CN109134504A - 1/2 water cefmenoxime hydrochloride compound of one kind and its drug combination preparation - Google Patents
1/2 water cefmenoxime hydrochloride compound of one kind and its drug combination preparation Download PDFInfo
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- CN109134504A CN109134504A CN201710455095.XA CN201710455095A CN109134504A CN 109134504 A CN109134504 A CN 109134504A CN 201710455095 A CN201710455095 A CN 201710455095A CN 109134504 A CN109134504 A CN 109134504A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a kind of 1/2 water cefmenoxime hydrochloride compound and its drug combination preparation, every mole hydrochloride Cefmenoxime contains 1/2 mole of water.With 7 amino-cephalo-alkanoic acids (7ACA) for starting material, it is first reacted at C-3 with 5- sulfydryl-1- methyl-1 H- tetrazole (MMT) and generates 3- (1- methyl-1-tetrazole-5H base) sulfidomethyl-7-aminocephalosporanic acid (7ACT), again in C-7 and MAEM reaction synthesis Cefmenoximes, 1/2 water cefmenoxime hydrochloride compound is obtained at salt with hydrochloric acid again.This is easy to operate, and reactant is easy to get, and reaction condition is milder, high income.1/2 water cefmenoxime hydrochloride compound low in hygroscopicity of the invention, impurity content is low, good fluidity, and thermodynamic stability is good, has and prospect is applied even more extensively.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, more particularly to a kind of 1/2 water cefmenoxime hydrochloride compound and its
Drug combination preparation.
Background technique
The third generation cephalosporin that Cefmenoxime (cefmenoxime) is researched and developed military field the 1970s for Japan, 1983
It year is listed in Japan, later in succession in beauty, the listing of Han Deng state, antibacterial activity by its wide spectrum and to beta-lactamase high stable
Property, it is widely used in the treatment of various infectious diseases caused by sensitive bacteria.
Cefmenoxime category Cell wall synthesis inhibitor is made by inhibiting the biosynthesis of bacteria cell wall to reach sterilization
With.This product has effect to gram-positive bacteria and negative bacterium.In gram-positive bacteria, to micrococcus scarlatinae, pneumonia ball
The antibacterial action of bacterium is also relatively strong.Also there is powerful antibacterial action to Peptococcus, Peptostreptococcus.Gram-negative bacteria
In, it is slightly stronger than Cefotiam to the antibacterial action of Escherichia coli, pneumobacillus, hence it is evident that be better than the cephazoline of the first generation, convection current
It is also stronger that blood bacillus, proteus, serratia marcesens, Citrobacter, the antibacterial action of Enterobacter are bitten in sense, to quasi- bar
Pseudomonas also has very strong antibacterial action.
Cefmenoxime Hcl is with 7-amino-cephalosporanic acid (abbreviation 7-ACA, English name: 7-amino-
Cephalosporanic acid) C7And C3Position is transformed simultaneously, then is made through hydrochloric acid.Early literatures are to C7Position transformation also carries out
A variety of testing programs, according to the document analysis of Cefmenoxime: early stage cefotaxime side chain is the C in 7-ACA7It is first connected on position
It methylates after acetoacetate through nitrosation, the multistep reactions such as cyclization form C7Position intermediate, such synthesis are extremely unreasonable.Also there is text
It offers report and directly uses 2- (thiazolamine -4- base)-(cis-) -2- methoxy imino acetyl thio benzothiazole active ester and 7-
ACA reacts in ice water generates cefotaxime acid, then reacts with 5- sulfydryl -1- methyl-1 H- tetrazole and hydrochloric acid cephalo first is made
Oxime.The synthesis route of Cefmenoxime Hcl was long in the past, complex process, and the organic solvent conversion ratio used is low, and solvent is not allowed
Easily recycling needs by other separation means such as absorption, is not using single recrystallization method, crystal form obtained is bad, no
It can be easily separated drying.
