CN106279210B - A kind of composition of Cefotetan Disodium - Google Patents
A kind of composition of Cefotetan Disodium Download PDFInfo
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Abstract
The invention belongs to field of medicine and chemical technology, in particular to a kind of composition of Cefotetan Disodium.The applicant passes through a large amount of experimental study; it was found that when chloracetyl 7-MAC takes off benzophenone protecting group by means of the present invention; chloracetyl -7-MAC acid tetrazole condensation impurity can be generated; and it was unexpectedly found that; in the presence of a small amount of chloracetyl -7-MAC acid tetrazole is condensed impurity; the composition for the Cefotetan Disodium that preparation method through the invention obtains is compared with commercially available cefotetan disodium for injection; the content of cefotetan lactone and 1- methyl -5- mercapto tetrazole is substantially reduced, and product purity significantly improves.
Description
Technical field
The invention belongs to field of medicine and chemical technology, in particular to a kind of composition of Cefotetan Disodium.
Background technique
Cefotetan Disodium (Cefotetan Disodium, formula I), entitled (6R, 7S) -7- [[[4- (the 2- amino-of chemistry
1- carboxylic acid -2- oxygen ethylidene) -1,3- dithiane -2- base] carbonyl] amino] -7- methoxyl group -3- [[(1- methyl-1 H- tetrazolium -5-
Base) thia] methyl] -2 carboxylic acid disodium salt of -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene, belong to the interior acyl of β -
Amine antibiotic, bactericidal effect is derived from the synthesis for inhibiting bacteria cell wall, to Gram-positive and gram-negative aerobic bacteria
And anaerobic bacteria has extensive antibacterial activity in vitro.
CN102250125 is disclosed and is prepared chloracetyl 7-MAC by starting material of 7-MAC, then takes off hexichol first with methyl phenyl ethers anisole
The protection of ketone finally reacts the method for obtaining cefotetan acid with isothiazole trisodium:
The method discloses the yield for the cefotetan acid being prepared and purity, but do not refer to any specific impurity,
Therefore there is still a need for the cefotetan acids of preparation higher purity, and then obtain the Cefotetan Disodium composition of higher purity.
Summary of the invention
The applicant passes through a large amount of experimental study, and discovery chloracetyl 7-MAC takes off benzophenone by means of the present invention
When protecting group, entitled (6R, the 7S) -7- [[[(1- methyl-1 H- tetrazolium -5- base) thia] methyl-carbony] of chemistry can be generated
Amino] -7- methoxyl group -3- [[(1- methyl-1 H- tetrazolium -5- base) thia] methyl] -8- oxo -5- thia -1- azabicyclo
Chloracetyl -7-MAC acid the tetrazole of -2 carboxylic acid (formula II) of [4.2.0] oct-2-ene is condensed impurity,
And it was unexpectedly found that passing through this in the presence of a small amount of chloracetyl -7-MAC acid tetrazole is condensed impurity
Compared with commercially available cefotetan disodium for injection, cephalo replaces the composition for the Cefotetan Disodium that the preparation method of invention obtains
The content of smooth lactone (formula III) and 1- methyl -5- mercapto tetrazole (formula IV) is substantially reduced, and product purity significantly improves.
On the one hand, the present invention provides a kind of composition of Cefotetan Disodium, the composition contains cefotetan two
The compound of sodium, formula II, formula III and formula IV, in which:
The content of Cefotetan Disodium is not less than 96.7%, and the content of II compound of formula is not higher than 0.3%, III compound of formula
Content be not higher than 1.0%, the content of IV compound of formula is not higher than 2.0%.
In a preferred embodiment of the invention, the content of Cefotetan Disodium is not less than 98.5%, II compound of formula
Content is not higher than 0.25%, and the content of III compound of formula is not higher than 0.2%, and the content of IV compound of formula is not higher than 0.5%.
In more preferred of the present invention, the content of Cefotetan Disodium is not less than 98.8%, II compound of formula
Content is not higher than 0.2%, and the content of III compound of formula is not higher than 0.1%, and the content of IV compound of formula is not higher than 0.25%.
In one embodiment of the invention, the Cefotetan Disodium is amorphous forms.
In one embodiment of the invention, II compound of formula in the composition of Cefotetan Disodium is such as
It is generated under lower step:
A) it is added methyl phenyl ethers anisole in reaction vessel, system is cooled to -5 DEG C to 5 DEG C, it is added alchlor, 20 DEG C of control system
Stirring and dissolving to 30 DEG C is added methylene chloride I, is cooled to 0 DEG C to 5 DEG C after mixing evenly, obtains alchlor-after dissolution
Methyl phenyl ethers anisole solution,
Methylene chloride II is added in another reaction vessel, nitrogen protection is cooled to -5 DEG C to 5 DEG C, and chloracetyl 7- is added
MAC after stirring and dissolving, is cooled to -25 DEG C to -15 DEG C, above-mentioned alchlor-methyl phenyl ethers anisole solution is added dropwise into system, was added dropwise
- 25 DEG C to -10 DEG C of process control system, drop finishes, and is stirred to react 1 hour,
B) 5 to 15 DEG C of temperature control system is slowly added to acetone-hydrochloric acid solution, finishes, 10 DEG C to 20 DEG C of temperature control stirrings to system
Dissolution continues stirring 0.5 hour, stands 30 minutes, layering, separates organic phase, and organic phase is washed with sodium chloride solution I, collects
Water phase is washed in organic phase, merging twice, the addition sodium chloride II into water phase, after stirring and dissolving, with ethyl acetate I, ethyl acetate
II and ethyl acetate III extract, combined ethyl acetate phase,
C) ethyl acetate phase mutually merges with original machine, and 0 DEG C to 10 DEG C of temperature control, sodium bicarbonate solution is added dropwise, adjusts pH=6.9 extremely
