CN106831821A - 1/4 water Cefamandole nafate compounds - Google Patents
1/4 water Cefamandole nafate compounds Download PDFInfo
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- CN106831821A CN106831821A CN201710004476.6A CN201710004476A CN106831821A CN 106831821 A CN106831821 A CN 106831821A CN 201710004476 A CN201710004476 A CN 201710004476A CN 106831821 A CN106831821 A CN 106831821A
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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
- 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
- C07D501/12—Separation; Purification
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Abstract
The invention discloses 1/4 water Cefamandole nafate compounds and its preparation method, every mole of Cefamandole Nafate contains 1/4 mole of water.Cefamandole nafate compounds prepared by the inventive method, impurity content is low, good stability, good fluidity, draws moist small, with wider application prospect.
Description
Technical field
The invention belongs to Chemical Engineering medicine crystallization technique field, and in particular to a kind of 1/4 water Mandokef sodium is closed
Thing and its preparation method.
Background technology
Cefamandole Nafate was formulated successfully in 1972 by Lilly companies of the U.S., was listed in Britain first within 1978, head
Spore Meng's polyester sodium alias is formic acid (acyl) benzyl tetrazolium cephalothin sodium, cefadole, cefadole, hydroxyl azoles cephalo bacterium
Element, Cefamandole Nafate, Cefadole, Cefamandole Nafate etc., are a kind of bactericidal action semi-synthetic cephalos of strong 2nd generation
Rhzomorph, has some advantages of 1st generation and third-generation cephalosporin concurrently, beta-lactamase is relatively stablized, has a broad antifungal spectrum.
Document report, the synthesis of Cefamandole Nafate mainly has following several routes：Route 1, with 3- acetyl-o-methyls -5-
The carboxylic acid of sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2 is initiation material, 3- acetyl-o-methyl -5- sulphur -7- amino -8-
The carboxylic acid of oxygen -1- azabicyclics oct-2-ene -2 and 1- methyl -5- sulfydryl -1,2,3,4- tetrazoles reaction generation intermediate (6R,
7R) -7 amino -3 [(Z) -2- (4- methylthiazols) -5- bases] vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] octyl-
2- alkene -2- carboxylic acids, (6R, 7R) -7 amino -3 [(Z) -2- (4- methylthiazols) -5- bases] oxo -5- thia -1- nitrogen of vinyl -8
The generation Mandokef acid of miscellaneous bicyclic [4.2.0] oct-2-ene -2- carboxylic acids and formoxyl almond acyl chloride reaction, with sodium iso-octoate into
Salt obtains Cefamandole Nafate, and the technique introduces first mercapto tetrazole using Aqueous phase, need to carry out at relatively high temperatures, reactant 3-
The carboxylic acid of acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2 and the amino -3 of product (6R, 7R) -7
[(Z) -2- (4- methylthiazols) -5- bases] vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids
Easily degraded, product purity is relatively low.Oxalyl chloride price is high simultaneously, toxicity is big, and uses oxalyl chloride so that asymmetric carbon atom is produced
Raw racemic modification, contains isomers in product.Route 2, formyl mandelic acid and 1-Methyl-5-mercapto-1,2,3,4-tetrazole
Reaction generation active ester, then with (6R, 7R) -7 amino -3 [(Z) -2- (4- the methylthiazols) -5- bases] oxo -5- sulphur of vinyl -8
Miscellaneous -1- azabicyclos [4.2.0] oct-2-ene -2- carboxylic acid reactions generation Cefamandole acid, cephalo Meng is obtained with sodium iso-octoate into salt
Polyester sodium.The technique has used the toxicity such as DCC larger and the larger material of anaphylaxis, needs to carry out strict work guarantor in production
Shield.Route 3, with (6R, 7R) -7 amino -3 [(Z) -2- (4- the methylthiazols) -5- bases] oxo -5- thia -1- azepines of vinyl -8
Bicyclic [4.2.0] oct-2-ene -2- carboxylic acids are initiation material, through [(Z) -2- (the 4- first of (6R, 7R) -7 amino -3 that silanization is protected
Base thiazole)-5- bases] oxo of vinyl-8-5- thia-1- azabicyclo [4.2.0] oct-2-ene-2- carboxylic acids and formoxyl almond
Acyl chloride reaction generation Cefamandole acid, Cefamandole Nafate is obtained with sodium iso-octoate into salt.The technique has used the silicon of hexamethyl two
Amine alkane protects 7 bit aminos and 2 carboxyls, the accessory substance NH produced in reaction3Influence acylation reaction, it is necessary to the long period could be by
It is removed totally, and the reaction time is long, high cost, while the HCl produced in Fu's acid agent DMA neutralization reaction is added,
Because DMA has carcinogenic toxicity, therefore production security is difficult to ensure that.Route 4, with (6R, 7R) -7 amino -3
[(Z) -2- (4- methylthiazols) -5- bases] vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids
It is initiation material, step is essentially identical with synthetic route 2, simply silylating reagent is different, using chlorosilane and amine alkane mixing silicon
Alkylators, the accessory substance NH that silicon amine alkane is produced3The HCl that can be produced by chlorosilane is neutralized, it is not necessary to add N, N- dimethyl
Aniline, increased the security of operation, reduce environmental pollution.