The problems such as it is too long that the present invention specifically addresses synthetic routes, complex process improves the conversion ratio of product, prepares single
The cefmenoxime hydrochloride compound of crystal form, process route is simple, and synthesis yield is high, production cost is reduced, using recrystallization
Method prepare crystal, be suitble to industrialized production.By sufficiently investigating between the reaction temperature stirred in synthesis technology, material
Influence of the factors such as molar ratio, reaction time to crystallization has obtained a kind of conversion rate of products height, the good hydrochloric acid cephalo of thermal stability
First oxime compound, the production process is simple, and raw material, reagent price are cheap, is suitable for industrial-scale production.
Summary of the invention
The invention discloses a kind of solvates of new Cefmenoxime Hcl, are more specifically 1/2 water hydrochloric acid cephalo first
Oxime compound, i.e., every mole hydrochloride Cefmenoxime compound contain 1/2 mole of water, and molecular formula is (C16H17N9O5S3)2·HCl·1/
2H2O, molecular weight 1068.59, structural formula is as follows:
1/2 water cefmenoxime hydrochloride compound of the present invention, preparation include step are as follows: with 7 amino-cephalo-alkanoic acids
(7ACA) is starting material, first reacts at C-3 with 5- sulfydryl-1- methyl-1 H- tetrazole (MMT) and generates 3- (1- methyl-1-
Tetrazole -5H base) sulfidomethyl -7-aminocephalosporanic acid (7ACT), then in C-7 and MAEM reaction synthesis Cefmenoximes, then
With hydrochloric acid at salt, the compound of Cefmenoxime Hcl is obtained；The specific method is as follows:
(1) 7 amino-cephalo-alkanoic acids (7ACA) are added into reactor 1 and 5- sulfydryl -1- methyl-1 H- tetrazole (MMT) exists
2~3h is reacted in acetonitrile under boron trifluoride ether catalysis, controls temperature at 40~50 DEG C；
(2) to the end of above-mentioned reaction, pH to 3.5 is adjusted with concentrated ammonia liquor and is precipitated crystal, is filtered, filter cake is washed with water, vacuum
Dry off-white powder I；
(3) above-mentioned solid I is added in reactor 2, methylene chloride then is added and 2- (- 4 base of 2 aminothiazole) is (suitable
Formula) -2- methoxy imino acetyl thio benzene benzothiazole active ester (MEAM), it is molten that triethylamine adjusting is added portionwise under agitation
The pH of liquid, room temperature reaction.After reaction, add water to extract, merge water phase, through active carbon decoloring, filtering, filtrate is adjusted with hydrochloric acid
PH, filtering, filters out crystal and is washed with water, and is dried in vacuo, obtains 1/2 water cefmenoxime hydrochloride compound.
Preferably, reaction temperature is controlled at 30~60 DEG C in above-mentioned steps (1)；It is preferred that 40~50 DEG C.
Preferably, the reaction time is 1~5h, preferably 2~3h under boron trifluoride ether catalysis in above-mentioned steps (1).
Preferably, off-white powder and 2- (- 4 base of 2 aminothiazole) (cis-) -2- methoxy imino second in above-mentioned steps (3)
The molar ratio of acyl thio phenyl benzothiazole active ester (MEAM) is 1:(1~10)；It is preferred that 1:2.
Preferably, the mass volume ratio of solid I and methylene chloride is 1:(5~20 in above-mentioned steps (3))；It is preferred that 1:10.
Preferably, the room temperature reaction time controls in 2~8h in above-mentioned steps (3)；It is preferred that 4~6h.
Karl_Fischer method is one of the most single-minded, accurate method in various measurement substance moisture content methods, is had been cited as perhaps
The standard method of determination of moisture in more substances, especially to organic compound, as a result accurately and reliably.Hydrochloric acid cephalo disclosed by the invention
First oxime hydrate Karl_Fischer method measures moisture weight content between 0.75~0.95%, theoretical water content 0.84%,
It can determine that each cefmenoxime hydrochloride compound of the present invention contains 1/2 mole of water.