7.1, it stirs 0.5 hour, stratification, collects water phase, organic phase is extracted with purified water, merges aqueous phase extracted twice, temperature control 0
DEG C to 10 DEG C, diatomite drainage filters out suspended matter, collects filtrate, and filtrate uses ethyl acetate IV and ethyl acetate V to wash respectively,
Collect water phase, into water phase be added ethyl acetate VI, 0 DEG C to 10 DEG C of temperature control, be added dropwise hydrochloric acid solution adjust water phase pH=1.5 to
2.0, it drips and finishes stirring 0.5 hour, stratification collects ethyl acetate phase, and water phase uses ethyl acetate VII, ethyl acetate VIII anti-respectively
Extraction merges 3 ethyl acetate phases, and sodium chloride solution II washs, and the stirring of organic phase anhydrous sodium sulfate is 1 hour dry, filters, acetic acid
Ethyl ester Ⅸ elutes, and filtrate stirs decoloration 0.5 hour, filters pressing with active carbon, and ethyl acetate Ⅹ elutes, -5 DEG C of filtrate temperature control~5 DEG C,
The wherein mass ratio of the chloracetyl 7-MAC of step a), methylene chloride I, methylene chloride II, alchlor and methyl phenyl ethers anisole
For 1:1.1:12.9:0.82:2.6,
Wherein in acetone-hydrochloric acid solution of step b), the mass ratio of acetone, hydrochloric acid and water is 6:0.23:8.19,
The wherein matter of the sodium chloride solution I of step b), sodium chloride II, ethyl acetate I, ethyl acetate II and ethyl acetate III
Than being 6.8:0.5:2.2:1.5:0.7, and in sodium chloride solution I, the mass ratio of sodium chloride and water is 0.5:6.3 to amount,
Wherein in the sodium bicarbonate solution of step c), the mass ratio of sodium bicarbonate and water is 0.2:0.9,
Wherein in the hydrochloric acid solution of step c), the mass ratio of hydrochloric acid and water is 0.19:1.7,
Wherein purified water, sodium chloride solution II, ethyl acetate IV, ethyl acetate V, ethyl acetate VI, acetic acid in step c)
Ethyl ester VII, ethyl acetate VIII, ethyl acetate Ⅸ, ethyl acetate Ⅹ, anhydrous sodium sulfate, active carbon mass ratio be 4.2:4.5:
2.6:2.1:5.6:3.0:1.5:1:0.5:2:0.09 and the mass ratio of sodium chloride and water is 0.9 in sodium chloride solution II:
3.6。
On the other hand, the present invention provides a kind of preparation method of Cefotetan Disodium composition, include the following steps:
1) preparation of chloracetyl 7-MAC carboxylic acid
A) it is added methyl phenyl ethers anisole in reaction vessel, system is cooled to -5 DEG C to 5 DEG C, it is added alchlor, 20 DEG C of control system
Stirring and dissolving to 30 DEG C is added methylene chloride I, is cooled to 0 DEG C to 5 DEG C after mixing evenly, obtains alchlor-after dissolution
Methyl phenyl ethers anisole solution,
Methylene chloride II is added in reaction vessel, nitrogen protection is cooled to -5 DEG C to 5 DEG C, and chloracetyl 7-MAC is added, stirs
After mixing dissolution, -25 DEG C to -15 DEG C are cooled to, above-mentioned alchlor-methyl phenyl ethers anisole solution is added dropwise into system, process control is added dropwise
- 25 DEG C to -10 DEG C of system, drop finishes, and is stirred to react 1 hour,
B) 5 to 15 DEG C of temperature control system is slowly added to acetone-hydrochloric acid solution, finishes, 10 DEG C to 20 DEG C of temperature control stirrings to system
Dissolution continues stirring 0.5 hour, stands 30 minutes, layering, separates organic phase, and organic phase is washed with sodium chloride solution I, collects
Water phase is washed in organic phase, merging twice, the addition sodium chloride II into water phase, after stirring and dissolving, with ethyl acetate I, ethyl acetate
II and ethyl acetate III extract, combined ethyl acetate phase,
C) ethyl acetate phase mutually merges with original machine, and 0 DEG C to 10 DEG C of temperature control, sodium bicarbonate solution is added dropwise, adjusts pH=6.9 extremely
7.1, it stirs 0.5 hour, stratification, collects water phase, organic phase is extracted with purified water, merges aqueous phase extracted twice, temperature control 0
DEG C to 10 DEG C, diatomite drainage filters out suspended matter, collects filtrate, and filtrate uses ethyl acetate IV and ethyl acetate V to wash respectively,
Collect water phase, into water phase be added ethyl acetate VI, 0 DEG C to 10 DEG C of temperature control, be added dropwise hydrochloric acid solution adjust water phase pH=1.5 to
2.0, it drips and finishes stirring 0.5 hour, stratification collects ethyl acetate phase, and water phase uses ethyl acetate VII, ethyl acetate VIII anti-respectively
Extraction merges 3 ethyl acetate phases, and sodium chloride solution II washs, and the stirring of organic phase anhydrous sodium sulfate is 1 hour dry, filters, acetic acid
Ethyl ester Ⅸ elutes, and filtrate stirs decoloration 0.5 hour, filters pressing with active carbon, and ethyl acetate Ⅹ elutes, and -5 DEG C to 5 DEG C of filtrate temperature control,
The wherein mass ratio of the chloracetyl 7-MAC of step a), methylene chloride I, methylene chloride II, alchlor and methyl phenyl ethers anisole
For 1:1.1:12.9:0.82:2.6,
Wherein in acetone-hydrochloric acid solution of step b), the mass ratio of acetone, hydrochloric acid and water is 6:0.23:8.19,
The wherein matter of the sodium chloride solution I of step b), sodium chloride II, ethyl acetate I, ethyl acetate II and ethyl acetate III
Than being 6.8:0.5:2.2:1.5:0.7, and in sodium chloride solution I, the mass ratio of sodium chloride and water is 0.5:6.3 to amount,
Wherein in the sodium bicarbonate solution of step c), the mass ratio of sodium bicarbonate and water is 0.2:0.9,
Wherein in the hydrochloric acid solution of step c), the mass ratio of hydrochloric acid and water is 0.19:1.7,
Wherein purified water, sodium chloride solution II, ethyl acetate IV, ethyl acetate V, ethyl acetate VI, acetic acid in step c)
Ethyl ester VII, ethyl acetate VIII, ethyl acetate Ⅸ, ethyl acetate Ⅹ, anhydrous sodium sulfate, active carbon mass ratio be 4.2:4.5:
2.6:2.1:5.6:3.0:1.5:1:0.5:2:0.09 and the mass ratio of sodium chloride and water is 0.9 in sodium chloride solution II:
3.6
2) preparation of chloracetyl 7-MAC carboxylic acid sodium
Sodium iso-octoate-aqueous isopropanol is added dropwise in -10 DEG C to 0 DEG C of step 1) filtrate temperature control, and drop finishes, and -10 DEG C to 0 DEG C of temperature control