Additionally, Cefamandole nafate compounds prepared by the above method are anhydride, poor storage stability, heat point are there is
Solve low temperature, poor fluidity, easy moisture absorption etc. serious problems.So as to influence product quality, formulation products are caused not clarify, turbidity
It is unqualified, and reduce the stability of preparation.The present invention is closed on the basis of route 3 and route 4 to Mandokef sodium
The synthesis technique of thing is improved and optimized, so as to obtain a kind of more excellent Cefamandole nafate compounds of performance.
The content of the invention
More specifically it is 1/4 water Cefamandole Nafate the invention discloses a kind of new solvate of Cefamandole Nafate
Compound, i.e., every mole Cefamandole Nafate contains 1/4 mole of water, and molecular formula is：Molecular weight
For：516.99, structural formula is：
1/4 water Cefamandole nafate compounds of the present invention, specific preparation method includes：
(1) by acetonitrile, the carboxylic acid of 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2, first mercapto
The mixing of tetrazole, boron trifluoride/acetonitrile complex compound, is heated up, quick stirring reaction, and reaction is lowered the temperature after terminating, by reaction solution with it is pre-
Cold purified water is mixed, and is slowly stirred to after there is crystal to separate out, and is stirred for 30min, adds ammoniacal liquor regulation pH value, control temperature
Degree, growing the grain, filtering, acetone washing, vacuum drying obtains [(Z) -2- (the 4- methyl of -7 amino of white crystalline powder (6R, 7R) -3
Thiazole) -5- bases] vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids；
(2) by (6R, 7R) -7 amino -3 [(Z) -2- (4- the methylthiazols) -5- bases] oxo -5- thia -1- nitrogen of vinyl -8
Miscellaneous bicyclic [4.2.0] oct-2-ene -2- carboxylic acids mix with ethyl acetate, stirring at normal temperature, the double trimethylsilyl acetamides of addition N, O-,
Heat up, quick stirring reaction to system is clarified, cooling is slowly added to formyl mandelic acid chloride, finishes temperature reaction, adds pure
Change water, stirring, stratification, aqueous phase discarded is organic to be added to activated carbon and anhydrous MgSO4Stirring is decolourized, filtering, controls temperature
It is concentrated under reduced pressure into and obtains thick white solid, adds the mixed solution of ether and ethyl acetate, stirring and dissolving to add activated carbon to stir
Decolouring is mixed, is filtered, obtain Mandokef acid solution；
(3) Mandokef acid solution is lowered the temperature, rapidly joins the sodium iso-octoate of ether and ethyl acetate dissolving, stirring rises
Temperature, growing the grain, filtering, washing, vacuum drying obtains Cefamandole nafate compounds.
In above-mentioned preparation method, 30~40 DEG C are warming up to described in step (1), the described reaction time is 2~3h, institute
The reaction stated is cooled to 0~5 DEG C after terminating, described purifying water cooling temperature is 0~5 DEG C, described dropwise addition ammoniacal liquor regulation pH
It is worth to 3.0~3.4.
In above-mentioned preparation method, 30~35 are warming up to after the double trimethylsilyl acetamides of addition N, O- described in step (2)
DEG C, described reaction is cooled to -16~-10 DEG C after terminating, add and be warming up to after formyl mandelic acid chloride -5~0 DEG C, described
Addition formyl mandelic acid chloride after react 1~2h, described temperature control concentrated under reduced pressure is≤30 DEG C, described ether
It is 1 with ethyl acetate volume ratio:1.
