CN103113408B - A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt - Google Patents
A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt Download PDFInfo
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- CN103113408B CN103113408B CN201210527035.1A CN201210527035A CN103113408B CN 103113408 B CN103113408 B CN 103113408B CN 201210527035 A CN201210527035 A CN 201210527035A CN 103113408 B CN103113408 B CN 103113408B
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- phosphonomycin
- phenylethylamine
- dextrorotation
- present
- fosfomycin
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- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 16
- 101100059652 Mus musculus Cetn1 gene Proteins 0.000 title claims abstract description 8
- 101100059655 Mus musculus Cetn2 gene Proteins 0.000 title claims abstract description 8
- ODALAXKSIBESFV-PXRNWTNJSA-N [(2r,3s)-3-methyloxiran-2-yl]phosphonic acid;(1r)-1-phenylethanamine Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O.C[C@@H](N)C1=CC=CC=C1 ODALAXKSIBESFV-PXRNWTNJSA-N 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims abstract description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000007925 phenylethylamine derivatives Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 238000006735 epoxidation reaction Methods 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 208000012839 conversion disease Diseases 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 229910052698 phosphorus Inorganic materials 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- -1 Amine salt Chemical class 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 1
- 206010011844 Dacryocystitis Diseases 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010056254 Intrauterine infection Diseases 0.000 description 1
- 241001263448 Mycetozoa Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 206010061512 Serratia infection Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000008025 hordeolum Diseases 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Abstract
The present invention relates to a kind of method preparing phosphonomycin fosfomycin phenylethylamine calt, the present invention proposes the synthetic method of easier a, low cost, belong to the field of chemical synthesis.Method of the present invention take cis-propene phosphoric acid as raw material, is oxidized to ring, under specific solvent condition, carries out dynamic resolution under catalyzer, oxygenant effect, separate out phosphonomycin, then drop into a certain proportion of dextrorotation phenylethylamine, reaction, refine and obtain phosphonomycin dextrorotation phenylethylamine salt.This preparation method's reaction cost is low, and step is few, and by product is few, and environmental pollution is little, is applicable to the large manufacture of factory.
Description
Technical field
The present invention relates to a kind of method preparing phosphonomycin fosfomycin phenylethylamine calt, the present invention proposes the synthetic method of easier a, low cost, belong to the field of chemical synthesis.
Background technology
Phosphonomycin is a kind of wide spectrum, low toxicity, not easily sensitization, not easily produce resistance, with most of antibiotic, there is synergistic a kind of antibiotic, all responsive to staphylococcus, intestinal bacteria, meningococcus, gonococcus, Corynebacterium diphtheriae, Serratia, Bacillus proteus, Pseudomonas aeruginosa, dysentery bacterium and Hp etc., can the synthesis of anti-bacteria cell walls, the sterilant of a kind of nursery stage, all inhibited to the negative mycetozoan of most of suis, Pseudomonas aeruginosa, Proteus mirabilis and part pneumobacillus and indoles.Phosphonomycin is applicable to urinary tract, respiratory tract, digestive tube, gynaecology, skin soft tissue and other site infections and septicemia.Oral administration can treat intestinal tract infections, urinary tract infections, Serratia infection, Helicobacter pylori infection and blepharitis, hordeolum, otitis media, nasal sinusitis, dacryocystitis etc.; Intravenous injection can treat the gynaecopathias such as respiratory tract infection, urinary tract infection, septicemia and pelvic inflammatory disease, appendagitis, intra-uterine infection, and range of application is very extensive.
Phosphonomycin starts to be extract from actinomycetes nutrient solution, is all produced by synthetic method at present.
Various phosphonomycin salt is usually transformed by phosphonomycin dextrorotation phenylethylamine salt and generates, and the route of synthesis of phosphonomycin dextrorotation phenylethylamine salt is as follows:
In above formula, effective body (A) is phosphonomycin dextrorotation phenylethylamine salt, the left-handed benzene second of invalid body (B) dextrorotation phosphonomycin
Amine salt, both respectively account for half.
Fosfomycin phenylethylamine calt splits the prior art of preparation:
Domestic patent or some english literatures describe: adopt induced crystallization method, add left salt as crystal seed, make it separate out, reach separation object whereby in the solution of racemic modification.