Lower stirring and crystallizing 0.5 hour, rejection filter, filter cake are eluted with ethyl acetate Ⅺ, and drying, filter cake is dried under reduced pressure 20 hours in 25 DEG C extremely
24 hours, chloracetyl 7-MAC carboxylic acid sodium is obtained,
Wherein the mass ratio of sodium iso-octoate and isopropanol is 0.31:1 in sodium iso-octoate-aqueous isopropanol,
3) preparation of cefotetan acid
Neutral alumina is added in purified water, hydrochloric acid solution tune pH=0.8 to 1.2 is added, is stirred 1 hour, rejection filter, filter cake
With purified water mashing, rejection filter, repetitive operation dries until filtrate pH=3.7 to 4.5, for use,
Be pumped into purified water in reaction vessel, be cooled to 0 DEG C to 5 DEG C, sequentially added under stirring chloracetyl 7-MAC carboxylic acid sodium,
Sodium bicarbonate I and disodium ethylene diamine tetraacetate, stir the lower dropwise addition different thiophene of 3- hydroxyl -4- carboxy thiol groups by -1 DEG C to 5 DEG C of system temperature control
Process control system pH=7.0 to 8.5 is added dropwise in three sodium solution of azoles.Drop finish, add II regulation system pH to 8.2 of sodium bicarbonate to
8.5, -1 DEG C to 5 DEG C of temperature control is stirred to react 3 hours.It is passed through CO2Regulation system pH to 7.8 to 8.0, continues by -1 DEG C to 5 DEG C of temperature control
It is stirred to react 22 hours, then uses CO2PH to 7.4 to 7.6 is adjusted, the reaction was continued 72 hours for -1 DEG C to 5 DEG C of temperature control,
Reaction terminates, rejection filter, collects filtrate, 0 DEG C to 10 DEG C of filtrate temperature control, adjusts pH=5.4 to 5.6 with hydrochloric acid solution,
It is added the neutral alumina of above-mentioned activation processing, temperature control stirring 1 hour,
Rejection filter, filter cake are eluted with aqueous sodium acetate solution, are collected water phase, 0 DEG C to 5 DEG C of water phase temperature control, are stirred lower dropwise addition hydrochloric acid
Solution, 0 DEG C to 5 DEG C of temperature control slowly adjust pH value of solution=1.0 to 1.5, continue stirring and crystallizing 0.5 hour, rejection filter, filter cake pre-cooling
0 to 5 DEG C of purified water elution, dries to obtain cefotetan diacid,
Wherein chloracetyl 7-MAC carboxylic acid sodium, 3- hydroxyl -4- carboxy thiol groups isothiazole trisodium, neutral alumina, sodium bicarbonate
I and disodium ethylene diamine tetraacetate, sodium bicarbonate II mass ratio be 1:0.65:7.4:0.4:0.008:6.3,
Wherein the mass ratio of sodium acetate and water is 0.061:5.5 in aqueous sodium acetate solution,
4) preparation of Cefotetan Disodium
Methyl ethyl ketone I is added in reaction vessel, 0 DEG C to 10 DEG C of temperature control, nitrogen displacement protection is added with stirring step 3)
Sodium chloride solution is added in the cefotetan diacid of preparation after dissolution, stir 0.5 hour, stands 30 minutes, and layering is collected organic
Phase, water phase are extracted with methyl ethyl ketone II, merge organic phase, and organic phase is washed with sodium chloride solution, are stirred 0.5 hour, stand 1
Hour, organic phase is collected in liquid separation,
Dehydrated alcohol is added in organic phase, 0 DEG C to 10 DEG C of system temperature control, under nitrogen displacement protection, active carbon stirring is added
Decoloration 0.5 hour, filters pressing are kept at this temperature, and sodium iso-octoate-ethyl alcohol is slowly added dropwise into filtrate for the displacement protection of filtrate nitrogen
Solution adjusts pH value of solution=7.8 to 8.3, stops being added dropwise, and system continues stirring 1 hour, rejection filter, filter cake methyl ethyl ketone with
Alcohol mixed solution elution, rejection filter,
Filter cake acetone is beaten 1 hour at 0 DEG C~10 DEG C, and drying, filter cake is dried under reduced pressure 30 hours in 20 DEG C to 30 DEG C, obtains
Cefotetan Disodium,
Wherein the mass ratio of the methyl ethyl ketone I, methyl ethyl ketone II, dehydrated alcohol and sodium iso-octoate of step 4) is 7.8:
1.2:4.3:0.55, and the mass ratio of sodium iso-octoate and ethyl alcohol is 0.55:0.9 in sodium iso-octoate-ethanol solution,
Wherein in the methyl ethyl ketone and alcohol mixed solution of step 4), the mass ratio of methyl ethyl ketone and ethyl alcohol is 1.2:
1.9。
The present invention further provides the preparation methods of chloracetyl 7-MAC, and steps are as follows:
Methylene chloride, nitrogen protection, -25 DEG C to -10 DEG C addition 7-MAC of system temperature control, stirring are added into reaction vessel
After dissolution, pyridine is added.- 25 DEG C to -10 DEG C of temperature control, lower dropwise addition chloracetyl chloride is stirred, drop finishes, and insulation reaction 1 hour,
Reaction terminates, -5 DEG C to 5 DEG C of reaction system temperature control, molten with sodium chloride-hydrochloric acid solution I and sodium chloride-hydrochloric acid respectively
Liquid II washs, and stirring stands 30 minutes, collects organic phase.- 5 DEG C to 5 DEG C of temperature control, organic phase is small with active carbon stirring decoloration 0.5
When, filters pressing, the stirring of filtrate anhydrous sodium sulfate is 1 hour dry, filtering, and filter cake eluent methylene chloride collects filtrate,
Muddy is concentrated under reduced pressure into for 20 DEG C to 30 DEG C of temperature control in filtrate reaction vessel, is added anhydrous methanol, 20 DEG C to 30 DEG C
Release material after mixing evenly, mechanical stirring gradient crystallization is stirred for crystallization 1 hour to 2 hours after 0 DEG C, rejection filter, filter cake first
Alcohol elution, is dried under reduced pressure 14 hours in 40 DEG C, obtains chloracetyl 7-MAC,
Wherein the mass ratio of 7-MAC, pyridine and chloracetyl chloride is 1:0.22:0.24,
Wherein the mass ratio of sodium chloride, hydrochloric acid and water is 0.3:0.15:6.05, sodium chloride-in sodium chloride-hydrochloric acid solution I
The mass ratio of sodium chloride, hydrochloric acid and water is 0.3:0.04:5.86 in hydrochloric acid solution II.