In above-mentioned preparation method, the Mandokef acid solution described in step (3) is cooled to 0~5 DEG C, described ether
It is 1 with ethyl acetate volume ratio:1, described is warming up to 28~32 DEG C.
Karl_Fischer method be in various measure materials containing one of the most single-minded, accurate method in moisture method, by
The basic skills of determination of moisture in many materials is classified as, especially to organic compound, as a result accurately and reliably.It is disclosed by the invention
1/4 water Cefamandole nafate compounds Karl_Fischer method determines moisture between 0.85%-0.89%, and theoretical moisture contains
Measure is 0.87%, it may be determined that Cefamandole nafate compounds of the present invention contain 1/4 mole of water.
1/4 water Cefamandole nafate compounds of the present invention, its infrared spectrum is 3318.8 ± 2cm in wave number-1,
1760.1±2cm-1, 1734.5 ± 2cm-1, 1682.2 ± 2cm-1, 1627.4 ± 2cm-1, 1533.5 ± 2cm-1, 1412.5 ±
2cm-1, 1373.5 ± 2cm-1, 1238.5 ± 2cm-1, 1165.9 ± 2cm-1, 1016.8 ± 2cm-1There is characteristic absorption peak at place, such as attached
Shown in Fig. 1.Examination of infrared spectrum condition is：Agilent Cary 630, pressing potassium bromide troche.
1/4 water Cefamandole nafate compounds of the present invention, its TG analysis result shows, 1/4 water Mandokef
The percentage loss of weight result of calculation of sodium compound understands that weightlessness is about 0.87%, theoretical the hundred of Mandokef sodium molecule reclaimed water
Point content is 0.87%, and it is 0.85~0.89% to measure Cefamandole Nafate moisture with reference to Karl_Fischer method, and tests and survey
It is 0.87% to obtain TG weightless, is consistent substantially with theoretical water.It can be inferred that Cefamandole Nafate TG weightlessness be removing water caused by, and
Every mole of Cefamandole Nafate contains 1/4 mole of water.As shown in Figure 2.Data are by heat analysis-GC-MS (NETZSCH STA
449C) analysis is obtained.Analysis condition is：2~10mg of sample, alumina crucible, high pure nitrogen does reaction gas and protection gas, flow
Respectively 40ml/min and 30ml/min.Heating rate 10K/min, temperature test scope is 25~450 DEG C.Sample decomposition temperature
About 202.9 DEG C.
1/4 water Cefamandole nafate compounds of the present invention, its dsc analysis result shows there is suction at about 201.6 DEG C
Thermal spike, has exothermic peak, as shown in Figure 3 at about 207.6 DEG C.DSC data is by heat analysis-GC-MS (NETZSCH STA
449C) analysis is obtained, and analysis condition is：2~10mg of sample, alumina crucible, high pure nitrogen does reaction gas and protection gas, flow
Respectively 40ml/min and 30ml/min.10 DEG C/min of heating rate, 25~450 DEG C of temperature range.
The preparation method advantage of 1/4 water Cefamandole nafate compounds that the present invention is provided is：High income, low cost, product
Product stay in grade.1/4 prepared water Cefamandole nafate compounds content and purity are better than States Pharmacopoeia specifications.
The 1/4 water Cefamandole nafate compounds heat endurance that the present invention is provided is good, and dsc analysis show it about 201.6
DEG C there is endothermic peak, have exothermic peak at about 207.6 DEG C.Accelerated stability test shows that 1/4 water Mandokef sodium of the invention is closed
The stability of thing is better than Cefamandole Nafate anhydride.The 1/4 water Cefamandole nafate compounds that the present invention is provided and cephalo Meng
Polyester sodium anhydride is compared and is less susceptible to moisture absorption.Therefore the 1/4 water Cefamandole nafate compounds that the present invention is provided are in stability, anti-
Moist aspect is better than Cefamandole Nafate anhydride, with wider application prospect.
A kind of further purpose of the invention, there is provided pharmaceutical composition for containing 1/4 water Cefamandole nafate compounds.