Detailed process is as follows: by the mixed salt (the right amine of left phosphorus and the left amine salt of right phosphorus) 330 kilograms obtained after epoxidation, 0.25 kilogram of right amine crystal seed of left phosphorus and 400 liters of dehydrated alcohol heating for dissolving, stirs and is cooled to 20 degree to the right amine of the left phosphorus of crystallization 1.65 kilograms.Add 1.65 kilograms of mixed salts after filtration again, add the left amine salt crystal seed of right phosphorus, after separating out the left amine salt of right phosphorus.Repeat above operation can not be used to mother liquor for 60 times, merge each fractionation and obtain fosfomycin phenylethylamine calt about 100 kilograms, fractionation rate is 60%, is 132 degree with fusing point after ethyl alcohol recrystallization again.
Shortcoming: in fractionation operation, need to repeat tens of crystallizations and obtain fosfomycin phenylethylamine calt, one is lose time, and two is that whole fractionation rate is not high, cost becomes large.The left amine salt of the right phosphorus of ineffective treatment compound accounts for the composition of half simultaneously, does not add utilization and causes the wasting of resources.
The present invention be directed to above-mentioned present situation, provide that a kind of raw material is cheap and easy to get, toxicity is little, reactions steps is few, side reaction is few, and the three wastes are few, is applicable to this method for splitting of industrialized production, the method is being primary solvent with water, adds appropriate dimethyl sulfoxide (DMSO), avoids the pollution in classical resolution method.This resolution process is easy and simple to handle simultaneously, and raw material is easy to get, mild condition, and product purity is high, steady quality.
Summary of the invention
The object of the invention is to provide a kind of novel method for splitting to prepare phosphonomycin dextrorotation phenylethylamine, for the synthesis of Fosmicin sodium salt, to meet the needs that medicinal industry department produces.The present invention does not adopt common induced crystallization method, and adopts Dynamic Kinetic Resolution method.We find under study for action, and when the phosphonomycin racemic modification spontaneous crystallization slowly in the solution that reaction generates, phosphonomycin is preferentially separated out, and the racemic modification in mother liquor has asymmetric transformation phenomenon.Also having a kind of is that in the patent of invention of one section of fosfomycin trometamol as previous in this institute, utilize outside chiral reagent effect, its isomeric equilibration is moved, obtain the phosphonomycin that ee value is 90%, this no longer describes.
Concrete steps are described as follows:
(1) DL phosphonomycin is prepared: under the catalysis of catalyzer, by oxygenant to cis-propene phosphoric acid asymmetric Epoxidation.Whole oxidising process uses HPLC nh 2 column monitoring reaction conversion ratio.
(2) dynamic resolution: under specific solvent condition, phosphonomycin is separated out.
(3) preparation of phosphonomycin dextrorotation phenylethylamine: the phosphonomycin obtain step (2) and dextrorotation phenylethylamine feed intake after reaction according to a certain percentage, separate out the phosphonomycin dextrorotation phenylethylamine salt obtaining refining in ethanol.
Embodiment
The present invention is set forth below with example:
1. compound
1synthesis:
Get 1.2g(10mmol) cis-propene phosphoric acid and dehydrated alcohol (5 milliliters) be added in 50 milliliters of three-necked bottles, stirs entirely molten.Drip by 0.5gNa
2wO
4with the solution of water-soluble 5 milliliters of 0.13gEDTA-2Na, then add the hydrogen peroxide 1.7g(15mmol of 30%), be heated to 40 degree entirely molten, reaction 1h.High performance liquid phase monitoring reaction.Cooling filtering insolubles, steams ethanol after removing, adds the DL phosphonomycin that extraction into ethyl acetate generates, anhydrous sodium sulfate drying, filter, concentrate and obtain colorless oil (1.3g, yield 94%).
2. dynamic resolution
Deionized water 8 milliliters and dimethyl sulfoxide (DMSO) 2 milliliters are added in reaction flask, open stirring, the DL phosphonomycin of upper step product 1.3 grams drops into wherein, is warmed up to 40 degree and is incubated 15 minutes, cool to 5 degree, vapor away most of solvent, phosphonomycin is separated out from this solution, leaches fast, and vacuum Air drying obtains clear crystal 0.6g, split productive rate and reach 91%, ee value 98%.Mother liquor, by surveying specific optical rotation, finds that dextrorotation phosphonomycin has part configuration conversion, collects pending.
3. the preparation of phosphonomycin dextrorotation phenylethylamine
Under nitrogen protection; being dropped into by phosphonomycin (0.6g) is equipped with in the dehydrated alcohol reaction flask of 5 milliliters; the dextrorotation phenylethylamine syringe of 0.53g is slowly squeezed into wherein; keep room temperature reaction 3 hours; leach and obtain white solid phosphonomycin dextrorotation phenylethylamine salt (1.05g, yield 93%).
