CN110724162B - Preparation method of fosfomycin trometamol impurity D - Google Patents
Preparation method of fosfomycin trometamol impurity D Download PDFInfo
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- CN110724162B CN110724162B CN201910945476.5A CN201910945476A CN110724162B CN 110724162 B CN110724162 B CN 110724162B CN 201910945476 A CN201910945476 A CN 201910945476A CN 110724162 B CN110724162 B CN 110724162B
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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 79
- 229960000308 fosfomycin Drugs 0.000 title claims abstract description 77
- 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 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 239000007791 liquid phase Substances 0.000 claims abstract description 10
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000006731 degradation reaction Methods 0.000 claims abstract description 3
- 238000012544 monitoring process Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000012071 phase Substances 0.000 claims description 23
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 21
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 21
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000523 sample Substances 0.000 description 21
- 238000012360 testing method Methods 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 7
- 239000013068 control sample Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000000539 dimer Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000009736 wetting Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000012795 verification Methods 0.000 description 3
- YMZJBJPWTXJQMR-MUWMCQJSSA-L calcium;[(2s,3r)-3-methyloxiran-2-yl]-dioxido-oxo-$l^{5}-phosphane Chemical compound [Ca+2].C[C@H]1O[C@H]1P([O-])([O-])=O YMZJBJPWTXJQMR-MUWMCQJSSA-L 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- QZIQJIKUVJMTDG-OTUWWBTESA-L disodium;[(2s,3r)-3-methyloxiran-2-yl]-dioxido-oxo-$l^{5}-phosphane Chemical class [Na+].[Na+].C[C@H]1O[C@H]1P([O-])([O-])=O QZIQJIKUVJMTDG-OTUWWBTESA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 fosfomycin benzylamine salt Chemical class 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- UDPGUMQDCGORJQ-UHFFFAOYSA-N (2-chloroethyl)phosphonic acid Chemical compound OP(O)(=O)CCCl UDPGUMQDCGORJQ-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 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
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004690 coupled electron pair approximation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960001806 fosfomycin trometamol salt Drugs 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 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
- 238000012545 processing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010998 test method 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)]
- C07F9/40—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
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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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of fosfomycin trometamol impurity D, belonging to the technical field of medicines, and the technical key points of the preparation method comprise the following operation steps: dissolving fosfomycin trometamol in a solvent I, and heating for degradation reaction; monitoring the reaction degree by the liquid phase, adding a second solvent after the reaction is finished to dissolve and dilute the second solvent to obtain 20ml of liquid phase, and shaking up to obtain a crude product of the impurity D; and step two, freeze-drying the impurity D crude product to obtain the fosfomycin trometamol impurity D. The method has the advantages of simple and convenient operation steps, short reaction flow, mild reaction conditions and high production safety.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a fosfomycin trometamol impurity D.
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, overseas manufacturers of fosfomycin mainly comprise SAWEI company and Mingzhi fruit-control company in Japan; maduos company in germany; greek, Martos; perdufredrick International, USA, etc.
Phosphomycin, jointly developed in 1967 by Merck, USA, and CEPA, Spain.
Sodium and calcium fosfomycin salts were marketed in europe in 1975, and were first put into industrial production in spain, after which they were also started in italy and germany; the product of Mingmu 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.
Fosfomycin trometamol impurity D, [2- [2- [ 2-amino-3-hydroxy-2- (hydroxymethyl) propoxy ] -1-hydroxypropyl ] hydroxyphosphoryl ] oxy ] -1-hydroxypropyl ] phosphonic acid (aminomethoxyfosfomycin dimer), is an important impurity in the european and american pharmacopoeia for fosfomycin trometamol. No method for preparing the impurity is reported at present through retrieval, so that the development of a preparation method of the fosfomycin trometamol impurity D is of great significance.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the preparation method of the fosfomycin trometamol impurity D, which has simple and convenient operation steps and short reaction flow.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of fosfomycin trometamol impurity D comprises the following operation steps: and heating and degrading the fosfomycin trometamol, adding a second solvent to dissolve the fosfomycin trometamol to prepare a liquid phase, and freeze-drying to obtain the fosfomycin trometamol impurity D.
Further, the preparation method of the fosfomycin trometamol impurity D comprises the following operation steps:
dissolving fosfomycin trometamol in a solvent I, and heating for degradation reaction; monitoring the reaction degree by the liquid phase, adding a second solvent after the reaction is finished to dissolve and dilute the second solvent to obtain 20ml of liquid phase, and shaking up to obtain a crude product of the impurity D;
and step two, freeze-drying the impurity D crude product to obtain the fosfomycin trometamol impurity D.
