin sodium as raw material, protect through esterificationAfter protecting, under low temperature, react with t-butyl hypochlorate and highly basic, successfully introduce methoxyl group at 6, then hydrogenation sloughs benzyl protection,To temocillin sodium. Described route is longer, and wherein protection has increased production difficulty, reduced yield with deprotection.
Temocillin sodium is as a kind of benzathine penicillin class antibiotic, and its use amount is larger, raw-material price and roadLine is all being related to the control of the production cost of temocillin sodium, therefore, is necessary to select a kind of simple and convenient process for preparing, shortens techniqueRoute, reduces the cost of product, increases economic efficiency.
Summary of the invention
Order of the present invention is for the deficiencies in the prior art, provides a kind of safe, cheaply, is applicable to suitability for industrialized productionThe preparation method of temocillin sodium.
Object of the present invention can realize by following technical scheme:
A preparation method for temocillin sodium, is characterized in that: with ticarcillin sodium be initiation material and halogenating agentUnder methoxyl group alkali condition, react, cancellation, post processing, freeze-drying obtain temocillin sodium.
Preferably, the preparation method of described temocillin sodium, is characterized in that comprising the steps:
(1) ticarcillin sodium adds solvent orange 2 A stirring and dissolving, obtains Ticarcillin sodium solution;
(2) by methoxyl group alkali and solvent B, drop in dry reaction bulb, be cooled to-30 DEG C～-60 DEG C, drip above-mentioned replacingThe mixed liquor of card XiLin sodium solution and halogenating agent, drips to finish in-30 DEG C～-60 DEG C and reacts 2～5 hours, cancellation, post processing, freezesThe dry temocillin sodium that obtains; The wherein yield 50%～65% of compound temocillin sodium, purity is greater than 95%.
Its synthetic route is as follows:
Further preferred, in step (1), described solvent orange 2 A is methyl alcohol and dimethyl sulfoxide (DMSO), dimethyl sulfoxide (DMSO), tetrahydrochyseneThe mixed liquor of a kind of in furans, acetonitrile or any two kinds.
Further preferred, the solvent B described in step (2) is methyl alcohol, dimethyl sulfoxide (DMSO), oxolane, acetonitrile, acetic acidThe mixed liquor of a kind of in methyl esters, ethyl acetate, butyl acetate or any two kinds; Described methoxyl group alkali is alkali metal or alkaline earth goldThe methoxide belonging to; Described halogenating agent be N-chlorosuccinimide, N-bromo-succinimide, N-N-iodosuccinimide,A kind of or any two kinds of mixtures in t-butyl hypochlorate, the hypobromous acid tert-butyl ester, the hypoiodous acid tert-butyl ester.
Further preferred, it is characterized in that: in step (1), described ticarcillin sodium is Ticarcillin list sodium or replacesCard XiLin disodium; Described ticarcillin sodium is 1:(1～3 with the mass/volume of solvent orange 2 A ratio) g/ml.
Further preferred, in step (2), the mol ratio of described ticarcillin sodium and methoxyl group alkali is 1:(1～3),Described ticarcillin sodium and the mol ratio of halogenating agent are 1:(1～3).
Further preferred, the reaction temperature described in step (2) is-40 DEG C～-50 DEG C, and the reaction time is 3 hours.
Further preferred, in step (1), described solvent orange 2 A is the mixed liquor of methyl alcohol and dimethyl sulfoxide (DMSO).
Further preferred, in step (2), described methoxyl group alkali particular methanol lithium, also can adopt with sodium methoxide withThe form of the mixture of one or both in lithium chloride, lithium bromide, lithium iodide adds, or with potassium methoxide and lithium chloride, bromineThe form of the mixture of one or both in change lithium, lithium iodide adds; Described halogenating agent is t-butyl hypochlorate.
In the present invention, temocillin sodium and ticarcillin sodium structure are similar, and its structural difference is 6-bit substituentDifference, only need on 6, build methoxyl group can obtain temocillin sodium, therefore by the synthetic temocillin sodium of ticarcillin sodiumBe a good approach, route is short, and ticarcillin sodium is that common commercially available product, source are sufficient. Taking ticarcillin sodium as raw material,The structure of realizing temocillin sodium 6-position methoxyl group, solve following problem:
(1) at lower temperature, ticarcillin sodium is converted into Ticarcillin alkene imine structure, the halo using examinationAgent comprises halogen, halogenated succinimide acid imide or hypohalite etc.
(2) by use highly basic on Ticarcillin alkene imine structure, introduce methoxyl group, as the alkali metal of methoxyl group withAlkaline earth metal compound etc.
The present invention is synthetic temocillin sodium taking ticarcillin sodium as initiation material, and initiation material ticarcillin sodium source is filledFoot. The present invention does not need as the use high-pressure hydrogenation reduction protection of mentioning in patent GB1538052 and patent GB1578748Base, has reduced reactions steps, has improved yield, can effectively reduce costs.