Specific embodiment
For the present invention by following embodiment, they are only embodiment, are not intended to limit the present invention, all to be based on institute of the present invention
The technology of realization, all belongs to the scope of the present invention.
HPLC detection method:
It takes this product appropriate, adds water-methanol-acetonitrile (90:5:5) to dissolve and dilute and be made in every 1ml containing Cefotetan Disodium
The solution of 0.4mg, as test solution (test solution is newly matched before use), precision is measured in right amount, adds water-methanol-acetonitrile
The solution for containing 4 μ g in every 1ml solution is made in (90:5:5) dilution, as contrast solution；Take system suitability reference substance about
10mg is set in 25ml measuring bottle, is added water-methanol-acetonitrile (90:5:5) to dissolve and is diluted to scale, as system suitability
Solution.It is measured according to high performance liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010), uses octadecylsilane chemically bonded silica
[Thermo BDS HYPERSIL C is used for filler18(4.6 × 250mm, 5 μm)]；With 0.1mol/L phosphoric acid solution-methanol-
Acetonitrile-glacial acetic acid (1700:105:105:100) is mobile phase；Flow velocity is 1.0ml per minute；Detection wavelength is 254nm.It takes and is
The 20 μ l of employment and suitability test (E & ST) solution that unites injects liquid chromatograph.It takes 20 μ l of contrast solution to inject liquid chromatograph, it is sensitive to adjust detection
Degree, making principal component chromatography peak height is about the 10% of full scale；It is accurate again to measure test solution and each 20 μ l of contrast solution, respectively
Inject liquid chromatograph, record chromatographic data is to 3.5 times of main peak retention time, such as aobvious impurity in the chromatography of test solution
The percentage of each impurity is calculated according to the following formula in peak:
100×f×(rFor/rIt is right)×(CIt is right/CFor)
F is the relative correction factor of each impurity in following table
rForFor the peak area of impurity each in test solution
rIt is rightFor contrast solution main peak area
CForFor test solution concentration
CIt is rightFor contrast solution concentration
The relative correction factor and limit of each impurity of table 1
The preparation of 1 chloracetyl 7-MAC of embodiment
Methylene chloride I, N are pumped into 200L reaction kettle2Protection, -25 DEG C~-10 DEG C addition 7-MAC of system temperature control, stirring
After dissolution, pyridine is added.- 25 DEG C~-10 DEG C of temperature control, lower dropwise addition chloracetyl chloride is stirred, drop finishes, and insulation reaction 1 hour.
Reaction terminates, -5 DEG C of reaction system temperature control~5 DEG C, molten with sodium chloride-hydrochloric acid solution I and sodium chloride-hydrochloric acid respectively
Liquid II washs, and stirring stands 30 minutes, collects organic phase.- 5 DEG C of temperature control~5 DEG C, organic phase is stirred with White Dew Z active carbon decolourizes
0.5 hour, filters pressing, the stirring of filtrate anhydrous sodium sulfate was 1 hour dry, and filtering, filter cake methylene chloride II elutes, and collects filtrate.
Filtrate is concentrated under reduced pressure into muddy for 20 DEG C~30 DEG C of temperature control in 200L kettle, is added anhydrous methanol I, and 20 DEG C~30 DEG C
Release material after mixing evenly, mechanical stirring gradient crystallization is stirred for crystallization 1 hour~2 hours after 0 DEG C, rejection filter, filter cake first
Alcohol II divides 3 elution, is dried under reduced pressure 14 hours in 40 DEG C, obtains chloracetyl 7-MAC 19.48kg, yield 88.8%.
2 chloracetyl 7-MAC's of table prepares feed ratio
The preparation of 2 chloracetyl 7-MAC carboxylic acid sodium of embodiment
1) preparation of chloracetyl 7-MAC carboxylic acid
Alchlor-methyl phenyl ethers anisole solution is prepared: methyl phenyl ethers anisole is pumped into 100L reaction kettle, system is cooled to -5 DEG C~5 DEG C,
Alchlor is added portionwise, methylene chloride I is added, after mixing evenly in stirring and dissolving at 20 DEG C~30 DEG C of control system after dissolution
It is cooled to 0 DEG C~5 DEG C, it is spare.
