CN107556328A - Prepare the intermediate and its crystal of cephem compounds - Google Patents
Prepare the intermediate and its crystal of cephem compounds Download PDFInfo
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- CN107556328A CN107556328A CN201610518134.1A CN201610518134A CN107556328A CN 107556328 A CN107556328 A CN 107556328A CN 201610518134 A CN201610518134 A CN 201610518134A CN 107556328 A CN107556328 A CN 107556328A
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- 0 C*C1=C(C*)C*[C@]([C@]2NC(C(c3n[s]c(N)n3)=NOC(C)(C)*)=O)N1C2=O Chemical compound C*C1=C(C*)C*[C@]([C@]2NC(C(c3n[s]c(N)n3)=NOC(C)(C)*)=O)N1C2=O 0.000 description 4
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses the intermediate and its crystal for preparing cephem compounds, in particular to the intermediate for preparing cephalo spy and coughing up a ceremonial jade-ladle, used in libation, the crystal of intermediate and the method that cephalo spy coughs up a ceremonial jade-ladle, used in libation is prepared.The content that sulfuric acid cephalo spy coughs up a ceremonial jade-ladle, used in libation and significantly reduces impurity is prepared using the intermediate of solid form (amorphous and crystal), products therefrom high income, purity are good, post processing is simple, are more suitable for industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry art, is related to the intermediate and its crystal for preparing cephem compounds, specifically
It is related to and prepares the intermediate that cephalo spy coughs up a ceremonial jade-ladle, used in libation, the crystal of intermediate and prepares the method that cephalo spy coughs up a ceremonial jade-ladle, used in libation.
Background technology
It is a kind of cephalosporin antibacterial agent that cephalo spy, which coughs up a ceremonial jade-ladle, used in libation, and the antibacterial activity that cephalo spy coughs up a ceremonial jade-ladle, used in libation is combined from it with penicillin
The effect that albumen is combined, and suppress the biosynthesis of bacteria cell wall, FDA approval listings for its sulfate.Sulfuric acid cephalo
Spy coughs up chemical entitled 5- amino -4- { [(2- amino-ethyls) carbamyl] amino } -2- { [(6R, 7R) -7- ({ (2Z) -2- of a ceremonial jade-ladle, used in libation
(5- amino -1,2,4- thiadiazoles -3- bases) -2- [(1- carboxyl -1- methyl ethoxies) imino group] acetyl group } amino) -2- carboxylics
Base -8- oxo -5- thia -1- azabicyclos [4.2.0] oct-2-ene -3- bases] methyl } -1- methyl isophthalic acid H- pyrazoles sulfate monos
Salt, its chemical structural formula are as follows：
Compound patent application WO2004039814 discloses the preparation method that sulfuric acid cephalo spy coughs up a ceremonial jade-ladle, used in libation, as follows.
The route is with 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl
Ethoxy imino) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is initiation material to methoxybenzyl base ester, with 4-
[N- (2- t-butoxycarbonyl aminos ethyl)-carbamoylamino] -1- methyl -5- tritylamino pyrazoles direct polycondensation systems
Standby intermediate, then further reaction obtains sulfuric acid cephalo spy and coughs up a ceremonial jade-ladle, used in libation.The β of initiation material 7 of the route-[(Z) -2- (5- amino -
1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies imino group) acetylamino] -3- chloromethyls -3-
Cephem -4- formic acid is precipitated from Di Iso Propyl Ether to methoxybenzyl base ester and obtained.
WO2016025813 discloses 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxies
Carbonyl -1- methyl ethoxies imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to the crystalline substance of methoxybenzyl base ester
Body.
The preparation of a ceremonial jade-ladle, used in libation is coughed up in view of cephalo spy needs multiple steps and post processing is complicated, still needs to develop and new is more suitable for work
The preparation method of industry.
The content of the invention
On the one hand, there is provided herein a kind of formula (II ') compound of solid form, wherein, R1And R2It is each independently selected from
Hydroxyl protecting group.
In some embodiments, R1And R2It is each independently selected from the tert-butyl group, t-Butyldimethylsilyl, 4- methoxyl groups
Benzyl, 2- methoxy-benzyls or trityl group.
In some embodiments, the weight percentage of formula (II ') compound Chinese style (II ') compound of solid form
For more than 90%；In some embodiments, the weight percent of formula (II ') compound Chinese style (II ') compound of solid form
Content is 92%-96%；In some embodiments, the weight of formula (II ') compound Chinese style (II ') compound of solid form
Percentage composition is more than 97%.
In some embodiments, described solid form includes unformed, crystal and its mixture.
In some embodiments, there is provided the crystal composition of the crystal containing formula (II ') compound, wherein formula
The crystal of (II ') compound accounts for more than the 50% of crystal composition weight, it is therefore preferable to more than 80%, preferably for 90% with
On, more preferably more than 95%.
Formula (II ') compound has the structure of following formula (II) in some embodiments：
In some embodiments, there is provided unformed formula (II) compound.In some embodiments, there is provided nothing
Formula (II) compound of sizing, it has XRD spectrum as described in Figure 7.
In some embodiments, there is provided the crystal of formula (II) compound.In some embodiments, the crystal is
Solvate；In some embodiments, described crystal is the toluene solvate of formula (II) compound；In some embodiment party
In case, the crystal is essentially free of solvent；In some embodiments, the crystal is substantially free of an organic solvent and water
Point；In some embodiments, the crystal contains certain moisture.