Further, the chemical formula for preparing the fosfomycin trometamol impurity D is as follows:
by adopting the technical scheme, the raw material fosfomycin trometamol is wetted by the first solvent, the dissolving of the fosfomycin trometamol can enable the whole reaction system to be in a homogeneous phase, and then the second solvent added in the second step is taken as a mobile phase, so that the dissolving of the raw material fosfomycin trometamol is facilitated, the reaction system is in a homogeneous phase, and the forward proceeding of the reaction is facilitated. Meanwhile, the whole operation steps are simple and convenient, the reaction flow is short, and the method is suitable for batch production and processing.
Further, the chemical structural formula of the fosfomycin trometamol impurity D is as follows:
by adopting the technical scheme, the chemical name of the fosfomycin trometamol impurity D is as follows: [2- [ 2-amino-3-hydroxy-2- (hydroxymethyl) propoxy ] -1-hydroxypropyl ] hydroxyphosphoryl ] oxy ] -1-hydroxypropyl ] phosphonic acid (aminomethoxyfosfomycin dimer), which is an important impurity in the European and American pharmacopoeia of fosfomycin trometamol.
Further, the second solvent is a mobile phase for dissolving the fosfomycin trometamol impurity D.
Further, the mobile phase adopts 0.005-0.015g/mol potassium dihydrogen phosphate water solution.
Further, the concentration of the mobile phase is preferably 0.01-0.015g/mol of potassium dihydrogen phosphate aqueous solution, and most preferably 0.01089g/mol of potassium dihydrogen phosphate aqueous solution.
By adopting the technical scheme, the mobile phase adopts the aqueous solution of the monopotassium phosphate, and the optimal solution is to take 10.89g of the monopotassium phosphate and add 1000ml of water for dissolution.
Further, the heating temperature is 50-80 ℃, and the reaction time is 20-40 h.
Further, the heating temperature is 60-80 ℃, and the reaction time is 24-36 h.
By adopting the technical scheme, the reaction temperature is mild, and the safety of the production process is high.
Further, the first solvent is water.
Preferably, the water is any one of purified water, deionized water or sterile water.
By adopting the technical scheme, water is used as a solvent for wetting the fosfomycin trometamol, so that the cost is low and the wetting effect is good.
Further, the mass volume ratio of the fosfomycin trometamol to the first solvent is 1g (100-.
Furthermore, the mass volume ratio of the fosfomycin trometamol to the solvent I is 1g to 180 mu L.
By adopting the technical scheme, the adding proportion of the fosfomycin trometamol and the first solvent is controlled, the dissolving of the raw material fosfomycin trometamol can be effectively accelerated, the forward proceeding of the reaction is promoted, and meanwhile, the dosage of the first solvent is the least.
In conclusion, the invention has the following beneficial effects:
1. the method of the invention has simple steps;
2. optimally, water and a mobile phase are used as solvents, so that the dissolving of the raw material fosfomycin trometamol is facilitated, a reaction system is in a homogeneous phase, and the forward proceeding of the reaction is facilitated;
3. the optimized heating reaction temperature is 60-80 ℃, the reaction time is 24-36 h, the reaction temperature is mild, and the safety of the production process is high.
Drawings
FIG. 1 is a process flow diagram of fosfomycin trometamol impurity D;
FIG. 2 is an HPLC chromatogram of fosfomycin trometamol impurity D;
FIG. 3 is a mass spectrum of fosfomycin trometamol impurity D.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
First, examples 1 to 11
Example 1: a preparation method of fosfomycin trometamol impurity D is shown in figure 1, and comprises the following operation steps:
step one, taking 1g of fosfomycin trometamol, wetting with 180 mu L of deionized water (solvent I), heating in a 60 ℃ oven for 24 hours, adding a mobile phase (solvent II) for dissolving and diluting to 20ml, and shaking up to be used as a preparation mother liquor.
Step two, separating and purifying the [2- [ 2-amino-3-hydroxy-2- (hydroxymethyl) propoxy ] -1-hydroxypropyl ] hydroxyphosphoryl ] oxy ] -1-hydroxypropyl ] phosphonic acid (aminomethoxyfosfomycin dimer).
Mobile phase: taking 10.89g of monopotassium phosphate, adding 1000mL of water for dissolving to obtain a mobile phase;
a detector: a differential refractive detector;
detector temperature: 35 ℃; flow rate: 1.0 mL/min.
The specific operation of separation and purification is as follows: adding 1g of the prepared mother liquor into a preparation separation liquid phase system according to the bearing capacity of a chromatographic column to obtain 0.2g of liquid, and performing freeze-drying treatment by using vacuum freeze-drying technology through medicine production type vacuum freeze-drying equipment with the model of GLZY (CIP) to obtain 0.1g of solid (namely fosfomycin trometamol impurity D).