Claims (1)
1. prepare a method for phosphonomycin fosfomycin phenylethylamine calt, it is characterized in that the operation steps of the method is as follows:
(1) DL phosphonomycin is prepared: under the catalysis of catalyzer, by oxygenant to cis-propene phosphoric acid asymmetric Epoxidation,
Whole oxidising process uses HPLC nh 2 column monitoring reaction conversion ratio;
(2) dynamic resolution: under specific solvent condition, phosphonomycin is separated out;
(3) preparation of phosphonomycin dextrorotation phenylethylamine: the phosphonomycin obtain step (2) and dextrorotation phenylethylamine feed intake after reaction according to a certain percentage, separate out the phosphonomycin dextrorotation phenylethylamine salt obtaining refining in ethanol;
Catalyzer described in step (1) is sodium wolframate, and oxygenant is hydrogen peroxide;
Specific solvent described in step (2) is the mixed solvent of deionized water and dimethyl sulfoxide (DMSO), and volume ratio both this is 4:1; Certain proportion described in step (3) is the mol ratio of phosphonomycin and dextrorotation phenylethylamine is 1:1.
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| CN201210527035.1A CN103113408B (en) | 2012-12-10 | 2012-12-10 | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt |
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| CN201210527035.1A CN103113408B (en) | 2012-12-10 | 2012-12-10 | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt |
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| CN103113408B true CN103113408B (en) | 2015-11-18 |
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| CN107382752B (en) * | 2017-07-12 | 2021-03-30 | 杭州科兴生物化工有限公司 | Method for recovering raw material dextroamine for preparing d-biotin |
| CN112442084B (en) * | 2020-12-03 | 2022-09-09 | 国药集团致君（深圳）制药有限公司 | Preparation method of antibacterial drug intermediate |
| CN112409410A (en) * | 2020-12-09 | 2021-02-26 | 商河探荣新技术开发中心 | Application of silver catalyst in preparation of antibacterial intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723979A (en) * | 2009-12-08 | 2010-06-09 | 张庆武 | Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate |
| CN101759719A (en) * | 2010-01-18 | 2010-06-30 | 张庆武 | Method for synthesizing fosfomycin phenylethylamine calt |
| CN101928301A (en) * | 2009-10-19 | 2010-12-29 | 湖北迅达药业股份有限公司 | Method for synthesizing levofosfomycin dextrophenethylamine salt from dextrofosfomysin levophenethylamine salt |
| CN102807586A (en) * | 2012-08-31 | 2012-12-05 | 东北制药（沈阳）科技发展有限公司 | Preparation method of fosfomycin amine salt |
-
2012
- 2012-12-10 CN CN201210527035.1A patent/CN103113408B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928301A (en) * | 2009-10-19 | 2010-12-29 | 湖北迅达药业股份有限公司 | Method for synthesizing levofosfomycin dextrophenethylamine salt from dextrofosfomysin levophenethylamine salt |
| CN101723979A (en) * | 2009-12-08 | 2010-06-09 | 张庆武 | Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate |
| CN101759719A (en) * | 2010-01-18 | 2010-06-30 | 张庆武 | Method for synthesizing fosfomycin phenylethylamine calt |
| CN102807586A (en) * | 2012-08-31 | 2012-12-05 | 东北制药（沈阳）科技发展有限公司 | Preparation method of fosfomycin amine salt |
Non-Patent Citations (2)
| Title |
|---|
| (1R,2S)-(-)-cis-1,2-环氧丙基膦酸(R)-(+)-α-苯乙胺盐的合成;冯晓玲等;《中国医药工业杂志》;20090410;第40卷(第4期);第255-257页 * |
| 在水中由钼(VI)或钨(VI)吡啶醇络合物进行的顺丙烯膦酸的异相催化不对称环氧化;唐洁等;《有机化学》;20060425;第26卷(第4期);第508-513页 * |
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Effective date of registration: 20220114 Address after: 210033 9th floor, F6 building, No.9, Weidi Road, Qixia District, Nanjing City, Jiangsu Province Patentee after: SKYRUN PHARMA Co.,Ltd. Address before: 238251 Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee before: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee before: Jiangsu Kaiyuan Pharmaceutical Co.,Ltd. |
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| TR01 | Transfer of patent right |
Effective date of registration: 20240304 Address after: 234000, No. 368 Jinjiang Fifth Road, Economic Development Zone, Suzhou City, Anhui Province Patentee after: Kaiyuan Pharmaceutical (Anhui) Co.,Ltd. Country or region after: China Address before: 210033 9th floor, F6 building, No.9, Weidi Road, Qixia District, Nanjing City, Jiangsu Province Patentee before: SKYRUN PHARMA Co.,Ltd. Country or region before: China |