In some embodiments, there is provided the crystal A of formula (II) compound, radiated using Cu-K α, it is in X-ray powder
It is about to have diffraction maximum at 21.96 in the 2 θ number of degrees in last diffracting spectrum；In some embodiments, formula (II) compound
Crystal A is radiated using Cu-K α, and it is about in the X-ray powder diffraction pattern to have diffraction maximum at 7.08,21.96 in the 2 θ number of degrees；
In some embodiments, the crystal A of formula (II) compound is radiated using Cu-K α, and it is in X-ray powder diffraction collection
In, it is about to have diffraction maximum at 7.08,11.00,14.14,21.96 in the 2 θ number of degrees；In some embodiments, the formula (II) is changed
The crystal A of compound is radiated using Cu-K α, its in the X-ray powder diffraction pattern, the 2 θ number of degrees be about 7.08,11.00,
14.14th, there is diffraction maximum at 17.10,19.10,21.96；In some embodiments, the crystal A of formula (II) compound makes
Radiated with Cu-K α, its in the X-ray powder diffraction pattern, the 2 θ number of degrees be about 7.08,11.00,14.14,17.10,
19.10th, there is diffraction maximum at 21.96,23.36,23.66,24.22,25.34；In some embodiments, formula (II) chemical combination
The crystal A of thing is radiated using Cu-K α, its in the X-ray powder diffraction pattern, the 2 θ number of degrees be about 7.08,11.00,14.14,
16.44th, there is diffraction maximum at 17.10,19.10,21.96,22.14,23.36,23.66,24.22,25.34.
In some embodiments, the crystal A of formula (II) compound is radiated using Cu-K α, and it is in X-ray powder
In diffracting spectrum, there is XRD spectrum substantially as shown in, it has following feature：
In some embodiments, there is provided crystal composition, it contains the crystal A of formula (II) compound, wherein formula
(II) the crystal A of compound accounts for more than the 50% of crystal composition weight, it is therefore preferable to more than 80%, preferably for 90% with
On, more preferably more than 95%.Wherein in addition to crystal A, crystal B and/or amorphous substance can be also included.
In some embodiments, crystal A is substantially free of water and organic solvent.In some embodiments, crystal A contains
There is a certain amount of toluene.In some embodiments, crystal A has the thermogravimetric analysis shown in DSC figures and Fig. 4 shown in Fig. 3
(TG) figure.
In some embodiments, there is provided the crystal B of formula (II) compound, radiated using Cu-K α, it is in X-ray powder
It is about to have diffraction maximum at 22.3 in the 2 θ number of degrees in last diffracting spectrum；In some embodiments, the crystalline substance of formula (II) compound
Body B is radiated using Cu-K α, and it is about in the X-ray powder diffraction pattern to have diffraction maximum at 6.32,22.30 in the 2 θ number of degrees；
In some embodiments, the crystal B of formula (II) compound is radiated using Cu-K α, its in the X-ray powder diffraction pattern,
It is about to have diffraction maximum at 6.32,10.78,15.62,19.30,22.3 in the 2 θ number of degrees；In some embodiments, the formula (II)
The crystal B of compound is radiated using Cu-K α, its in the X-ray powder diffraction pattern, the 2 θ number of degrees be about 6.32,10.78,
12.50th, there is diffraction maximum at 15.18,15.62,19.30,21.24,21.54,22.3；In some embodiments, the formula
(II) the crystal B of compound is radiated using Cu-K α, its in the X-ray powder diffraction pattern, the 2 θ number of degrees be about 6.32,
10.78th, there is diffraction maximum at 12.50,15.18,15.62,17.84,19.30,19.74,21.24,21.54,22.30.
In some embodiments, the crystal B of formula (II) compound is radiated using Cu-K α, and it is in X-ray powder
In diffracting spectrum, there is XRD spectrum substantially as shown in Figure 2, it has following feature：
In some embodiments, there is provided crystal composition, it contains the crystal B of formula (II) compound, wherein formula
(II) the crystal B of compound accounts for more than the 50% of crystal composition weight, it is therefore preferable to more than 80%, preferably for 90% with
On, more preferably more than 95%.Wherein in addition to crystal B, crystal A and/or amorphous substance can be also included.
In some embodiments, crystal B is toluene compound；In some embodiments, crystal B has shown in Fig. 5
DSC schemes and thermogravimetric analysis (TG) figure shown in Fig. 6.
Another aspect, there is provided herein the preparation method of formula (II ') compound of solid form, including：In organic solvent
In the presence of, formula (I ') compound is reacted with iodating agent, wherein R1And R2Hydroxyl protecting group is each independently selected from, described is organic
Solvent includes but is not limited to acetone, N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAc), dichloromethane, second
Acetoacetic ester, tetrahydrofuran.
In some embodiments, described preparation method further comprises：(1) prepare containing formula (II ') compound and the
The mixture of one solvent, alternatively carry out in a heated condition；(2) mixture of step (1) mixes with the second solvent；(3)
Solid is separated, alternatively, dries isolated solid.Alternatively, step (2) still further comprises the temperature for reducing mixture
Degree.The first described solvent is the solvent that can dissolve formula (II ') compound, such as ethyl acetate.The second described solvent includes
But it is not limited to toluene and isopropyl ether.
In some embodiments, R1And R2It is each independently selected from the tert-butyl group, t-Butyldimethylsilyl, 4- methoxyl groups
Benzyl, 2- methoxy-benzyls or trityl group.
Described iodating agent is including well known to a person skilled in the art substitution reaction can occur with formula (I ') compound
Containing iodine reagent, the example that can be enumerated includes sodium iodide, KI.Wherein for formula (I ') compound molal quantity, make
With the iodating agent of excess.In some embodiments, for formula (I ') compound molal quantity, 1~10 times of iodine is used
Agent.In some embodiments, for formula (I ') compound molal quantity, 7 times of iodating agent is used.In some implementations
In scheme, the process of the iodide reaction can use the common detection methods (such as HPLC) of this area to monitor, such as formula (I ')
Compound<Terminating reaction when 2%.