Preferably, described pharmaceutical composition includes 1/4 water Cefamandole nafate compounds and pharmaceutically acceptable excipient.More preferably
Ground, pharmaceutical composition is selected from pharmaceutically acceptable formulation.
Brief description of the drawings
Fig. 1 is the FTIR spectrum figure of 1/4 water Cefamandole nafate compounds.
Fig. 2 is the TG analysis collection of illustrative plates of 1/4 water Cefamandole nafate compounds.
Fig. 3 is the dsc analysis collection of illustrative plates of 1/4 water Cefamandole nafate compounds.
Specific embodiment
Below will by specific embodiment, the present invention will be further described, but not therefore limit the present invention to institute
In the scope of embodiments stated, it should be understood by those skilled in the art that the equivalent done to present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
The preparation of the water Cefamandole nafate compounds of embodiment 1 1/4
(1) by 1L acetonitriles, the carboxylic of 200g 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
Acid, 1kg first mercaptos tetrazole, 900ml boron trifluorides/acetonitrile complex compound mixing, are warming up to 30 DEG C, quick stirring reaction 2h, reaction
0 DEG C is cooled to after end, the purified water that reaction solution is cooled to 0 DEG C in advance with 1.5L is mixed, be slowly stirred to there is crystal to separate out
Afterwards, 30min is stirred for, adds 10% ammoniacal liquor to adjust pH value to 3.0, control 0~5 DEG C of temperature, growing the grain 2h, filtering, the third of 1L
Ketone is washed 2 times, vacuum drying, obtains the amino -3 [(Z) -2- (4- methylthiazols) -5- bases] of white crystalline powder (6R, 7R) -7
Vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids (223.5g)；
(2) by (6R, 7R) -7 amino -3 [(Z) -2- (4- the methylthiazols) -5- bases] oxo -5- thia -1- nitrogen of vinyl -8
Miscellaneous bicyclic [4.2.0] oct-2-ene -2- carboxylic acids mix with 2L ethyl acetate, stirring at normal temperature 20min, add the double front threes of 300g N, O-
Silicon substrate acetamide, is warming up to 30 DEG C, and quick stirring reaction to system is clarified, and is cooled to -16 DEG C, is slowly added to 150ml formoxyls
Mandelic acid chloride, finishes and is warming up to 0 DEG C of reaction 1h, adds 1L purified waters, stirs 30min, and stratification, aqueous phase discarded is organic
It is added to 20g activated carbon and the anhydrous MgSO of 60g4Stirring is decolourized, filtering, controls temperature≤30 DEG C, is concentrated under reduced pressure into and is obtained white
Sticky solid, it is 1 to add 2.25L volume ratios:1 ether and the mixed solvent of ethyl acetate, stirring and dissolving add 20g activity
Charcoal stirring is decolourized, and filtering obtains Mandokef acid solution；
(3) Mandokef acid solution is cooled to 0 DEG C, is rapidly joined with 600ml ether and ethyl acetate (1:1) mixed
The sodium iso-octoate (100g) of solution dissolving is closed, stirring is warming up to 28 DEG C, and growing the grain 1.5h, filtering, absolute ethanol washing, vacuum is done
It is dry, obtain Cefamandole nafate compounds 284g.