1/2 water cefmenoxime hydrochloride compound of the present invention, TG analysis is the results show that Cefmenoxime Hcl is hydrated
The percentage loss of weight the calculation shows that weightlessness of object is about 0.87%.The theoretical single-detector of Cefmenoxime Hcl is 0.84%,
It is 0.75~0.95% that Karl Fischer, which measures Cefmenoxime Hcl moisture content, and it is 0.87% that experiment, which measures TG weightlessness,
It is consistent substantially with theoretical water content.Deviation is probably derived from the solvent loss in drying process.It can be inferred that hydrochloric acid cephalo first
Oxime compound weightlessness be removing water caused by, and every mole hydrochloride Cefmenoxime compound contain 1/2 mole of water.As shown in Fig. 1.Number
It is obtained according to by heat analysis-mass spectrometer (NETZSCH STA 449C) analysis.Analysis condition are as follows: 2~10mg of sample, aluminium oxide
Crucible, high pure nitrogen do reaction gas and protection gas, and flow is respectively 40ml/min and 30ml/min, heating rate 10K/min, temperature
Spending test scope is 25~400 DEG C.Sample decomposition temperature is about 205.4 DEG C.
1/2 water cefmenoxime hydrochloride compound of the present invention, x-ray diffractogram of powder spectrum are in 2 θ of the angle of diffraction
13.14 ± 0.2 °, 17.77 ± 0.2 °, 21.69 ± 0.2 °, 22.28 ± 0.2 °, 23.82 ± 0.2 °, 25.35 ± 0.2 °, 25.84
There are characteristic diffraction peak, the opposite diffracted intensity of the angle of diffraction at ± 0.2 °, 30.08 ± 0.2 °, 35.19 ± 0.2 °, 37.92 ± 0.2 °
Respectively 35.22,93.56,51.85,49.33,100,55.83,50.02,55.11,49.84,50.51, as shown in Fig. 2.X
Ray powder diffraction test condition: EMPYREAN (sharp shadow) X-ray diffractometer of Dutch Panalytical company, CuK α radiation,
Light pipe voltage 40kV, heater current 300mA, continuous scanning, 0.02 ° of step-length, 8 °/min of scanning speed, scanning range is 2~
50°。
1/2 water cefmenoxime hydrochloride compound of the present invention, infrared spectroscopy are 3267.5 ± 2cm in wave number-1,
3159.7±2cm-1, 1785.5 ± 2cm-1, 1648.1 ± 2cm-1, 1572.0 ± 2cm-1, 1381.5 ± 2cm-1, 1275.9 ±
2cm-1, 1176.1 ± 2cm-1, 1043.5 ± 2cm-1There is characteristic absorption peak at place.As shown in Fig. 3.Examination of infrared spectrum condition are as follows:
Agilent Cary 630, pressing potassium bromide troche.
1/2 water cefmenoxime hydrochloride compound of the present invention, dsc analysis is the results show that in 209.6 DEG C of heat release
Peak is fusion and decomposition peak, as shown in Fig. 4.DSC data is analyzed by heat analysis-mass spectrometer (NETZSCH STA 449C)
It arrives, analysis condition are as follows: 2~10mg of sample, alumina crucible, high pure nitrogen do reaction gas and protection gas, and flow is respectively 40ml/
Min and 30ml/min.10 DEG C/min of heating rate, 25~400 DEG C of temperature range.
Further purpose of the invention provides a kind of pharmaceutical composition containing 1/2 water cefmenoxime hydrochloride compound.
Preferably, described pharmaceutical composition includes 1/2 water cefmenoxime hydrochloride compound and the excipient pharmaceutically received.More preferably
Ground, pharmaceutical composition are selected from pharmaceutically acceptable dosage form.