And (3) small sample verification result: taking a little solid to carry out HPLC and mass spectrum detection on the solid, and finally verifying that the solid is the fosfomycin trometamol impurity D, wherein the chemical structural formula is as follows:
The chemical formula for preparing the fosfomycin trometamol impurity D is as follows:
example 2: a preparation method of fosfomycin trometamol impurity D comprises the following operation steps:
step one, taking 2g of fosfomycin trometamol, wetting by using 360 mu L of purified water, heating in an oven at 60 ℃ for 36 hours, adding a mobile phase for dissolving and diluting to 20ml, and shaking up to be used as a prepared mother solution.
Step two, separating and purifying the [2- [2- [ 2-amino-3-hydroxy-2- (hydroxymethyl) propoxy ] -1-hydroxypropyl ] hydroxyphosphoryl ] oxy ] -1-hydroxypropyl ] phosphonic acid (aminomethoxyfosfomycin dimer).
Mobile phase: taking 10.89g of monopotassium phosphate, adding 1000mL of water for dissolving to obtain a mobile phase;
a detector: a differential refractive detector;
detector temperature: 35 ℃; flow rate: 1.0 ml/min.
The specific operation of separation and purification is as follows: adding 2g of the above mother liquid into a preparative separation liquid phase system according to the loading capacity of a chromatographic column to obtain 0.4g of liquid, and performing freeze-drying treatment by using vacuum freeze-drying technology through a medicine production type vacuum freeze-drying device with the model of GLZY (CIP) to obtain 0.2g of solid (i.e. fosfomycin trometamol impurity D).
And (3) small sample verification result: and (3) taking a little solid to carry out HPLC and mass spectrum detection, and obtaining the solid which is the fosfomycin trometamol impurity D, namely [2- [2- [ 2-amino-3-hydroxy-2- (hydroxymethyl) propoxy ] -1-hydroxypropyl ] oxyphosphoryl ] oxy ] -1-hydroxypropyl ] phosphonic acid after analysis and verification.
Example 3: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the heating temperature is 50 ℃, and the reaction time is 40 h.
Example 4: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the heating temperature is 70 ℃, and the reaction time is 20 h.
Example 5: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the heating temperature is 80 ℃, and the reaction time is 25 h.
Example 6: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, sterile water is used as the first solvent.
Example 7: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mobile phase is 0.005g/mol potassium dihydrogen phosphate water solution, i.e. 5g potassium dihydrogen phosphate is dissolved by adding 1000ml water.
Example 8: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mobile phase is 0.015g/mol potassium dihydrogen phosphate water solution, namely 15g potassium dihydrogen phosphate is taken, and 1000ml water is added for dissolving.
Example 9: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mobile phase is 0.01g/mol potassium dihydrogen phosphate water solution, i.e. 10g potassium dihydrogen phosphate is dissolved by adding 1000ml water.
Example 10: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mass volume ratio of the fosfomycin trometamol to the first solvent is 1g to 100 mu L.
Example 11: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mass volume ratio of the fosfomycin trometamol to the first solvent is 1g to 200 mu L.
Second, comparative examples 1 to 4
Comparative example 1: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mass volume ratio of the fosfomycin trometamol to the first solvent is 1g to 50 mu L.
Comparative example 2: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mass volume ratio of the fosfomycin trometamol to the first solvent is 1g to 300 mu L.
Comparative example 3: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mobile phase is 0.001g/mol potassium dihydrogen phosphate water solution, i.e. 1g potassium dihydrogen phosphate is dissolved by adding 1000ml water.
Comparative example 4: a preparation method of fosfomycin trometamol impurity D is different from that of example 1 in that: in the first step, the mobile phase is 0.02g/mol potassium dihydrogen phosphate water solution, namely 20g potassium dihydrogen phosphate is taken and 1000ml water is added for dissolving.
Thirdly, analyzing and testing the detection data: performance testing
Test subjects: the fosfomycin trometamol impurities D obtained in examples 1 to 11 were used as test samples 1 to 12, and the fosfomycin trometamol impurities D obtained in comparative examples 1 to 4 were used as comparative samples 1 to 4.
The test method comprises the following steps: 1g of each sample was sampled to examine the yield and purity of the test samples 1 to 11 and the comparative samples 1 to 4.