The preparation of the water Cefamandole nafate compounds of embodiment 2 1/4
(1) by 1.5L acetonitriles, 300g 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
The mixing of carboxylic acid, 1.5kg first mercaptos tetrazole, 1.4L boron trifluorides/acetonitrile complex compound, is warming up to 40 DEG C, quick stirring reaction 1h, instead
5 DEG C are cooled to after should terminating, the purified water that reaction solution is cooled to 5 DEG C in advance with 2.25L is mixed, be slowly stirred to there is crystal to analyse
After going out, 30min is stirred for, adds 10% ammoniacal liquor to adjust pH value to 3.4, control 0~5 DEG C of temperature, growing the grain 3h, filtering, 1.5L
Acetone wash 2 times, vacuum drying, obtain the amino -3 of white crystalline powder (6R, 7R) -7 [(Z) -2- (4- methylthiazols) -
5- yls] vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids (319.6g)；
(2) by (6R, 7R) -7 amino -3 [(Z) -2- (4- the methylthiazols) -5- bases] oxo -5- thia -1- nitrogen of vinyl -8
Miscellaneous bicyclic [4.2.0] oct-2-ene -2- carboxylic acids mix with 3L ethyl acetate, stirring at normal temperature 30min, add the double front threes of 450g N, O-
Silicon substrate acetamide, is warming up to 35 DEG C, and quick stirring reaction to system is clarified, and is cooled to -10 DEG C, is slowly added to 225ml formoxyls
Mandelic acid chloride, finishes and is warming up to -2 DEG C of reaction 1.5h, addition 1.5L purified waters, stirring 30min, stratification, aqueous phase discarded,
It is organic to be added to 30g activated carbon and the anhydrous MgSO of 90g4Stirring is decolourized, filtering, controls temperature≤30 DEG C, is concentrated under reduced pressure into and is obtained
Thick white solid, it is 1 to add 3.38L volume ratios:1 ether and the mixed solvent of ethyl acetate, stirring and dissolving add 30g
Activated carbon stirring is decolourized, and filtering obtains Mandokef acid solution；
(3) Mandokef acid solution is cooled to 5 DEG C, is rapidly joined with 900ml ether and ethyl acetate (1:1) mixed
The sodium iso-octoate (150g) of solution dissolving is closed, stirring is warming up to 30 DEG C, and growing the grain 2h, filtering, absolute ethanol washing is vacuum dried,
Obtain Cefamandole nafate compounds 436g.
The preparation of the water Cefamandole nafate compounds of embodiment 3 1/4
(1) by 1.25L acetonitriles, 250g 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
The mixing of carboxylic acid, 1.25kg first mercaptos tetrazole, 1.17L boron trifluorides/acetonitrile complex compound, is warming up to 35 DEG C, quick stirring reaction 2h,
Reaction is cooled to 3 DEG C after terminating, and the purified water that reaction solution is cooled to 2 DEG C in advance with 1.88L is mixed, and is slowly stirred to there is crystal
After precipitation, 30min is stirred for, adds 10% ammoniacal liquor to adjust pH value to 3.2, control 0~5 DEG C of temperature, growing the grain 2h is filtered,
The acetone of 1.3L is washed 2 times, vacuum drying, obtains [(Z) -2- (the 4- methyl thiazoliums of -7 amino of white crystalline powder (6R, 7R) -3
Azoles) -5- bases] vinyl -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids (261.1g)；
(2) by (6R, 7R) -7 amino -3 [(Z) -2- (4- the methylthiazols) -5- bases] oxo -5- thia -1- nitrogen of vinyl -8
Miscellaneous bicyclic [4.2.0] oct-2-ene -2- carboxylic acids mix with 2.5L ethyl acetate, stirring at normal temperature 30min, add 375g N, O- double three
First silicon substrate acetamide, is warming up to 32 DEG C, and quick stirring reaction to system is clarified, and is cooled to -12 DEG C, is slowly added to 188ml formyls
Base mandelic acid chloride, finishes and is warming up to -5 DEG C of reaction 1.5h, adds 1.25L purified waters, stirs 30min, and stratification discards water
Phase, it is organic to be added to 25g activated carbon and the anhydrous MgSO of 75g4Stirring is decolourized, filtering, controls temperature≤30 DEG C, is concentrated under reduced pressure into
To thick white solid, it is 1 to add 2.82L volume ratios:1 ether and the mixed solvent of ethyl acetate, stirring and dissolving are added
The stirring of 25g activated carbons is decolourized, and filtering obtains Mandokef acid solution；
(3) Mandokef acid solution is cooled to 2 DEG C, is rapidly joined with 750ml ether and ethyl acetate (1:1) mixed
Close the sodium iso-octoate (125g) of solution dissolving, stirring is warming up to 32 DEG C, growing the grain 2h, filtering, respectively with 1.25L absolute ethyl alcohols and
1.25L acetone is washed, vacuum drying, obtains Cefamandole nafate compounds 359g.