Detailed description of the invention
The TG of 1/2 water cefmenoxime hydrochloride compound of Fig. 1 schemes；
The X ray diffracting spectrum of 1/2 water cefmenoxime hydrochloride compound of Fig. 2；
The FTIR spectrum figure of 1/2 water cefmenoxime hydrochloride compound of Fig. 3；
The DSC of 1/2 water cefmenoxime hydrochloride compound of Fig. 4 schemes.
Specific embodiment
Below will by specific embodiment, the present invention will be further described, but therefore do not limit the present invention to institute
In the scope of embodiments stated, it should be understood by those skilled in the art that changing to the equivalent replacement that the content of present invention is done, or accordingly
Into still falling within protection scope of the present invention.
The preparation of embodiment 1:1/2 water cefmenoxime hydrochloride compound
Preparation process
(1) 7 amino-cephalo-alkanoic acids (7ACA) (136g, 0.5mol) and 5- sulfydryl -1- methyl-1 H- are added into reactor 1
Tetrazole (MMT) (70g, 0.6mol) reacts 2h under the catalysis of 600ml boron trifluoride ether in 1500ml acetonitrile, controls temperature
At 45 DEG C；
(2) to the end of above-mentioned reaction, pH to 3.6 is adjusted with concentrated ammonia liquor and is precipitated crystal, is filtered, filter cake is washed with water, vacuum
Dry off-white powder I；
(3) above-mentioned solid I (82g, 0.25mol) is added in reactor 2, then be added methylene chloride (900ml) and
2- (- 4 base of 2 aminothiazole) (cis-) -2- methoxy imino acetyl thio benzene benzothiazole active ester (MEAM) (105g,
0.3mol), the pH=7.0 that triethylamine (75ml) adjusts solution is added portionwise under agitation, reacts at room temperature 4h.Reaction terminates
Afterwards, add water to extract, merge water phase, through active carbon decoloring, filtering, filtrate adjusts the pH=2.1 of solution, mistake with hydrochloric acid (6mol/l)
Filter, filters out crystal and is washed with water, 50 DEG C of vacuum drying 40min obtain 1/2 water cefmenoxime hydrochloride compound 108.6g.
X-ray diffractogram of powder spectrum 2 θ of the angle of diffraction be 13.14 °, 17.77 °, 21.69 °, 22.28 °, 23.82 °,
There is characteristic diffraction peak at 25.35 °, 25.84 °, 30.08 °, 35.19 °, 37.92 °, the opposite diffracted intensity of the angle of diffraction is respectively
35.22,93.56,51.85,49.33,100,55.83,50.02,55.11,49.84,50.51.
FTIR spectrum diagram data is as follows:
| Serial number | Wave number | Area |
| 1 | 3267.478 | 152.597 |
| 2 | 3159.712 | 315.144 |
| 3 | 1785.545 | 1585.683 |
| 4 | 1648.079 | 243.559 |
| 5 | 1571.993 | 100.242 |
| 6 | 1381.458 | 221.843 |
| 7 | 1275.943 | 121.852 |
| 8 | 1176.104 | 143.061 |
| 9 | 1043.462 | 711.205 |
It is 99.52% that HPLC method, which detects purity,；It is 0.85% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.87%, it is almost the same with the result (theoretical value 0.84%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
35.97%, H:3.40%, N:23.59%, O:15.72%, S:18.00%, Cl:3.32%；Measured value are as follows: C:35.96%,
H:3.42%, N:23.57%, O:15.73%, S:18.02%, Cl:3.30%.