In some embodiments, formula (I ') compound has the structure of formula (I)：
In some embodiments, there is provided herein the preparation method of the formula of solid form (II) compound, including：Having
In the presence of solvent, formula (I) compound is reacted with iodating agent, wherein described organic solvent includes but is not limited to acetone, N, N-
Dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAc), dichloromethane, ethyl acetate, tetrahydrofuran.
In some embodiments, there is provided the preparation method of unformed formula (II) compound, further comprise：
(1) mixture containing formula (II) compound and ethyl acetate is prepared, is alternatively carried out in a heated condition；(2) step (1) is mixed
Compound mixes with isopropyl ether；(3) solid is separated.
In some embodiments, there is provided the crystal A of formula (II) compound preparation method, further comprise：(1)
The mixture with the first solvent containing formula (II) compound is prepared, is alternatively carried out in a heated condition；(2) mixing of step (1)
Thing mixes with the second solvent；(3) separate and dry gained solid.The first described solvent is that can dissolve formula (II) compound
Organic solvent, such as ethyl acetate.The second described solvent includes but is not limited to toluene and isopropyl ether.
In some specific embodiments, there is provided the crystal A of formula (II) compound preparation method, further
Also include：(1) mixture containing formula (II) compound and ethyl acetate is prepared, is alternatively carried out in a heated condition；(2) step
(1) mixture mixes with toluene；(3) temperature of the mixture of step (2) is reduced, separates and dries gained solid.
In some embodiments, there is provided the crystal B of formula (II) compound preparation method, further comprise：(1)
The mixture with the first solvent containing formula (II) compound is prepared, is alternatively carried out in a heated condition；(2) mixing of step (1)
Thing mixes with the second solvent；(3) separating obtained solid.The first described solvent is the organic molten of dissolvable formula (II) compound
Agent, such as ethyl acetate.The second described solvent includes but is not limited to toluene and isopropyl ether.
In some specific embodiments, there is provided the crystal B of formula (II) compound preparation method, further also wrap
Include：(1) mixture containing formula (II) compound and ethyl acetate is prepared, is alternatively carried out in a heated condition；(2) step (1)
Mixture mixed with toluene；(3) separating obtained solid.Alternatively, step (2) also includes reducing temperature.
On the other hand, there is provided herein a kind of preparation method of formula (IV ') compound, including：
Formula (the II ') compound of solid form is reacted in the presence of an organic with formula (III ') compound,
Wherein R1And R2It is each independently selected from hydroxyl protecting group, R5And R6It is each independently selected from amino protecting group, A-For
Pharmaceutically acceptable anion；Formula (II ') compound of wherein described solid form includes unformed, crystal and its mixing
Thing.
In some embodiments, R1And R2It is each independently selected from the tert-butyl group, t-Butyldimethylsilyl, 4- methoxyl groups
Benzyl, 2- methoxy-benzyls or trityl group.In some embodiments, R5And R6It is each independently selected from the tert-butyl group, uncle
Butoxy carbonyl, 2- trimethyl silicane base oxethyl carbonyls or trityl.In some embodiments, A-For chlorion, bromide ion,
Iodide ion, sulfate radical, bisulfate ion, tosylate, methanesulfonate, trifluoracetic acid root or trifluoromethanesulfonic acid root.
In some embodiments, formula (IV ') compound has the structure such as following formula (IV)；In some embodiments,
Formula (IV ') compound has the structure such as following formula (IV -1).
In some embodiments, (III ') has the structure such as following formula (III).
In some embodiments, there is provided the method for formula (V) compound, including by above-mentioned formula (IV ') chemical combination
Thing deprotection base and/or by formula (IV ') compound and sulfuric acid contact, is changed into formula (V) compound.
In some embodiments, there is provided herein the preparation method of formula (IV) compound, including：The formula of solid form
(II) compound is reacted in the presence of an organic with formula (III) compound.
In some embodiments, formula (II) compound of described solid form is unformed formula (II) compound；
In some embodiments, formula (II) compound of described solid form is the crystal A of formula (II) compound；In some implementations
In scheme, formula (II) compound of described solid form is the crystal B of formula (II) compound.
In some embodiments, the weight percentage of formula (II) compound Chinese style (II) compound of solid form is
More than 90%；In some embodiments, the weight percentage of formula (II) compound Chinese style (II) compound of solid form
For 92%-96%；In some embodiments, the weight percent of formula (II) compound Chinese style (II) compound of solid form contains
Measure as more than 97%.
In the embodiment of some formula (IV) compounds process for production thereof, described organic solvent is N, N- dimethylacetamides
Amine, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran, dichloromethane；In some embodiments, silicon is further added
Alkane protective agent (such as 1,3- bis- (double trimethyl silyls) urea (BSU) or double (trimethyl silicon substrate) acetamides (BSA) of N, O-),
It is preferred that BSU and BSA combination；In some embodiments, iodating agent (such as KI, sodium iodide) can further be added；
In some embodiments, the iodating agent of catalytic amount is added；In some embodiments, mole of formula (II) compound and formula (III)
Than for 1:1~10；In some embodiments, the mol ratio of formula (II) compound and formula (III) is 1:2~6；In some implementations
In scheme, the mol ratio of formula (II) compound and formula (III) is 1:4.
In the embodiment of some formula (IV) compounds process for production thereof, reacted at 25 DEG C -80 DEG C；In some embodiment party
In case, 20~50 hours reaction time, 25~50 DEG C of reaction temperature.The process of the reaction can use the conventional inspection of this area
Survey method (such as HPLC) monitors, such as formula (II) compound<Terminating reaction when 2%.