The preparation (anhydride) of the Cefamandole nafate compounds of comparative example 1
The method of circuit 1 prepares Cefamandole nafate compounds according to the literature
(1) carboxylic acid of 272g 3- acetyl-o-methyls -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2 is dissolved in 2L water
In the mixed solvent of 1L acetone, saturated solution of sodium bicarbonate is added while stirring, control temperature 45 C, add 2L's 10%
1- methyl 1H-TETRAZOLE -5- mercaptan acetone solns, stirring mixing, 80 DEG C of reaction 3h are cooled to 10 DEG C, the hydrochloric acid regulation of 6mol/L
To 3.9, crystallization, filtering, washing is dried pH value, obtains (6R, 7R) -7 amino -3 [(Z) -2- (4- methylthiazols) -5- bases] ethene
Base -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids (269g)；
(2) by 15.2gD- mandelic acids addition 2.5L formic acid, room temperature is placed 2 days, and be dissolved in for drying solid by high-pressure drying
In benzene, 180ml oxalyl chlorides and 4ml NMFs are added, stir 2h, vacuum concentration obtains D- mandelic acid chloride oxalates；
(3) by D- mandelic acid chlorides oxalate, (6R, 7R) -7 amino -3 [(Z) -2- (4- methylthiazols) -5- bases] ethene
The oxo of base-8-5- thia-1- azabicyclo [4.2.0] oct-2-ene-2- carboxylic acids and 360g sodium acid carbonates are dissolved in 1L water and 5L acetone
In mixed solution (2 DEG C), 1h is stirred, 2h is then stirred at room temperature, removed under reduced pressure acetone adds the mixing of 1L water and 2L ethyl acetate
Solution, hydrochloric acid solution adjusts pH value to 2.0, and filtering, layering, collected organic layer is concentrated in vacuo to obtain grease, adds 10% carbonic acid
Hydrogen sodium solution 2.5L, mixes 2h, adds ethyl acetate 5L, ice bath to cool down, salt acid for adjusting pH value to 2.0, collected organic layer,
It is concentrated under reduced pressure, Mandokef acid is obtained, Mandokef acid is dissolved in 500ml ethanol, add the acetic acid of 260ml 1mol/L
Sodium ethoxide solution, stirring, cooling, crystallization obtains Cefamandole Nafate (anhydride) 115g.
Comparative example 2 prepares 2.5 Cefamandole Nafates of the crystallization water according to prior art literature CN101829118A
Hydrate
Using the identical preparation method of patent document embodiment 1, at ambient temperature, 2.6g Cefamandole Nafates are consolidated
Body is dissolved in 5.2mL distilled water, is subsequently adding the isopropanol of 47mL and organic mixed solution (isopropanol and the ether of ether
Volume ratio is 1: 2.5), 5 hours is stood at 5 DEG C, obtains white crystal, filtered, filter cake washs secondary with ethanol, after vacuum drying
2 hours, obtain containing 2.5 Cefamandole nafate hydrate crystal of the crystallization water.
Experiment 1 determines the FTIR spectrum figure of 1/4 water Cefamandole nafate compounds
1st, instrument reagent：Agilent Cary630 infrared spectrometers, manual powder compressing machine, infrared lamp, mortar, tweezers, medicine
Spoon, sample holder, KBr (spectroscopic pure).
2nd, sample preparation：
(1) open computer, connection infrared spectrometer is installed, preheat stand-by；
(2) 500mg KBrs are taken to be put into mortar, is ground 20 minutes, be flat-white powder to KBr；
(3) the appropriate potassium bromide powders of about 200mg are taken to be put into compression mold, compression mold is placed on tablet press machine, adjusted
It is whole to 20MPa, keep 1min；
(4) the KBr blank that will be pressed is toasted 2 hours under being placed in infrared lamp；
(5) about 2mg samples separately are taken and 300mg KBrs is put into mortar, ground 20 minutes, mixed with sample to KBr
Uniformly；
(6) the appropriate KBrs of about 200mg are taken to be put into compression mold with the mixed-powder of sample, compression mold is placed in
On tablet press machine, adjust to 20MPa, keep 1min；
(7) the KBr sample strip that will be pressed is toasted 2 hours under being placed in infrared lamp.
3rd, method of testing：
(1) blank is fixed with sample holder first, is put into the transmission storehouse of infrared spectrometer, according to program setting
Carry out background signal collection；
(2) after the completion of background signal collection, blank is removed, sample strip is fixed with sample holder, by same
Method carries out signal acquisition；
(3) after the completion of sample signal collection, data are derived, is preserved pending.