Methylene chloride II, N are pumped into 500L reaction kettle2Protection is cooled to -5 DEG C~5 DEG C, and chloracetyl 7-MAC is added, stirs
After mixing dissolution, it is cooled to -25 DEG C~-15 DEG C.Alchlor-methyl phenyl ethers anisole solution is added dropwise into system, process control system-is added dropwise
25 DEG C~-10 DEG C, drop finishes, and is stirred to react 1 hour.
5~15 DEG C of temperature control system, it is slowly added to acetone-hydrochloric acid solution, is finished, 10 DEG C~20 DEG C stirrings of temperature control are molten to system
Solution continues stirring 0.5 hour, stands 30 minutes, and layering separates organic phase (lower layer).Organic phase is washed with sodium chloride solution I,
Collect organic phase.Water phase is washed in merging twice, and sodium chloride II is added into water phase, after stirring and dissolving, successively with ethyl acetate I,
Ethyl acetate II, ethyl acetate III extract, combined ethyl acetate phase.
Ethyl acetate phase mutually merges with original machine, and 0 DEG C~10 DEG C of temperature control, dropwise addition sodium bicarbonate solution, tune pH=6.9~
7.1, it stirs 0.5 hour, stratification, collects water phase.Organic phase is extracted with purified water IV, merges aqueous phase extracted twice.Temperature control
0 DEG C~10 DEG C, diatomite drainage filters out suspended matter, collects filtrate, and filtrate uses ethyl acetate IV and ethyl acetate V to wash respectively,
Collect water phase.The addition ethyl acetate VI into water phase, 0 DEG C~10 DEG C of temperature control, dropwise addition hydrochloric acid solution adjusting water phase pH=1.5~
2.0, it drips and finishes stirring 0.5 hour, stratification collects ethyl acetate phase.Water phase uses ethyl acetate VII, ethyl acetate VIII respectively
Back extraction, merges 3 ethyl acetate phases, and sodium chloride solution II washs.The stirring of organic phase anhydrous sodium sulfate is 1 hour dry, filters, second
Acetoacetic ester Ⅸ elutes.Filtrate stirs decoloration 0.5 hour, filters pressing with White Dew Z active carbon, and ethyl acetate Ⅹ elutes.Filtrate temperature control -5
DEG C~5 DEG C, it is spare.
2) preparation of chloracetyl 7-MAC carboxylic acid sodium
Sodium iso-octoate-aqueous isopropanol is added dropwise in upper spare -10 DEG C of filtrate temperature control~0 DEG C of step, and drop finishes, -10 DEG C of temperature control~0
Stirring and crystallizing 0.5 hour at DEG C, rejection filter, filter cake with ethyl acetate Ⅺ elute, drying, filter cake be dried under reduced pressure in 25 DEG C 20 hours~
24 hours, obtain chloracetyl 7-MAC carboxylic acid sodium (SM1) 18.22kg, yield 87.3%.
3 chloracetyl 7-MAC carboxylic acid of table prepares feed ratio
The preparation of 3 cefotetan acid of embodiment
Neutral alumina is activated: neutral alumina is added in purified water IV, hydrochloric acid II is added to adjust pH=0.8-1.2,
Stirring 1 hour, rejection filter.Filter cake purified water V divides 5-7 mashing, rejection filter, repetitive operation until filtrate pH=3.7~4.5,
Drying, for use.
It is pumped into purified water I in 300L reaction kettle, is cooled to 0 DEG C~5 DEG C, chloracetyl 7-MAC carboxylic is sequentially added under stirring
Sour sodium (SM1), sodium bicarbonate I and disodium ethylene diamine tetraacetate.Lower dropwise addition 3- hydroxyl -4- carboxylic is stirred in -1 DEG C of system temperature control~5 DEG C
Process control system pH=7.0~8.5 are added dropwise in base sulfydryl isothiazole trisodium (SM2) solution.Drop finishes, and sodium bicarbonate II is added to adjust
System pH to 8.2~8.5, -1 DEG C of temperature control~5 DEG C are stirred to react 3 hours.It is passed through CO2Regulation system pH to 7.8~8.0, temperature control-
1 DEG C~5 DEG C, continue to be stirred to react 22 hours.CO is used again2PH to 7.4~7.6 is adjusted, it is 72 small that the reaction was continued for -1 DEG C of temperature control~5 DEG C
When.HPLC monitors reaction end, controls cefotetan tautomer < 5.0% (area normalization method).
Reaction terminates, rejection filter, collects filtrate.0 DEG C~10 DEG C of filtrate temperature control, with dilute hydrochloric acid solution adjust pH=5.4~
5.6, the neutral alumina (weight is in terms of wet product) of activation processing is added, temperature control stirring 1 hour, adsorption liquid HPLC detection controlled
Cefotetan tautomer < 0.5% (area normalization method).
Rejection filter, filter cake are eluted with aqueous sodium acetate solution, collect water phase.0 DEG C~5 DEG C of water phase temperature control, stir lower dropwise addition hydrochloric acid
Solution, 0 DEG C~5 DEG C of temperature control slowly adjust pH value of solution to 1.0~1.5, continue stirring and crystallizing 0.5 hour, rejection filter, filter cake pre-cooling
0~5 DEG C of purified water VII elutes, and dries to obtain cefotetan diacid.
4 cefotetan acid of table prepares feed ratio
The preparation of 4 Cefotetan Disodium of embodiment
Methyl ethyl ketone I is pumped into 300L reaction kettle, 0 DEG C~10 DEG C of temperature control, nitrogen displacement protection is added with stirring head
Spore replaces smooth diacid, and sodium chloride solution I is added after dissolution, stirs 0.5 hour, stands 30 minutes, and organic phase, water phase are collected in layering
It is extracted with methyl ethyl ketone II.Merge organic phase, organic phase is washed with sodium chloride solution II, is stirred 0.5 hour, and it is small to stand 1
When, organic phase is collected in liquid separation.