The preparation of embodiment 2:1/2 water cefmenoxime hydrochloride compound
Preparation process
(1) 7 amino-cephalo-alkanoic acids (7ACA) (272g, 1mol) and 5- sulfydryl -1- methyl-1 H- tetra- are added into reactor 1
Nitrogen azoles (MMT) (139g, 1.2mol) reacts 2.5h, control temperature under the catalysis of 600ml boron trifluoride ether in 3000ml acetonitrile
Degree is at 50 DEG C；
(2) to the end of above-mentioned reaction, pH to 3.5 is adjusted with concentrated ammonia liquor and is precipitated crystal, is filtered, filter cake is washed with water, vacuum
Dry off-white powder I；
(3) above-mentioned solid I (164g, 0.5mol) is added in reactor 2, then be added methylene chloride (1800ml) and
2- (- 4 base of 2 aminothiazole) (cis-) -2- methoxy imino acetyl thio benzene benzothiazole active ester (MEAM) (210g,
0.6mol), the pH=7.1 that triethylamine (150ml) adjusts solution is added portionwise under agitation, reacts at room temperature 5h.Reaction knot
Shu Hou adds water to extract, and merges water phase, and through active carbon decoloring, filtering, filtrate adjusts the pH=2.0 of solution with hydrochloric acid (6mol/l),
Filtering, filters out crystal and is washed with water, 50 DEG C of vacuum drying 40min obtain 1/2 water cefmenoxime hydrochloride compound 216.7g.
X-ray diffractogram of powder spectrum 2 θ of the angle of diffraction be 13.11 °, 17.73 °, 21.65 °, 22.24 °, 23.80 °,
There is characteristic diffraction peak at 25.41 °, 25.89 °, 30.05 °, 35.21 °, 37.95 °, the opposite diffracted intensity of the angle of diffraction is respectively
37.86,92.13,53.46,47.35,100,56.28,54.34,52.77,48.39,50.20.
FTIR spectrum diagram data is as follows:
| Serial number | Wave number | Area |
| 1 | 3267.119 | 152.681 |
| 2 | 3159.808 | 315.426 |
| 3 | 1785.113 | 1585.519 |
| 4 | 1648.255 | 243.391 |
| 5 | 1571.727 | 100.209 |
| 6 | 1381.359 | 222.040 |
| 7 | 1275.731 | 121.997 |
| 8 | 1176.225 | 143.152 |
| 9 | 1043.370 | 711.319 |
It is 99.47% that HPLC method, which detects purity,；It is 0.75% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.86%, it is almost the same with the result (theoretical value 0.84%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
35.97%, H:3.40%, N:23.59%, O:15.72%, S:18.00%, Cl:3.32%；Measured value are as follows: C:35.98%,
H:3.40%, N:23.58%, O:15.74%, S:18.00%, Cl:3.30%.
The preparation of embodiment 3:1/2 water cefmenoxime hydrochloride compound
Preparation process
(1) 7 amino-cephalo-alkanoic acids (7ACA) (540g, 2mol) and 5- sulfydryl -1- methyl-1 H- tetra- are added into reactor 1
Nitrogen azoles (MMT) (280g, 2.4mol) reacts 3h under the catalysis of 1200ml boron trifluoride ether in 6000ml acetonitrile, controls temperature
At 50 DEG C；
(2) to the end of above-mentioned reaction, pH to 3.4 is adjusted with concentrated ammonia liquor and is precipitated crystal, is filtered, filter cake is washed with water, vacuum
Dry off-white powder I；
(3) above-mentioned solid I (320g, 1mol) is added in reactor 2, methylene chloride (3600ml) and 2- is then added
(- 4 base of 2 aminothiazole) (cis-) -2- methoxy imino acetyl thio benzene benzothiazole active ester (MEAM) (420g, 1.2mol),
The pH=7.2 that triethylamine (300ml) adjusts solution is added portionwise under agitation, reacts at room temperature 6h.After reaction, add water
Extraction merges water phase, and through active carbon decoloring, filtering, filtrate adjusts the pH=2.0 of solution with hydrochloric acid (6mol/l), and filtering filters out
Crystal is washed with water, and 50 DEG C of vacuum drying 40min obtain 1/2 water cefmenoxime hydrochloride compound 438.3g.