4th, data processing：
(1) Agilent data processing software, importing data film are opened；
(2) operations such as baseline correction, mark peak are carried out to data file, after the completion for the treatment of, file is preserved.
5th, result
Experiment 2 determines the TG analysis collection of illustrative plates of 1/4 water Cefamandole nafate compounds
Detecting instrument：Heat analysis-GC-MS (NETZSCH STA 449C).
Testing conditions：2~10mg of sample, alumina crucible, high pure nitrogen does reaction gas and protection gas, and flow is respectively
40ml/min and 30ml/min, heating rate 10K/min, temperature test scope are 25~450 DEG C.
Experimental implementation：
1st, start shooting, baseline test (buoyancy effect amendment --- fair curve).Put crucible and prepare a pair clean crucibles, point
It is not put on support as reference crucible and sample crucible.Whether crucible is added a cover depending on sample test below.Close body of heater.
If (by original ready-made baseline, having can skip this step, direct setting-out product).
2nd, arrange parameter, starts test.The parameters such as input sample title, numbering, the gas for being used and flow, start to survey
Amount.
3rd, it is measured, carries out data analysis, take out sample, closes instrument.
Experiment 3 determines the dsc analysis collection of illustrative plates of 1/4 water Cefamandole nafate compounds
Detecting instrument：Heat analysis-GC-MS (NETZSCH STA 449C)
Testing conditions：2~10mg of sample, alumina crucible, high pure nitrogen does reaction gas and protection gas, and flow is respectively
40ml/min and 30ml/min.10 DEG C/min of heating rate, 25~450 DEG C of temperature range.
Experimental implementation：
1st, start shooting, baseline test (buoyancy effect amendment --- fair curve).Put crucible and prepare a pair clean crucibles, point
It is not put on support as reference crucible and sample crucible.Whether crucible is added a cover depending on sample test below.Close body of heater.
If (by original ready-made baseline, having can skip this step, direct setting-out product).
2nd, arrange parameter, starts test.The parameters such as input sample title, numbering, the gas for being used and flow, start to survey
Amount.
3rd, it is measured, carries out data analysis, take out sample, closes instrument.
The study on the stability of test example 1
Head prepared by the 1/4 water Cefamandole nafate compounds and comparative example 1 that the present inventor prepares to the embodiment of the present invention 1
Spore Meng's polyester sodium compound, and the Cefamandole nafate hydrate of 2.5 crystallizations water of the preparation of comparative example 2 has carried out acceleration for stabilization
Property investigate experiment.Investigation condition is 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%.Place 6 months, respectively at 0,1,2,3,
6 the end of month sampled.Inspection target is proterties, clarity, moisture, acidity, Cefamandole, 2 ethyl hexanoic acid and relevant material.
Test example 2 draws moist investigation
1/4 water Cefamandole nafate compounds prepared by the embodiment of the present invention 1, and 2.5 crystallizations prepared by comparative example 2
The Cefamandole nafate compounds that the Cefamandole nafate hydrate of water is prepared with comparative example 1 are placed in 40 in dynamic vapor sorption instrument
Under the conditions of DEG C, weight when weight change is less than 0.01g in three hours is recorded, result of the test is as follows：
| Relative humidity RH/% | The weight rate of embodiment 1 | The weight rate of comparative example 1 | The weight rate of comparative example 2 |
| 0 | 0 | 0 | 0 |
| 10 | 0 | 0 | 0 |
| 20 | 0 | 0 | 0 |
| 30 | 0 | 0.03 | 0.01 |
| 40 | 0.02 | 0.07 | 0.06 |
| 50 | 0.39 | 0.89 | 0.75 |
| 60 | 0.48 | 0.94 | 0.84 |
| 70 | 0.85 | 1.52 | 1.27 |
Conclusion：The 1/4 water Cefamandole nafate compounds that the present invention is provided are less susceptible to moisture absorption.
The mobility of test example 3 is investigated
The present inventor is to the embodiment of the present invention 3 and Cefamandole Nafate prepared by comparative example 1, and prepared by comparative example 2
The Cefamandole nafate hydrate of 2.5 crystallizations water takes funnel method to determine angle of repose, and the mobility to Cefamandole Nafate is carried out
Research.Angle of repose testing result:
Angle of repose testing result:
| Embodiment | Angle of repose θ |
| Embodiment 3 | 28.7° |
| Comparative example 1 | 35.4° |
| Comparative example 2 | 32.4° |
As a result：The mobility of 1/4 water Cefamandole nafate compounds prepared by the present invention is apparently higher than the cephalo Meng of comparative example 1
The Cefamandole nafate hydrate of 2.5 crystallizations water of polyester sodium compound and comparative example 2, can meet need prepared by different preparations
Will.