TABLE 1 results of Performance testing of samples 1-11 and comparative samples 1-4
| Test sample | Product yield/% | Purity/%) |
| Test sample 1 | 85.1 | 99.5 |
| Test sample 2 | 88.5 | 99.4 |
| Test sample 3 | 85.6 | 99.2 |
| Test sample 4 | 85.2 | 98.5 |
| Test sample 5 | 86.9 | 99.1 |
| Test sample 6 | 87.2 | 99.6 |
| Test sample 7 | 82.3 | 99.0 |
| Test sample 8 | 83.9 | 99.1 |
| Test sample 9 | 80.2 | 99.4 |
| Test sample 10 | 85.5 | 99.5 |
| |
87.7 | 99.3 |
| Comparative sample 1 | 72.4 | 96.7 |
| Comparative sample 2 | 62.8 | 98.0 |
| Comparative sample 3 | 68.1 | 97.5 |
| Comparative sample 4 | 65.5 | 98.1 |
And (3) test results: as shown in Table 1, sample samples 1-11 were higher in both product yield and purity than control samples 1-4, with control sample 2 being lower in purity than sample samples 1-11. The specific reason is that the first solvent in the control sample 1 is added too little, so that the wetting effect is poor, and a good homogeneous environment cannot be obtained at the moment, so that the product yield of the control sample 1 is low;
when the amount of the solvent added in the control sample 2 was too large, the amount of the mobile phase added was reduced as a whole when the volume was increased to 20ml, which corresponds to a decrease in the concentration of the aqueous solution of potassium dihydrogen phosphate added, and the solubility for the raw material fosfomycin trometamol was reduced, whereby the yield was lowered. In addition, the concentration of potassium dihydrogen phosphate in control sample 3 was too low, at which time the dissolution of fosfomycin trometamol became poor, whereby the yield was lowered. In addition, in the control sample 4, the concentration of potassium dihydrogen phosphate is too high, which adversely affects the solubility of the raw material fosfomycin trometamol and lowers the yield.
The specific embodiments are only for explaining the present invention, and the present invention is not limited thereto, and those skilled in the art can make modifications without inventive contribution to the present embodiments as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.
Claims (1)
1. A preparation method of fosfomycin trometamol impurity D is characterized by comprising the following operation steps:
dissolving fosfomycin trometamol in a solvent I, and heating for degradation reaction at the temperature of 60-80 ℃ for 24-36 h; monitoring the reaction degree by the liquid phase, adding a second solvent after the reaction is finished to dissolve and dilute the second solvent to obtain 20ml of liquid phase, and shaking up to obtain a crude product of the impurity D; the second solvent is a mobile phase for dissolving the fosfomycin trometamol impurity D; the mobile phase adopts 0.005-0.015g/mol potassium dihydrogen phosphate water solution;
the first solvent is water; the mass volume ratio of the fosfomycin trometamol to the solvent I is 1g to 180 mu L;
step two, freeze-drying the impurity D crude product to obtain a fosfomycin trometamol impurity D;
the chemical structural formula of the fosfomycin trometamol impurity D is as follows:
the separation and purification of the [2- [ 2-amino-3-hydroxy-2- (hydroxymethyl) propoxy ] -1-hydroxypropyl ] hydroxyphosphoryl ] oxy ] -1-hydroxypropyl ] phosphonic acid comprises the following specific operations: adding the prepared mother liquor into a preparative separation liquid phase system according to the bearing capacity of a chromatographic column to obtain a liquid, and performing freeze-drying treatment by using a vacuum freeze-drying technology through a medicine production type vacuum freeze-drying device with the model of GLZY to obtain a solid.
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| CN201910945476.5A Active CN110724162B (en) | 2019-09-30 | 2019-09-30 | Preparation method of fosfomycin trometamol impurity D |
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Citations (4)
| 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) |
| CN104086592A (en) * | 2014-07-22 | 2014-10-08 | 桂林华信制药有限公司 | Preparation method of fosfomycin tromethamine |
| CN108997424A (en) * | 2017-06-06 | 2018-12-14 | 湖南华纳大药厂手性药物有限公司 | A kind of simple and direct method for preparing fosfomycin trometamol |
| CN109608497A (en) * | 2019-01-18 | 2019-04-12 | 科大华采(武汉)生物科技股份有限公司 | A kind of preparation method of fosfomycin trometamol |
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Patent Citations (4)
| 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) |
| CN104086592A (en) * | 2014-07-22 | 2014-10-08 | 桂林华信制药有限公司 | Preparation method of fosfomycin tromethamine |
| CN108997424A (en) * | 2017-06-06 | 2018-12-14 | 湖南华纳大药厂手性药物有限公司 | A kind of simple and direct method for preparing fosfomycin trometamol |
| CN109608497A (en) * | 2019-01-18 | 2019-04-12 | 科大华采(武汉)生物科技股份有限公司 | A kind of preparation method of fosfomycin trometamol |
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