Unless otherwise indicated, following term herein has following implication.
PMB refers to methoxy-benzyl；
Ph refers to phenyl；
DMF refers to N,N-dimethylformamide；
DMAc refers to DMAC N,N' dimethyl acetamide；
EA refers to ethyl acetate；
BSU refers to 1,3- bis- (double trimethyl silyls) urea；
BSA refers to N, double (trimethyl silicon substrate) acetamides of O-.
Herein, all patent documents being cited above are incorporated herein by reference.
Herein, formula (IV) and formula (V) compound are come using the formula (II) of solid form (amorphous and crystal),
Significantly reduce the content of double-bond isomerism impurity；Come formula (IV) and formula (V) chemical combination using the crystal of formula (II) compound
Thing, the content of aldehyde-based impurities can be substantially reduced.Products therefrom high income, purity are good, post processing is simple, are more suitable for industrial metaplasia
Production.A-Corresponding anion during to react, such as chlorion, bromide ion, iodide ion, sulfate radical, bisulfate ion, toluenesulfonic acid
Root, methanesulfonate, trifluoracetic acid root or trifluoromethanesulfonic acid root.It will be appreciated by those skilled in the art that contain double-bond isomerism impurity
Formula (IV) compound continue to react, such as deprotection base and/or when being changed into formula (V) compound with sulfuric acid contact, following formula
Double-bond isomerism impurity can also remove all protection groups accordingly and/or form corresponding salt.
The measure of content herein uses following analysis method, and using Aglient 1290UPLC instruments, chromatographic column is
Waters symmetry C18 (5 μm, 4.6mm × 250mm), wavelength 242nm, flow velocity 1.0ml/min, 30 DEG C of column temperature, mobile phase
A is 0.1% trifluoroacetic acid, and Mobile phase B is acetonitrile, by the way of gradient elution：
Unless otherwise indicated, the percentage composition that HPLC as described herein is measured is calculated according to area normalization method.
Herein, in HPLC analyses, when the cation of formula (IV) compound and formula (IV) compound has identical appearance
Between.
It is often spy for specific crystal formation by the diffraction spectrogram that crystalline compounds obtain it should be noted that in XRD
Sign property, wherein the relative intensity of bands of a spectrum (especially in low angle) may be because of crystallization condition, particle diameter and other measure bars
The difference of part and caused advantage orientation effect and change.Therefore, the relative intensity of diffraction maximum is not to targeted crystal formation
Characteristic, when judging whether identical with known crystal formation, it should be noted that the relative position at peak rather than their phase
To intensity.Peak position generally is represented away from d with 2 θ angles or crystal face in XRD spectrum, because the wavelength at 2 θ angles and incident X-rays has
Close, therefore represent more representative away from d with crystal face.There is simple conversion relation between the two：D=λ/2sin θ, wherein d
Represent crystal face away from, λ represent incident X-rays wavelength (for Cu-Ka,), θ is the angle of diffraction.For chemical combination of the same race
The crystal formation of the same race of thing, its XRD spectra have similitude on the whole, characterize the d values error of peak position typically within ± 2%,
Most of error is no more than ± 1%；The error of the value at 2 θ angles of peak position is characterized typically at ± 0.2 degree, relative intensity error can
It is larger, but variation tendency is consistent.In addition, judge crystal formation whether when should be noted that holding organic conception because being not one
Diffracted ray represents a thing phase, but a set of specific " d-I/I1 " data just represent a certain thing phase.It should be noted also that mixed
In the identification of compound, because the factors such as content decline can cause the missing of part diffracted ray, now, without relying in high-purity sample
It was observed that whole bands of a spectrum, or even several bands of a spectrum may also be characteristic to given crystallization.
Brief description of the drawings
Fig. 1 formulas (II) compound crystal A powder x-ray diffraction figure.
Fig. 2 formulas (II) compound crystal B powder x-ray diffraction figure.
Fig. 3 formulas (II) compound crystal A DSC figures.
Fig. 4 formulas (II) compound crystal A thermogravimetric analysis (TG) figure.
Fig. 5 formulas (II) compound crystal B DSC figures.
Fig. 6 formulas (II) compound crystal B thermogravimetric analysis (TG) figure.
The DSC figures of the unformed formulas of Fig. 7 (II) compound.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but present disclosure is not therefore limited in institute
Among the scope of embodiments stated, reagent and raw material used herein are commercially available.
Embodiment 1
7 β-[(1- tert-butoxycarbonyl -1- methyl ethoxies are sub- by (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2-
Amino) acetylamino] the preparation of -3- chloromethyl -3- cephem -4- formic acid to methoxybenzyl base ester
Under ice bath, by (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl second
Epoxide imino group) acetic acid (32g) adds potassium carbonate (11g) and methylsulfonyl in DMAC N,N' dimethyl acetamide (150mL) solution
Chlorine (12ml), the mixture is stirred 2 hours at 10 DEG C, the mixture is added in the mixture of ethyl acetate and water, will had
Machine layer water and salt water washing, the acid solution of activation is obtained, on the other hand, by 7 beta-amino -3- chloromethyl -3- heads under ice bath
Spore alkene -4- formic acid 4- methoxy-benzyls ester hydrochlorides (30g) are in the outstanding of the mixture of water (100ml) and ethyl acetate (100ml)
Supernatant liquid is adjusted to 6 with triethylamine, and at 10 DEG C, the acid solution of previously obtained activation is added dropwise into gained mixture with stirring, after
Continue and stir 1.5h at 5~10 DEG C, while the PH of the reactant mixture is maintained at 6 with triethylamine, the organic layer isolated is used
Water and salt water washing, and be evaporated in vacuo, concentrate is added into diisopropyl ether (150ml), and be collected by filtration to be formed it is heavy
Form sediment, and dry, obtain unformed 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyls -
1- methyl ethoxies imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to methoxybenzyl base ester.