X-ray diffractogram of powder spectrum 2 θ of the angle of diffraction be 13.16 °, 17.80 °, 21.73 °, 22.25 °, 23.83 °,
There is characteristic diffraction peak at 25.36 °, 25.81 °, 30.04 °, 35.15 °, 37.90 °, the opposite diffracted intensity of the angle of diffraction is respectively
37.85,95.60,52.16,50.45,100,53.26,51.12,54.38,47.41,52.39.
FTIR spectrum diagram data is as follows:
| Serial number | Wave number | Area |
| 1 | 3267.603 | 152.395 |
| 2 | 3159.542 | 315.002 |
| 3 | 1785.430 | 1585.722 |
| 4 | 1648.014 | 243.665 |
| 5 | 1572.022 | 100.295 |
| 6 | 1381.595 | 221.765 |
| 7 | 1275.688 | 121.678 |
| 8 | 1176.098 | 143.224 |
| 9 | 1043.586 | 711.125 |
It is 99.43% that HPLC method, which detects purity,；It is 0.95% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.85%, it is almost the same with the result (theoretical value 0.84%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
35.97%, H:3.40%, N:23.59%, O:15.72%, S:18.00%, Cl:3.32%；Measured value are as follows: C:35.97%,
H:3.41%, N:23.57%, O:15.73%, S:18.01%, Cl:3.31%.
Comparative example 1: Cefmenoxime Hcl anhydride is prepared according to existing technical literature CN105001239A
Using the identical preparation method of patent document embodiment 1
Preparation process:
(1) Cefmenoxime crude product 100g is weighed, water 1000ml is added, 4% sodium bicarbonate solution is slowly added dropwise until clear in stirring
Clearly, it is added with stirring 10ml ethyl acetate, is transferred in 1000ml pressure vessel, it is ensured that it is full of and bubble removal, sealing container,
It vibrates, is taken out after -18 DEG C of freezing 3h of temperature control；
(2) organic phase is removed, after ice-out, 10g active carbon, stirring decoloration, filtering is added；
(3) filtrate is transferred to crystallizing tank, 10~15 DEG C of temperature control, adjusts pH to 1.5 with dilute hydrochloric acid, continues growing the grain 1h, filter,
It is washed with water, 40 DEG C of vacuum drying are to get Cefmenoxime Hcl anhydride 89.6g.
It is 98.40% that HPLC method, which detects purity,；It is 0.20% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.15%, it is almost the same with anhydride result in this way；Elemental Analysis theory are as follows: C:36.27%, H:3.33%, N:
23.79%, O:15.10%, S:18.15%, Cl:3.35%；Measured value are as follows: C:36.25%, H:3.32%, N:23.80%,
O:15.11%, S:18.17%, Cl:3.34%.
1 mobility of test example is investigated
The present inventor grinds the mobility of Cefmenoxime Hcl prepared by the embodiment of the present invention 1 and comparative example 1
Study carefully.Angle of repose detection method is to be placed in particle in fixed funnel, drops down onto its freely on horizontal plane, forms a bottom radius
For the disc accumulation body of r, the height for measuring accumulation body is H, is calculated according to formula tan θ=H/r.
Test results in the following table:
As a result: the mobility of 1/2 water cefmenoxime hydrochloride compound prepared by the present invention is compared significantly better than the prior art
Cefmenoxime Hcl anhydride prepared by example 1 can satisfy the needs of a variety of preparation methods in the preparation process of preparation.
2 purity detecting of test example
The present inventor has carried out purity and related to Cefmenoxime Hcl prepared by the embodiment of the present invention 1 and comparative example 1
Substance detection.
Test results in the following table:
As a result: 1/2 water cefmenoxime hydrochloride compound purity prepared by the present invention is higher than hydrochloric acid cephalo prepared by comparative example 1
First oxime anhydride, related substance are lower than Cefmenoxime Hcl anhydride prepared by comparative example 1, and product of the present invention quality is preferable.