The dissolubility of test example 4 is investigated
By the Cefamandole Nafate prepared by embodiment 1 and comparative example 1, and the head of 2.5 crystallizations water prepared by comparative example 2
Spore Meng's polyester sodium hydrate is dissolved in the aqueous solution respectively, shakes 20min, and embodiment 1, the and of comparative example 1 are calculated by detection level
Solubility of the compound in water prepared by comparative example 2.
Solubility testing result
| Embodiment | Solubility |
| Embodiment 1 | 0.81g/ml |
| Comparative example 1 | 0.43g/ml |
| Comparative example 2 | 0.52g/ml |
Conclusion：The dissolubility of 1/4 water Cefamandole nafate compounds prepared by the embodiment of the present invention 1 is significantly better than comparative example
The Cefamandole nafate hydrate of 2.5 crystallizations water of 1 Cefamandole nafate compounds and comparative example 2.
Claims (4)
1. a kind of 1/4 water Cefamandole nafate compounds, it is characterised in that every mole of Cefamandole Nafate contains 1/4 mole of water, point
Minor is：Molecular weight is：516.99, structural formula is：
2. a kind of pharmaceutical composition, it is characterised in that comprising 1/4 water Cefamandole nafate compounds described in claim 1.
3. a kind of pharmaceutical composition, it is characterised in that comprising 1/4 water Cefamandole nafate compounds and medicine described in claim 1
The excipient received on.
4. pharmaceutical composition according to claim 3, it is characterised in that described pharmaceutical composition is selected from pharmaceutically acceptable
Formulation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134506A (en) * | 2017-07-19 | 2019-01-04 | 宁应 | One water cefotiam hydrochloride compound of one kind and its pharmaceutical composition |
| CN109134504A (en) * | 2017-06-16 | 2019-01-04 | 陈立平 | 1/2 water cefmenoxime hydrochloride compound of one kind and its drug combination preparation |
| CN109134502A (en) * | 2017-06-15 | 2019-01-04 | 海南灵康制药有限公司 | A kind of 1/2 water cefuroxime sodium compound |
| CN109160924A (en) * | 2017-07-26 | 2019-01-08 | 海南美大制药有限公司 | Two water cefotiam hydrochloride compounds of one kind and its drug combination preparation |
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| CN101829118A (en) * | 2010-06-12 | 2010-09-15 | 山东罗欣药业股份有限公司 | Cefamandole nafate composition powder injection |
| CN101914106A (en) * | 2010-08-20 | 2010-12-15 | 湖北济生医药有限公司 | Cefamandole nafate hydrate and preparation method thereof |
| CN105037391A (en) * | 2015-07-07 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Cefamandole nafate compound and preparation thereof |
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| CN101829118A (en) * | 2010-06-12 | 2010-09-15 | 山东罗欣药业股份有限公司 | Cefamandole nafate composition powder injection |
| CN101914106A (en) * | 2010-08-20 | 2010-12-15 | 湖北济生医药有限公司 | Cefamandole nafate hydrate and preparation method thereof |
| CN105037391A (en) * | 2015-07-07 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Cefamandole nafate compound and preparation thereof |
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| CN109134502A (en) * | 2017-06-15 | 2019-01-04 | 海南灵康制药有限公司 | A kind of 1/2 water cefuroxime sodium compound |
| CN109134504A (en) * | 2017-06-16 | 2019-01-04 | 陈立平 | 1/2 water cefmenoxime hydrochloride compound of one kind and its drug combination preparation |
| CN109134506A (en) * | 2017-07-19 | 2019-01-04 | 宁应 | One water cefotiam hydrochloride compound of one kind and its pharmaceutical composition |
| CN109160924A (en) * | 2017-07-26 | 2019-01-08 | 海南美大制药有限公司 | Two water cefotiam hydrochloride compounds of one kind and its drug combination preparation |
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