Embodiment 2
7 β-[(1- tert-butoxycarbonyl -1- methyl ethoxies are sub- by (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2-
Amino) acetylamino] the preparation of -3- chloromethyl -3- cephem -4- formic acid to methoxybenzyl base ester
By (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxy imido
Base) acetic acid (32g) is dissolved in DMA, is cooled to 0~5 DEG C, add methylsufonyl chloride and potassium carbonate, temperature control
3~7 DEG C of reaction 1h, then add ethyl acetate and 1.7% aqueous hydrochloric acid solution, it is organic be added to 7 beta-amino -3- chloromethyls -
In the ethyl acetate of 3- cephem -4- formic acid 4- methoxy-benzyls ester hydrochlorides (30g) and the mixed system of purified water, temperature control 5
DEG C, by being continuously added the ethyl acetate solution of triethylamine by the pH value control of reaction system 3.2~3.8, after reaction terminates
A small amount of sodium chloride is added, continues to stir 30min, liquid separation, organic phase is washed with 20% sodium-chloride water solution, concentrates organic phase,
Toluene is added, continues to stir 5H, filtering, filter cake is dried in vacuo to obtain white solid.
Embodiment 3
To 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid to methoxybenzyl base ester (according to embodiment 1 method prepare
Obtain, 1.8g) 1,3- bis- (double trimethyl silyls) urea is added in solution in DMF (8mL)
(2.7g), the mixture is stirred 30 minutes.KI (0.6g) is added in the solution, the mixture is stirred 30 minutes.
At 78 DEG C by 4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl amido] -1- methyl -5- trityls
Amino-pyrazol (1.76g) is dissolved in DMF (9ml), and the solution is cooled into 45 DEG C.The solution is added to
7 previously obtained β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to methoxy-benzyl ester solution.30~35 DEG C of continuation of temperature control
7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (tertiary fourth oxygen of 1- is treated in reaction 30 hours or so, sampling HPLC analyses
Base carbonyl -1- methyl ethoxies imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to methoxybenzyl base ester
Surplus stops reaction when being less than 2%.After reaction terminates, reaction solution is added to ethyl acetate (20ml)/purified water of precooling
(20ml), liquid separation, aqueous phase ethyl acetate (20ml back extraction), merge organic phase, 20% sodium-chloride water solution (40ml) is washed, organic phase
Anhydrous sodium sulfate drying 1 hour, filtering, when filtrate is concentrated into 4ml or so, isopropyl ether 50ml will be added in concentrate, be cooled to 0
~10 DEG C, it is stirred overnight, filters, filter cake is dried in vacuo to obtain target product, is faint yellow solid (2.10g), yield 65%.HPLC
Measure, the peak area of peak area/target product of aldehyde-based impurities is 22%, the peak face of peak area/target product of double bond impurity
Product is 5%.
Embodiment 4
To 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid to methoxybenzyl base ester (according to embodiment 1 method prepare
Obtain, 1.8g) 1,3- bis- (double trimethyl silyls) urea is added in solution in DMA (8mL)
(2.7g), the mixture is stirred 30 minutes.KI (0.6g) is added in the solution, the mixture is stirred 30 minutes.
At 78 DEG C by 4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl amido] -1- methyl -5- trityls
Amino-pyrazol (1.76g) is dissolved in DMA (9ml), and the solution is cooled into 45 DEG C.The solution is added to
7 previously obtained β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to methoxy-benzyl ester solution.30~35 DEG C of continuation of temperature control
7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (tertiary fourth oxygen of 1- is treated in reaction 30 hours or so, sampling HPLC analyses
Base carbonyl -1- methyl ethoxies imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to methoxybenzyl base ester
Surplus stops reaction when being less than 2%.After reaction terminates, reaction solution is added to ethyl acetate (20ml)/purified water of precooling
(20ml), liquid separation, aqueous phase ethyl acetate (20ml back extraction), merge organic phase, 20% sodium-chloride water solution (40ml) is washed, organic phase
Anhydrous sodium sulfate drying 1 hour, filtering, when filtrate is concentrated into 4ml or so, isopropyl ether 50ml will be added in concentrate, be cooled to 0
~10 DEG C, it is stirred overnight, filters, filter cake is dried in vacuo to obtain target product, is faint yellow solid (2.19g), yield 68%.HPLC
Measure, the peak area of peak area/target product of aldehyde-based impurities is 21%, the peak face of peak area/target product of double bond impurity
Product is 3.1%.
Embodiment 5
To 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid to methoxybenzyl base ester (according to embodiment 2 method prepare
Obtain, 2.0g) 1,3- bis- (double trimethyl silyls) urea is added in solution in DMA (8mL)
(2.7g), the mixture is stirred 30 minutes.KI (0.6g) is added in the solution, the mixture is stirred 30 minutes.
At 78 DEG C by 4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl amido] -1- methyl -5- trityls
Amino-pyrazol (1.76g) is dissolved in DMA (9ml), and the solution is cooled into 45 DEG C.The solution is added to
7 previously obtained β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- chloromethyl -3- cephem -4- formic acid is to methoxy-benzyl ester solution.30~35 DEG C of continuation of temperature control
7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (tertiary fourth oxygen of 1- is treated in reaction 30 hours or so, sampling HPLC analyses
Base carbonyl -1- methyl ethoxies imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid is to methoxybenzyl base ester
Surplus stops reaction when being less than 2%.After reaction terminates, reaction solution is added to ethyl acetate (20ml)/purified water of precooling
(20ml), liquid separation, aqueous phase ethyl acetate (20ml back extraction), merge organic phase, 20% sodium-chloride water solution (40ml) is washed, organic phase
Anhydrous sodium sulfate drying 1 hour, filtering, when filtrate is concentrated into 4ml or so, isopropyl ether 50ml will be added in concentrate, be cooled to 0
~10 DEG C, it is stirred overnight, filters, filter cake is dried in vacuo to obtain target compound, is faint yellow solid (2.26g), yield 70%.