Addition dehydrated alcohol I in organic phase, 0 DEG C~10 DEG C of system temperature control, N2Under displacement protection, it is de- that active carbon stirring is added
Color 0.5 hour, filters pressing.It keeps at this temperature, filtrate N2Displacement protection, it is molten that sodium iso-octoate-ethyl alcohol is slowly added dropwise into filtrate
Liquid adjusts pH value of solution=7.8~8.3, stops being added dropwise, system continues stirring 1 hour, rejection filter, filter cake methyl ethyl ketone and second
The elution of alcohol mixed liquor, rejection filter.
Filter cake uses acetone I and acetone II to be beaten 1 hour in 0 DEG C~10 DEG C respectively, drying.Filter cake is depressurized in 20 DEG C~30 DEG C
It is 30 hours dry, Cefotetan Disodium 7.40kg is obtained, yield: 44.1%.
5 Cefotetan Disodium of table prepares feed ratio
5 purity of embodiment and foreign impurity matters test
Purity and foreign impurity matters test, knot are carried out according to embodiment 1-4 three batches of Cefotetan Disodiums being prepared and commercially available product
Fruit is shown in Table 6.
Commercially available product: cefotetan disodium for injection, specification 1g/ branch, APP Pharmaceuticals, LLC production.
6 purity of table and foreign impurity matters test
Claims (7)
1. a kind of composition of Cefotetan Disodium, the composition contains Cefotetan Disodium, II compound of formula, III chemical combination of formula
The compound of object and formula IV,
Wherein the content of Cefotetan Disodium is not less than 96.7%, and the content of II compound of formula is not higher than 0.3%, III compound of formula
Content be not higher than 1.0%, the content of IV compound of formula is not higher than 2.0%.
2. the composition of claim 1, wherein the content of Cefotetan Disodium is not less than 98.5%, and the content of II compound of formula is not
Higher than 0.25%, the content of III compound of formula is not higher than 0.2%, and the content of IV compound of formula is not higher than 0.5%.
3. the composition of claim 2, wherein the content of Cefotetan Disodium is not less than 98.8%, and the content of II compound of formula is not
Higher than 0.2%, the content of III compound of formula is not higher than 0.1%, and the content of IV compound of formula is not higher than 0.25%.
4. the composition of claim 3, the Cefotetan Disodium is amorphous forms.
5. the composition of any one of claim 1-4, II compound of formula is generated in following steps:
A) it is added methyl phenyl ethers anisole in reaction vessel, system is cooled to -5 DEG C to 5 DEG C, it is added alchlor, 20 DEG C to 30 of control system
Stirring and dissolving at DEG C is added methylene chloride I, is cooled to 0 DEG C to 5 DEG C after mixing evenly, obtains alchlor-methyl phenyl ethers anisole after dissolution
Solution,
Methylene chloride II is added in another reaction vessel, nitrogen protection is cooled to -5 DEG C to 5 DEG C, and chloracetyl 7-MAC is added, stirs
After mixing dissolution, -25 DEG C to -15 DEG C are cooled to, above-mentioned alchlor-methyl phenyl ethers anisole solution is added dropwise into system, process control is added dropwise
- 25 DEG C to -10 DEG C of system, drop finishes, and is stirred to react 1 hour,
B) 5 to 15 DEG C of temperature control system is slowly added to acetone-hydrochloric acid solution, finishes, and 10 DEG C to 20 DEG C of temperature control stirrings are molten to system
Solution continues stirring 0.5 hour, stands 30 minutes, layering, separates organic phase, and organic phase is washed with sodium chloride solution I, and collection has
Water phase is washed in machine phase, merging twice, the addition sodium chloride II into water phase, after stirring and dissolving, with ethyl acetate I, ethyl acetate II
It is extracted with ethyl acetate III, combined ethyl acetate phase,
C) ethyl acetate phase mutually merges with original machine, and 0 DEG C to 10 DEG C of temperature control, sodium bicarbonate solution is added dropwise, adjusts pH=6.9 to 7.1,
Stirring 0.5 hour, stratification collect water phase, and organic phase extracts with purified water, merge aqueous phase extracted twice, and 0 DEG C to 10 of temperature control
DEG C, diatomite drainage filters out suspended matter, collects filtrate, and filtrate uses ethyl acetate IV and ethyl acetate V to wash respectively, collects water
Ethyl acetate VI is added into water phase, 0 DEG C to 10 DEG C of temperature control, hydrochloric acid solution is added dropwise and adjusts water phase pH=1.5 to 2.0, drop finishes for phase
Stirring 0.5 hour, stratification collect ethyl acetate phase, and water phase uses ethyl acetate VII, ethyl acetate VIII to be stripped respectively, merges 3
Secondary ethyl acetate phase, sodium chloride solution II wash, and the stirring of organic phase anhydrous sodium sulfate is 1 hour dry, filters, and ethyl acetate Ⅸ drenches
It washes, filtrate stirs decoloration 0.5 hour, filters pressing with active carbon, and ethyl acetate Ⅹ elutes, -5 DEG C of filtrate temperature control~5 DEG C,
Wherein the mass ratio of the chloracetyl 7-MAC of step a), methylene chloride I, methylene chloride II, alchlor and methyl phenyl ethers anisole is 1:
1.1:12.9:0.82:2.6
Wherein in acetone-hydrochloric acid solution of step b), the mass ratio of acetone, hydrochloric acid and water is 6:0.23:8.19,
The wherein mass ratio of the sodium chloride solution I of step b), sodium chloride II, ethyl acetate I, ethyl acetate II and ethyl acetate III
For 6.8:0.5:2.2:1.5:0.7, and the mass ratio of sodium chloride and water is 0.5:6.3 in sodium chloride solution I, wherein step c)