Improvement compared with prior art innovation of the present invention is as follows:
(1) sufficient raw, the commercially available abundance of initiation material ticarcillin sodium, is easy to get, and solvent for use is common solvent;
(2) reaction scheme is short, and yield is high, greatly reduces cost;
(3) do not need high-pressure hydrogenation deprotection base, little to device dependence, be conducive to produce and amplify;
(4) reagent toxicity that this route is used is low, little to ambient influnence.
Detailed description of the invention
The present invention is described in detail to use specific embodiment below, but do not limit this patent.
Embodiment 1: the preparation of temocillin sodium
。
In reaction bulb, add ticarcillin sodium 12.85g(0.03mol), methyl alcohol 30ml, dimethyl sulfoxide (DMSO) 25ml dissolve stirMix dissolving, for subsequent use;
By lithium methoxide 1.7g(0.045mol) drop in dry reaction bulb with dimethyl sulfoxide (DMSO) 120ml, be cooled to-30 DEG C～-60 DEG C drip the mixed liquor of Ticarcillin sodium solution and t-butyl hypochlorate 5.5ml, drip and finish in-30 DEG C～-60 DEG C reactions 3Hour, triethyl phosphite 4.5ml cancellation, add ether 1L to stir 20 minutes, filter the solid of gained, filter cake 80ml etherWashing, obtains temocillin sodium crude product, and the water-soluble solution of 50ml for crude product, separates organic phase, and water adds ethyl acetate 50ml, uses5mol/L salt acid for adjusting pH value is 2, separatory, and organic phase adds water 25ml, and regulating pH value with sodium carbonate is 6.5, separatory; Water is usedActivated carbon decolorizing, filtration freeze-drying obtain temocillin sodium 9g; The yield 65% of temocillin sodium, purity 96.4%.
Embodiment 2: the preparation of temocillin sodium
In reaction bulb, add ticarcillin sodium 12.85g(0.03mol), dimethyl sulfoxide (DMSO) 25ml dissolves stirring and dissolving, standbyWith;
By sodium methoxide 3.24g(0.06mol) drop in dry reaction bulb with methyl alcohol 20ml and oxolane 120ml, coldBut arrive-30 DEG C～-60 DEG C mixed liquors that drip Ticarcillin sodium solutions and hypobromous acid tert-butyl ester 5.5ml, droplet finish in-30 DEG C～-60 DEG C are reacted 5 hours, and triethyl phosphite 4.5ml cancellation, post processing are described with example 1, and freeze-drying obtains temocillin sodium 8.5g;The yield 62% of temocillin sodium, purity 96.3%.
Embodiment 3: the preparation of temocillin sodium
In reaction bulb, add ticarcillin sodium 12.85g(0.03mol), methyl alcohol 50ml, dissolve stirring and dissolving, for subsequent use;
By calcium methoxide 7.6g(0.075mol) drop into dry reaction bulb with dimethyl sulfoxide (DMSO) 60ml, ethyl acetate 60mlIn, be cooled to-30 DEG C～-60 DEG C mixed liquors that drip Ticarcillin sodium solution and N-bromo-succinimide 10.68g, drip and finishIn-30 DEG C～-60 DEG C reactions 4 hours, triethyl phosphite 4.5ml cancellation, post processing were described with example 1, and freeze-drying obtains replacing notXiLin sodium 8g; The yield 58% of temocillin sodium, purity 96.1%.
Embodiment 4: the preparation of temocillin sodium
In reaction bulb, add Ticarcillin list sodium 12.2g(0.03mol), methyl alcohol 20ml, dimethyl sulfoxide (DMSO) 30ml dissolveStirring and dissolving, for subsequent use;
Will be containing magnesium methoxide 3.88g(0.075mol) methanol solution 20ml and dimethyl sulfoxide (DMSO) 60ml, oxolane 60ml throwEnter in dry reaction bulb, be cooled to-30 DEG C～-60 DEG C to drip Ticarcillin list sodium solutions and hypoiodous acid tert-butyl ester 6.5mlMixed liquor, drips and finishes in-30 DEG C～-60 DEG C reactions 2 hours, and triethyl phosphite 4.5ml cancellation, post processing are described with example 1, freezeThe dry temocillin sodium 7.4g that obtains; The yield 54% of temocillin sodium, purity 95.8%.