HPLC is determined, and the peak area of peak area/target product of double bond impurity is 5%.
Embodiment 6
7 β-[(1- tert-butoxycarbonyl -1- methyl ethoxies are sub- by (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2-
Amino) acetylamino] the preparation of -3- iodomethyl -3- cephem -4- formic acid to methoxybenzyl base ester
Acetone is added in reaction bulb, vacuum nitrogen is replaced 3 times, 0~-10 DEG C of temperature control, adds NaI (16g) stirrings 30min
Afterwards, 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies Asias are added
Amino) acetylamino] to methoxybenzyl base ester, (method according to embodiment 1 is prepared into -3- chloromethyl -3- cephem -4- formic acid
Arrive, 40g), temperature control adds NaI (4g) and continued after stirring 2 hours, sampling HPLC is detected to 7 after 0~-10 DEG C are reacted 4 hours
β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies imino group) acetyl
Amino] -3- chloromethyl -3- cephem -4- formic acid is to methoxybenzyl base ester surplus<When 1%, stop reaction, by reaction solution plus
Enter pre- EA (the 500ml)/H for being cooled to 0~10 DEG C2In O (500ml), liquid separation is stirred, collects organic phase, aqueous phase EA (300ml) extractions
Take, merge organic phase, 10% Na2S2O3(300ml) solution washs 2 times, and saturated sodium-chloride (500ml) washs one time, organic phase
Anhydrous sodium sulfate drying 4 hours, filtering, when filtrate is concentrated into certain volume during 50ml or so, add toluene 1L, 20~30 DEG C of controls
Temperature continues stirring 6 hours, cooling, and 0~10 DEG C of temperature control is stirred overnight, and is filtered, and filter cake is detected as the Type B of title compound through XRD
Crystal, yield 90%.
Embodiment 7
7 β-[(1- tert-butoxycarbonyl -1- methyl ethoxies are sub- by (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2-
Amino) acetylamino] the preparation of -3- iodomethyl -3- cephem -4- formic acid to methoxybenzyl base ester
Acetone is added in reaction bulb, vacuum nitrogen is replaced 3 times, 0~-10 DEG C of temperature control, adds NaI (16g) stirrings 30min
Afterwards, 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies Asias are added
Amino) acetylamino] to methoxybenzyl base ester, (method according to embodiment 2 is prepared into -3- chloromethyl -3- cephem -4- formic acid
Arrive, 40g), temperature control adds NaI (4g) and continued after stirring 2 hours, sampling HPLC is detected to 7 after 0~-10 DEG C are reacted 4 hours
β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies imino group) acetyl
Amino] -3- chloromethyl -3- cephem -4- formic acid is to methoxybenzyl base ester surplus<When 1%, stop reaction, by reaction solution plus
Enter pre- EA (the 500ml)/H for being cooled to 0~10 DEG C2In O (500ml), liquid separation is stirred, collects organic phase, aqueous phase EA (300ml) extractions
Take, merge organic phase, 10% Na2S2O3(300ml) solution washs 2 times, and saturated sodium-chloride (500ml) washs one time, organic phase
Anhydrous sodium sulfate drying 4 hours, filtering, when filtrate is concentrated into certain volume during 50ml or so, add toluene 1L, 20~30 DEG C of controls
Temperature continues stirring 6 hours, cooling, and 0~10 DEG C of temperature control is stirred overnight, and is filtered, and filter cake is dried in vacuum overnight to obtain yellow solid 39g,
Yield 86%, it is the A type crystal of title compound.
Embodiment 8
7 β-[(1- tert-butoxycarbonyl -1- methyl ethoxies are sub- by (Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2-
Amino) acetylamino] the preparation of -3- iodomethyl -3- cephem -4- formic acid to methoxybenzyl base ester
Acetone is added in reaction bulb, vacuum nitrogen is replaced 3 times, 0~-10 DEG C of temperature control, adds NaI (16g) stirrings 30min
Afterwards, 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies Asias are added
Amino) acetylamino] to methoxybenzyl base ester, (method according to embodiment 2 is prepared into -3- chloromethyl -3- cephem -4- formic acid
Arrive, 40g), temperature control adds NaI (4g) and continued after stirring 2 hours, sampling HPLC is detected to 7 after 0~-10 DEG C are reacted 4 hours
β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies imino group) acetyl
Amino] -3- chloromethyl -3- cephem -4- formic acid is to methoxybenzyl base ester surplus<When 1%, stop reaction, by reaction solution plus
Enter pre- EA (the 500ml)/H for being cooled to 0~10 DEG C2In O (500ml), liquid separation is stirred, collects organic phase, aqueous phase EA (300ml) extractions
Take, merge organic phase, 10% Na2S2O3(300ml) solution washs 2 times, and saturated sodium-chloride (500ml) washs one time, organic phase
Anhydrous sodium sulfate drying 4 hours, filtering, when filtrate is concentrated into certain volume during 50ml or so, add isopropyl ether 300ml, cooling
To 0~10 DEG C, it is stirred overnight, filters, filter cake is dried in vacuo to obtain faint yellow solid, is unformed title compound, yield
89%.