Sodium bicarbonate solution in, the mass ratio of sodium bicarbonate and water is 0.2:0.9,
Wherein in the hydrochloric acid solution of step c), the mass ratio of hydrochloric acid and water is 0.19:1.7,
Wherein purified water, sodium chloride solution II, ethyl acetate IV, ethyl acetate V, ethyl acetate VI, ethyl acetate in step c)
VII, ethyl acetate VIII, ethyl acetate Ⅸ, ethyl acetate Ⅹ, anhydrous sodium sulfate, active carbon mass ratio be 4.2:4.5:2.6:
2.1:5.6:3.0:1.5:1:0.5:2:0.09 and the mass ratio of sodium chloride and water is 0.9:3.6 in sodium chloride solution II,
Wherein the structure of the chloracetyl 7-MAC is as follows:
6. the preparation method of any one of claim 1-4 composition, includes the following steps:
1) preparation of chloracetyl 7-MAC carboxylic acid
A) it is added methyl phenyl ethers anisole in reaction vessel, system is cooled to -5 DEG C to 5 DEG C, it is added alchlor, 20 DEG C to 30 of control system
Stirring and dissolving at DEG C is added methylene chloride I, is cooled to 0 DEG C to 5 DEG C after mixing evenly, obtains alchlor-methyl phenyl ethers anisole after dissolution
Solution,
Methylene chloride II is added in reaction vessel, nitrogen protection is cooled to -5 DEG C to 5 DEG C, and chloracetyl 7-MAC is added, and stirs molten
Xie Hou, is cooled to -25 DEG C to -15 DEG C, and above-mentioned alchlor-methyl phenyl ethers anisole solution is added dropwise into system, and process control system-is added dropwise
25 DEG C to -10 DEG C, drop finishes, and is stirred to react 1 hour,
B) 5 to 15 DEG C of temperature control system is slowly added to acetone-hydrochloric acid solution, finishes, and 10 DEG C to 20 DEG C of temperature control stirrings are molten to system
Solution continues stirring 0.5 hour, stands 30 minutes, layering, separates organic phase, and organic phase is washed with sodium chloride solution I, and collection has
Water phase is washed in machine phase, merging twice, the addition sodium chloride II into water phase, after stirring and dissolving, with ethyl acetate I, ethyl acetate II
It is extracted with ethyl acetate III, combined ethyl acetate phase,
C) ethyl acetate phase mutually merges with original machine, and 0 DEG C to 10 DEG C of temperature control, sodium bicarbonate solution is added dropwise, adjusts pH=6.9 to 7.1,
Stirring 0.5 hour, stratification collect water phase, and organic phase extracts with purified water, merge aqueous phase extracted twice, and 0 DEG C to 10 of temperature control
DEG C, diatomite drainage filters out suspended matter, collects filtrate, and filtrate uses ethyl acetate IV and ethyl acetate V to wash respectively, collects water
Ethyl acetate VI is added into water phase, 0 DEG C to 10 DEG C of temperature control, hydrochloric acid solution is added dropwise and adjusts water phase pH=1.5 to 2.0, drop finishes for phase
Stirring 0.5 hour, stratification collect ethyl acetate phase, and water phase uses ethyl acetate VII, ethyl acetate VIII to be stripped respectively, merges 3
Secondary ethyl acetate phase, sodium chloride solution II wash, and the stirring of organic phase anhydrous sodium sulfate is 1 hour dry, filters, and ethyl acetate Ⅸ drenches
It washes, filtrate stirs decoloration 0.5 hour, filters pressing with active carbon, and ethyl acetate Ⅹ elutes, and -5 DEG C to 5 DEG C of filtrate temperature control,
Wherein the mass ratio of the chloracetyl 7-MAC of step a), methylene chloride I, methylene chloride II, alchlor and methyl phenyl ethers anisole is 1:
1.1:12.9:0.82:2.6
Wherein in acetone-hydrochloric acid solution of step b), the mass ratio of acetone, hydrochloric acid and water is 6:0.23:8.19,
The wherein mass ratio of the sodium chloride solution I of step b), sodium chloride II, ethyl acetate I, ethyl acetate II and ethyl acetate III
For 6.8:0.5:2.2:1.5:0.7, and the mass ratio of sodium chloride and water is 0.5:6.3 in sodium chloride solution I, wherein step c)
Sodium bicarbonate solution in, the mass ratio of sodium bicarbonate and water is 0.2:0.9,
Wherein in the hydrochloric acid solution of step c), the mass ratio of hydrochloric acid and water is 0.19:1.7,
Wherein purified water, sodium chloride solution II, ethyl acetate IV, ethyl acetate V, ethyl acetate VI, ethyl acetate in step c)
VII, ethyl acetate VIII, ethyl acetate Ⅸ, ethyl acetate Ⅹ, anhydrous sodium sulfate, active carbon mass ratio be 4.2:4.5:2.6:
2.1:5.6:3.0:1.5:1:0.5:2:0.09 and the mass ratio of sodium chloride and water is 0.9:3.6 in sodium chloride solution II,
2) preparation of chloracetyl 7-MAC carboxylic acid sodium
- 10 DEG C to 0 DEG C of step 1) filtrate temperature control, is added dropwise sodium iso-octoate-aqueous isopropanol, and drop finishes, stirs at -10 DEG C to 0 DEG C of temperature control
Mix crystallization 0.5 hour, rejection filter, filter cake is eluted with ethyl acetate Ⅺ, and drying, filter cake is dried under reduced pressure 20 hours to 24 small in 25 DEG C
When, chloracetyl 7-MAC carboxylic acid sodium is obtained,
Wherein the mass ratio of sodium iso-octoate and isopropanol is 0.31:1 in sodium iso-octoate-aqueous isopropanol,
3) preparation of cefotetan acid
Neutral alumina is added in purified water, adds hydrochloric acid solution tune pH=0.8 to 1.2, is stirred 1 hour, rejection filter, filter cake is with pure
Change water mashing, rejection filter, repetitive operation dries until filtrate pH=3.7 to 4.5, for use,
It is pumped into purified water in reaction vessel, is cooled to 0 DEG C to 5 DEG C, chloracetyl 7-MAC carboxylic acid sodium, carbonic acid are sequentially added under stirring