Test example 3 draws moist investigation
The present inventor draws moist studied to Cefmenoxime Hcl prepared by the embodiment of the present invention 1 and comparative example 1.
Investigation condition is relative humidity 75% (RH) and relative humidity 92.5% (RH), and temperature is 40 DEG C, and inspection target is hydrochloric acid cephalo
Water content in first oxime.
Test results in the following table:
As a result: 1/2 water cefmenoxime hydrochloride compound prepared by the present invention draws moist significantly lower than prior art comparative example 1
The Cefmenoxime Hcl anhydride of preparation.Illustrate that 1/2 water cefmenoxime hydrochloride compound of the present invention has good stability, fits
The manufacture and long term storage of composite medicine preparation.
4 dissolubility of test example is investigated
Cefmenoxime Hcl prepared by embodiment 1 and comparative example 1 is dissolved in aqueous solution respectively, 20min is shaked, passes through
Detection level calculates the solubility of cefmenoxime hydrochloride compound in water prepared by embodiment 1, comparative example 1.
Solubility testing result
| Embodiment | Solubility |
| Embodiment 1 | 0.58mg/ml |
| Comparative example 1 | 0.37mg/ml |
Conclusion: the dissolubility of 1/2 water cefmenoxime hydrochloride compound prepared by the embodiment of the present invention 1 is significantly better than comparative example
The Cefmenoxime Hcl anhydride of 1 preparation.
5 study on the stability of test example
The present inventor has carried out accelerated stability to Cefmenoxime Hcl prepared by the embodiment of the present invention 1 and comparative example 1
It investigates.Investigation condition is 40 DEG C ± 2 DEG C of temperature, is placed 6 months, is sampled respectively at 0,1,2,3,6 the end of month.Inspection target is property
Shape, moisture, content and related substance.
Investigating result see the table below:
As a result: from the above results, by 6 months accelerated tests, sample items prepared by the embodiment of the present invention 1 were detected
Index is substantially better than the product of the preparation of comparative example 1, has absolutely proved that 1/2 water cefmenoxime hydrochloride compound prepared by the present invention is steady
Qualitative more preferable, quality is better than similar product, while the moisture of embodiment 1, substantially without significant change, the water for inferring that it contains is
The crystallization water, and non-adsorbed water.
1/2 water cefmenoxime hydrochloride compound of the invention is examined through indices and accelerated stability test investigation shows
Stability is good, far superior to the product of the prior art, and synthesis technology of the present invention is simple, and reaction condition is mild, and product yield is higher,
Stability is good, reliable in quality, it is easy to accomplish industrialized production.
The verifying of 6 crystallization water of test example is investigated
It is the crystallization water to sufficiently verify 1/2 water in cefmenoxime hydrochloride compound of the present invention, the present inventor passes through heat
Three kinds of weight analysis method, 60 DEG C of thermal stability 10 days, vacuum freezedrying weight-loss method methods, investigate the water of each embodiment and comparative example
Divide as a result, specific as follows:
1, thermogravimetry
Thermogravimetric analysis is the weightlessness before sample decomposes at high operating temperatures, is the important side for verifying the crystallization water or adsorbing water
Method, the present inventor have carried out thermogravimetric analysis to the cefmenoxime hydrochloride compound of each embodiment and comparative example preparation respectively, as a result
It is summarized as follows:
| Embodiment | Thermogravimetry weightlessness (%) |
| Embodiment 1 | 0.87 |
| Embodiment 2 | 0.86 |
| Embodiment 3 | 0.85 |
| Comparative example 1 | 0.15 |
As a result, the 1/2 water cefmenoxime hydrochloride compound weightlessness and the result of 1/2 water contained of Examples 1 to 3 preparation
(theoretical value 0.84%) is almost the same；Cefmenoxime Hcl weightlessness and anhydride theoretical value difference prepared by comparative example 1 is little.It pushes away
Aqueous cefmenoxime hydrochloride compound institute prepared by the disconnected embodiment of the present invention 1~3 is the crystallization water, hydrochloric acid head prepared by comparative example 1
Spore first oxime compound institute is aqueous for absorption water.