Embodiment 9
To 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid to methoxybenzyl base ester (according to embodiment 8 method prepare
Obtain, 2.0g) 1,3- bis- (double trimethyl silyls) urea is added in solution in DMA (8mL)
(2.7g), the mixture is stirred 30 minutes.KI (0.01g) is added in the solution, the mixture is stirred 30 minutes.
At 78 DEG C by 4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl amido] -1- methyl -5- trityls
Amino-pyrazol (1.76g) is dissolved in DMA (9ml), and the solution is cooled into 45 DEG C.The solution is added to
7 previously obtained β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid is to methoxy-benzyl ester solution.30~35 DEG C of continuation of temperature control
7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (tertiary fourth oxygen of 1- is treated in reaction 30 hours or so, sampling HPLC analyses
Base carbonyl -1- methyl ethoxies imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid is to methoxybenzyl base ester
Surplus stops reaction when being less than 2%.After reaction terminates, reaction solution is added to ethyl acetate (20ml)/purified water of precooling
(20ml), liquid separation, aqueous phase ethyl acetate (20ml back extraction), merge organic phase, 20% sodium-chloride water solution (40ml) is washed, organic phase
Anhydrous sodium sulfate drying 1 hour, filtering, when filtrate is concentrated into 40ml or so, isopropyl ether 40ml will be added in concentrate, be cooled to
0~10 DEG C, it is stirred overnight, filters, filter cake is dried in vacuo to obtain target product, is faint yellow solid (2.26g), yield 70%.
HPLC is determined, and the peak area of peak area/target product of aldehyde-based impurities is 11%, peak area/target product of double bond impurity
Peak area is 1.2%.
Embodiment 10
To 7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid to methoxybenzyl base ester (according to embodiment 6 method prepare
Obtain, 2.0g) 1,3- bis- (double trimethyl silyls) urea is added in solution in DMA (8mL)
(2.7g), the mixture is stirred 30 minutes.KI (0.01g) is added in the solution, the mixture is stirred 30 minutes.
At 78 DEG C by 4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl amido] -1- methyl -5- trityls
Amino-pyrazol (1.76g) is dissolved in DMA (9ml), and the solution is cooled into 45 DEG C.The solution is added to
7 previously obtained β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies
Imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid is to methoxy-benzyl ester solution.30~35 DEG C of continuation of temperature control
7 β-[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (tertiary fourth oxygen of 1- is treated in reaction 30 hours or so, sampling HPLC analyses
Base carbonyl -1- methyl ethoxies imino group) acetylamino] -3- iodomethyl -3- cephem -4- formic acid is to methoxybenzyl base ester
Surplus stops reaction when being less than 2%.After reaction terminates, reaction solution is added to ethyl acetate (20ml)/purified water of precooling
(20ml), liquid separation, aqueous phase ethyl acetate (20ml back extraction), merge organic phase, 20% sodium-chloride water solution (40ml) is washed, organic phase
Anhydrous sodium sulfate drying 1 hour, filtering, when filtrate is concentrated into 4ml or so, isopropyl ether 50ml will be added in concentrate, be cooled to 0
~10 DEG C, it is stirred overnight, filters, filter cake is dried in vacuo to obtain target compound, is faint yellow solid (2.26g), yield 70%,
HPLC is determined, and the peak area of peak area/target product of aldehyde-based impurities is 2.1%, peak area/target product of double bond impurity
Peak area is 2%.
Embodiment 11
At 78 DEG C by 4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl amido] -1- methyl -5- trityls
Amino-pyrazol (17.6g) is dissolved in DMA (90ml), by the solution be cooled to 45 DEG C it is stand-by.To 7 β-
[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies imino group) acetyl ammonia
Base] -3- iodomethyl -3- cephem -4- formic acid to methoxybenzyl base ester (method according to embodiment 7 is prepared, 20g) in N,
N, double (trimethyl silicon substrate) acetamides (BSA, 40g) of O- and 1,3- bis- (three are added in the solution of N- dimethyl acetamides (60ml)
Methyl silicane base) urea (BSU, 2g), vacuum nitrogen was replaced 3 times, by mixture stirring 30 minutes.KI (0.1g) is added, so
4- [N- (2- t-butoxycarbonyl aminos ethyl)-carbamoyl the amido] -1- methyl -5- trityl ammonia prepared is added afterwards
The DMA solution of base pyrazoles, 30~35 DEG C of temperature control continue reaction 30~40 hours, sampling HPLC analysis treat 7 β-
[(Z) -2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- (1- tert-butoxycarbonyl -1- methyl ethoxies imino group) acetyl ammonia
Base] -3- iodomethyl -3- cephem -4- formic acid stops reacting when being less than the surplus of methoxybenzyl base ester 2%.Reaction terminates
Afterwards, reaction solution is added to ethyl acetate (200ml)/purified water (200ml) of precooling, liquid separation, (200ml is anti-for aqueous phase ethyl acetate
Extraction), merge organic phase.20% sodium-chloride water solution (400ml) is washed, organic phase anhydrous sodium sulfate drying 4 hours, filtering, filtrate
When being concentrated into 40ml or so, isopropyl ether 500ml will be added in concentrate, be cooled to 0~10 DEG C, be stirred overnight, filtered, filter cake is true
Empty dry target product, be faint yellow solid (25.7g), purity 76%, yield 75%, and HPLC is determined, the peak of aldehyde-based impurities
The peak area of area/target product is 2.1%, and the peak area of peak area/target product of double bond impurity is 0.7%.
Embodiment 12
Compound (IV) 7g is dissolved in dichloromethane 20ml, adds methyl phenyl ethers anisole 7ml and three at -10 DEG C into the solution
Fluoroacetic acid 21ml, the mixture is warming up to room temperature and continues to stir 4h, and poured into isopropyl ether.Solid and drying is collected by filtration.