Hydrogen sodium I and disodium ethylene diamine tetraacetate, stir lower dropwise addition 3- hydroxyl -4- carboxy thiol groups isothiazole three by -1 DEG C to 5 DEG C of system temperature control
Process control system pH=7.0 to 8.5 is added dropwise in sodium solution, and drop finishes, and adds II regulation system pH to 8.2 to 8.5 of sodium bicarbonate, controls
- 1 DEG C to 5 DEG C of temperature is stirred to react 3 hours, is passed through CO2- 1 DEG C to 5 DEG C of temperature control, it is anti-to continue stirring by regulation system pH to 7.8 to 8.0
It answers 22 hours, then uses CO2PH to 7.4 to 7.6 is adjusted, the reaction was continued 72 hours for -1 DEG C to 5 DEG C of temperature control,
Reaction terminates, rejection filter, collects filtrate, 0 DEG C to 10 DEG C of filtrate temperature control, adjusts pH=5.4 to 5.6 with hydrochloric acid solution, be added
The neutral alumina of above-mentioned activation processing, temperature control stirring 1 hour,
Rejection filter, filter cake are eluted with aqueous sodium acetate solution, are collected water phase, 0 DEG C to 5 DEG C of water phase temperature control, are stirred lower dropwise addition hydrochloric acid solution,
0 DEG C to 5 DEG C of temperature control slowly adjusts pH value of solution=1.0 to 1.5, continues stirring and crystallizing 0.5 hour, rejection filter, filter cake pre-cooling 0 to 5
The elution of DEG C purified water, dries to obtain cefotetan diacid,
Wherein chloracetyl 7-MAC carboxylic acid sodium, 3- hydroxyl -4- carboxy thiol groups isothiazole trisodium, neutral alumina, I and of sodium bicarbonate
Disodium ethylene diamine tetraacetate, sodium bicarbonate II mass ratio be 1:0.65:7.4:0.4:0.008:6.3,
Wherein the mass ratio of sodium acetate and water is 0.061:5.5 in aqueous sodium acetate solution,
4) preparation of Cefotetan Disodium
Methyl ethyl ketone I is added in reaction vessel, 0 DEG C to 10 DEG C of temperature control, nitrogen displacement protection is added with stirring step 3) preparation
Cefotetan diacid, be added sodium chloride solution after dissolution, stir 0.5 hour, stand 30 minutes, organic phase, water are collected in layering
It mutually being extracted with methyl ethyl ketone II, merges organic phase, organic phase is washed with sodium chloride solution, is stirred 0.5 hour, 1 hour is stood,
Organic phase is collected in liquid separation,
Dehydrated alcohol is added in organic phase, 0 DEG C to 10 DEG C of system temperature control, under nitrogen displacement protection, active carbon stirring decoloration is added
0.5 hour, filters pressing was kept at this temperature, and sodium iso-octoate-ethanol solution is slowly added dropwise into filtrate for the displacement protection of filtrate nitrogen,
PH value of solution=7.8 are adjusted to 8.3, stop being added dropwise, system continues stirring 1 hour, and rejection filter, filter cake methyl ethyl ketone and ethyl alcohol are mixed
It closes solution to elute, rejection filter,
Filter cake acetone is beaten 1 hour at 0 DEG C~10 DEG C, and drying, filter cake is dried under reduced pressure 30 hours in 20 DEG C to 30 DEG C, obtains cephalo
For smooth disodium,
Wherein the mass ratio of the methyl ethyl ketone I, methyl ethyl ketone II, dehydrated alcohol and sodium iso-octoate of step 4) is 7.8:1.2:
4.3:0.55, and the mass ratio of sodium iso-octoate and ethyl alcohol is 0.55:0.9 in sodium iso-octoate-ethanol solution,
Wherein in the methyl ethyl ketone and alcohol mixed solution of step 4), the mass ratio of methyl ethyl ketone and ethyl alcohol is 1.2:1.9,
Wherein the structure of the chloracetyl 7-MAC is as follows:
7. the preparation method of claim 6, wherein chloracetyl 7-MAC is prepared via a method which:
Methylene chloride, nitrogen protection, -25 DEG C to -10 DEG C addition 7-MAC of system temperature control, stirring and dissolving are added into reaction vessel
Afterwards, pyridine is added, -25 DEG C to -10 DEG C of temperature control, stirs lower dropwise addition chloracetyl chloride, drop finishes, and insulation reaction 1 hour,
Reaction terminates, and -5 DEG C to 5 DEG C of reaction system temperature control, uses sodium chloride-hydrochloric acid solution I and sodium chloride-hydrochloric acid solution II respectively
Washing, stirring stand 30 minutes, collect organic phase, -5 DEG C to 5 DEG C of temperature control, organic phase stirs decoloration 0.5 hour, pressure with active carbon
Filter, the stirring of filtrate anhydrous sodium sulfate is 1 hour dry, filtering, and filter cake eluent methylene chloride collects filtrate,
Muddy is concentrated under reduced pressure into for 20 DEG C to 30 DEG C of temperature control in filtrate reaction vessel, and anhydrous methanol, 20 DEG C to 30 DEG C stirrings are added
Material is released after uniformly, mechanical stirring gradient crystallization is stirred for crystallization 1 hour to 2 hours after 0 DEG C, and rejection filter, filter cake is drenched with methanol
It washes, is dried under reduced pressure in 40 DEG C 14 hours, obtains chloracetyl 7-MAC,
Wherein the mass ratio of 7-MAC, pyridine and chloracetyl chloride is 1:0.22:0.24,
Wherein the mass ratio of sodium chloride, hydrochloric acid and water is 0.3:0.15:6.05, sodium chloride-hydrochloric acid in sodium chloride-hydrochloric acid solution I
The mass ratio of sodium chloride, hydrochloric acid and water is 0.3:0.04:5.86 in solution II.
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| CN101870704A (en) * | 2009-04-21 | 2010-10-27 | 扬子江药业集团有限公司 | Method for purifying cefotetan acid crude products |
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