2,60 DEG C thermal stability 10 days
Hydrochloric acid cephalo first prepared by 1/2 water cefmenoxime hydrochloride compound of preparation of the embodiment of the present invention and comparative example 1
Oxime is respectively placed in 60 DEG C of baking ovens 10 days, detects moisture with Karl_Fischer method respectively at 0,10 day, as a result as follows:
| Embodiment | 0 day (%) | 10 days (%) |
| Embodiment 1 | 0.85 | 0.83 |
| Embodiment 2 | 0.75 | 0.74 |
| Embodiment 3 | 0.95 | 0.93 |
| Comparative example 1 | 0.20 | 0.11 |
As a result, 60 DEG C of high temperature are placed 10 days, 1/2 water cefmenoxime hydrochloride compound moisture of Examples 1 to 3 preparation is basic
There is no significant change, Cefmenoxime Hcl moisture prepared by comparative example 1 is substantially reduced, and infers prepared by the embodiment of the present invention 1~3
Aqueous cefmenoxime hydrochloride compound institute is the crystallization water, and cefmenoxime hydrochloride compound institute prepared by comparative example 1 is aqueous for absorption
Water.
3, vacuum freezedrying 10 hours
Hydrochloric acid cephalo first prepared by 1/2 water cefmenoxime hydrochloride compound of preparation of the embodiment of the present invention and comparative example 1
Oxime, which is respectively placed in -45 DEG C of freeze driers, to be vacuumized 10 hours, detects moisture, knot with Karl_Fischer method respectively at 0,10 hour
Fruit is as follows:
| Embodiment | 0 hour (%) | 10 hours (%) |
| Embodiment 1 | 0.85 | 0.84 |
| Embodiment 2 | 0.75 | 0.75 |
| Embodiment 3 | 0.95 | 0.93 |
| Comparative example 1 | 0.20 | 0.09 |
As a result, -45 DEG C of vacuum freezedryings of low temperature 10 hours, 1/2 water Cefmenoxime Hcl of Examples 1 to 3 preparation
Object moisture is closed substantially without significant change, and Cefmenoxime Hcl moisture prepared by comparative example 1 is substantially reduced, and infers that the present invention is implemented
Aqueous cefmenoxime hydrochloride compound institute prepared by example 1~3 is the crystallization water, cefmenoxime hydrochloride compound prepared by comparative example 1
Institute is aqueous for absorption water.
Claims (4)
1. a kind of 1/2 water cefmenoxime hydrochloride compound, which is characterized in that every mole hydrochloride Cefmenoxime contains 1/2 mole of water, point
Minor is (C16H17N9O5S3)2·HCl·1/2H2O, molecular weight 1068.59, structural formula is as follows:
2. a kind of pharmaceutical composition, it is characterised in that include 1/2 water cefmenoxime hydrochloride compound described in claim 1.
3. a kind of drug combination preparation, it is characterised in that include 1/2 water cefmenoxime hydrochloride compound described in claim 1
The excipient pharmaceutically received.
4. pharmaceutical composition according to claim 3, it is characterised in that described pharmaceutical composition is selected from pharmaceutically acceptable
Dosage form.
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| CN109096308A (en) * | 2017-06-20 | 2018-12-28 | 海南灵康制药有限公司 | 1/4 water cefmenoxime hydrochloride compound of one kind and its pharmaceutical composition |
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| CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
| CN106699775A (en) * | 2017-01-18 | 2017-05-24 | 海南美大制药有限公司 | 1/5 water cefamandole sodium compound |
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