Embodiment 5: the preparation of temocillin sodium
In reaction bulb, add ticarcillin sodium list sodium 12.2g(0.03mol), methyl alcohol 30ml, dimethyl sulfoxide (DMSO) 25ml be moltenSeparate stirring and dissolving, for subsequent use;
Will be containing potassium methoxide 4.2g(0.06mol) methanol solution 20ml and methyl acetate 120ml drop in dry reaction bulb,Be cooled to-30 DEG C～-60 DEG C mixed liquors that drip Ticarcillin sodium solutions and t-butyl hypochlorate 4ml, droplet finish in-30 DEG C～-60 DEG C are reacted 3 hours, and triethyl phosphite 4.5ml cancellation, post processing are described with example 1, and freeze-drying obtains temocillin sodium 8.2g;The yield 60% of temocillin sodium, purity 96.3%.
Embodiment 6: the preparation of temocillin sodium
In reaction bulb, add ticarcillin sodium 12.85g(0.03mol), methyl alcohol 20ml, dimethyl sulfoxide (DMSO) 40ml dissolve stirMix dissolving, for subsequent use;
By sodium methoxide 2.43g(0.045mol) drop in dry reaction bulb with acetonitrile 120ml, be cooled to-30 DEG C～-60DEG C drip the mixed liquor of Ticarcillin sodium solution and N-chlorosuccinimide 4g and t-butyl hypochlorate 2.8ml, droplet finish in-30DEG C～-60 DEG C reaction 4 hours, triethyl phosphite 4.5ml cancellation, post processing is described with example 1, freeze-drying obtains temocillin sodium7.8g; The yield 57% of temocillin sodium, purity 95.6%.
Embodiment 7: the preparation of temocillin sodium
In reaction bulb, add ticarcillin sodium 12.85g(0.03mol), methyl alcohol 30ml, dimethyl sulfoxide (DMSO) 30ml dissolve stirMix dissolving, for subsequent use;
By potassium methoxide 4.2g(0.06mol) drop in dry reaction bulb with butyl acetate 60ml, oxolane 60ml, coldBut arrive-30 DEG C～-60 DEG C and drip the mixed of Ticarcillin sodium solution and N-chlorosuccinimide 6g and t-butyl hypochlorate 2.8mlClose liquid, drip and finish in-30 DEG C～-60 DEG C reactions 5 hours, triethyl phosphite 4.5ml cancellation, post processing is described with example 1, freeze-dryingObtain temocillin sodium 8.3g; The yield 61% of temocillin sodium, purity 95.4%.
Claims (5)
1. a preparation method for temocillin sodium, is characterized in that: be that initiation material and halogenating agent exist with ticarcillin sodiumUnder methoxyl group alkali condition, react, cancellation, post processing, freeze-drying obtain temocillin sodium;
Its preparation method comprises the steps:
(1) ticarcillin sodium adds solvent orange 2 A stirring and dissolving, obtains Ticarcillin sodium solution;
(2) by methoxyl group alkali and solvent B, drop in dry reaction bulb, be cooled to-30 DEG C～-60 DEG C, drip in step (1)Ticarcillin sodium solution and the mixed liquor of halogenating agent, drip finish in-30 DEG C～-60 DEG C reaction 2～5 hours, cancellation, Hou ChuReason, freeze-drying obtain temocillin sodium;
In step (1), described solvent orange 2 A is a kind of in methyl alcohol and dimethyl sulfoxide (DMSO), oxolane, acetonitrile or any two kindsMixed liquor; Described ticarcillin sodium is Ticarcillin list sodium or ticarcillin disodium; Described ticarcillin sodium and solvent orange 2 AMass/volume is than being 1:(1～3) g/ml;
Solvent B described in step (2) is methyl alcohol, dimethyl sulfoxide (DMSO), oxolane, acetonitrile, methyl acetate, ethyl acetate, secondThe mixed liquor of a kind of in acid butyl ester or any two kinds; The mol ratio of described ticarcillin sodium and methoxyl group alkali be 1:(1～3); Described ticarcillin sodium and the mol ratio of halogenating agent are 1:(1～3).
2. the preparation method of temocillin sodium according to claim 1, is characterized in that: described methoxyl group alkali is alkali metalOr the methoxide of alkaline-earth metal; Described halogenating agent is N-chlorosuccinimide, N-bromo-succinimide, N-iodo fourth twoA kind of or any two kinds of mixtures in acid imide, t-butyl hypochlorate, the hypobromous acid tert-butyl ester, the hypoiodous acid tert-butyl ester.
3. the preparation method of temocillin sodium according to claim 1, is characterized in that: the reaction described in step (2)Temperature is-40 DEG C～-50 DEG C, and the reaction time is 3 hours.
4. the preparation method of temocillin sodium according to claim 1, is characterized in that: in step (1), and described solvent orange 2 AFor the mixed liquor of methyl alcohol and dimethyl sulfoxide (DMSO).
5. the preparation method of temocillin sodium according to claim 1 and 2, is characterized in that: in step (2), and described firstOxygen base alkali is lithium methoxide; Described halogenating agent is t-butyl hypochlorate.
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