Solid is suspended in water, PH to regulation to 7. is filtered out into insoluble matter with concentrated hydrochloric acid at a temperature of less than 10 DEG C.Less than
The pH value of filtrate is adjusted to 1 with concentrated hydrochloric acid at a temperature of 10 DEG C, is filtered to remove insoluble matter.Filtrate is pure by preparing liquid phase separation
Change, collect corresponding eluent, eluent is concentrated into certain volume, 2.0M sulfuric acid is added, the mixture was stirred at room temperature
At night, it is cooled to 5~10 DEG C and continues to stir 2H, filtering, filter cake is dried in vacuo to obtain cephalo Luo Zan disulfates (0.7g).
Claims (10)
1. formula (II ') compound of solid form, wherein, R1And R2It is each independently selected from hydroxyl protecting group,
2. formula (II ') compound of claim 1, there is the structure of following formula (II),
3. formula (II ') compound of claim 2, is radiated using Cu-K α, its in the X-ray powder diffraction pattern, in 2 θ degree
There is diffraction maximum at number about 21.96；Preferably, there is diffraction maximum at 7.08,21.96；Preferably, 7.08,11.00,
14.14th, there is diffraction maximum at 21.96；Preferably, there is diffraction maximum at 7.08,11.00,14.14,17.10,19.10,21.96；
Preferably, there is diffraction at 7.08,11.00,14.14,17.10,19.10,21.96,23.36,23.66,24.22,25.34
Peak；Preferably, 7.08,11.00,14.14,16.44,17.10,19.10,21.96,22.14,23.36,23.66,24.22,
25.34 there is diffraction maximum at place.
4. formula (II ') compound of claim 2, is radiated using Cu-K α, its in the X-ray powder diffraction pattern, in 2 θ degree
There is diffraction maximum at number about 22.3；Preferably, there is diffraction maximum at 6.32,22.30；Preferably, 6.32,10.78,15.62,
19.30th, there is diffraction maximum at 22.3；Preferably, 6.32,10.78,12.50,15.18,15.62,19.30,21.24,21.54,
There is diffraction maximum at 22.3；Preferably, 6.32,10.78,12.50,15.18,15.62,17.84,19.30,19.74,21.24,
21.54th, there is diffraction maximum at 22.30.
5. formula (II ') compound of claim 2, it is unformed formula (II) compound.
The preparation method of formula 6. (IV ') compound, including：
Formula (the II ') compound of solid form is reacted in the presence of an organic with formula (III ') compound,
Wherein R1And R2It is each independently selected from hydroxyl protecting group, R5And R6It is each independently selected from amino protecting group, A-For pharmacy
Upper acceptable anion.
7. the preparation method of claim 6, wherein R1And R2It is each independently selected from the tert-butyl group, t-Butyldimethylsilyl, 4- first
Oxy-benzyl, 2- methoxy-benzyls or trityl group；R5And R6It is each independently selected from the tert-butyl group, tertbutyloxycarbonyl, 2- tri-
Methylsilyl ethoxy carbonyl or trityl；A-For chlorion, bromide ion, iodide ion, sulfate radical, bisulfate ion, toluene sulphur
Acid group, methanesulfonate, trifluoracetic acid root or trifluoromethanesulfonic acid root.
8. the preparation method of claim 6 or 7, wherein formula (IV ') compound have formula (IV) structure, formula (II ') compound tool
There is formula (II) structure, and formula (III ') compound has the structure of formula (III),
9. formula (II) compound of the preparation method of claim 8, wherein solid form is unformed, crystal or its mixture.
10. the preparation method of claim 9, wherein crystal include crystal A and crystal B, wherein crystal A, radiated using Cu-K α,
It is about in the X-ray powder diffraction pattern to have diffraction maximum at 21.96 in the 2 θ number of degrees；Preferably, crystal A is 7.08,21.96
There is diffraction maximum at place；Preferably, crystal A has diffraction maximum at 7.08,11.00,14.14,21.96；Preferably, crystal A 7.08,
11.00th, there is diffraction maximum at 14.14,17.10,19.10,21.96；Preferably, crystal A 7.08,11.00,14.14,17.10,
19.10, have diffraction maximum at 21.96,23.36,23.66,24.22,25.34；Preferably, crystal A 7.08,11.00,14.14,
16.44th, there is diffraction maximum at 17.10,19.10,21.96,22.14,23.36,23.66,24.22,25.34；Crystal B, uses Cu-
K α radiation, it is about in the X-ray powder diffraction pattern to have diffraction maximum at 22.3 in the 2 θ number of degrees；Preferably, crystal B exists
6.32nd, there is diffraction maximum at 22.30；Preferably, crystal B has diffraction maximum at 6.32,10.78,15.62,19.30,22.3；It is preferred that
Ground, crystal B have diffraction maximum at 6.32,10.78,12.50,15.18,15.62,19.30,21.24,21.54,22.3；It is preferred that
Ground, crystal B is at 6.32,10.78,12.50,15.18,15.62,17.84,19.30,19.74,21.24,21.54,22.30
There is diffraction maximum.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4929612A (en) * | 1987-04-17 | 1990-05-29 | Eisai Co., Ltd. | Thiadiazolylacetamide cephem derivatives |
| JPH04364189A (en) * | 1990-03-08 | 1992-12-16 | Fujisawa Pharmaceut Co Ltd | New cefem compound |
| CN1708502A (en) * | 2002-10-30 | 2005-12-14 | 安斯泰来制药有限公司 | Cephem compounds |
| CN102918047A (en) * | 2010-04-05 | 2013-02-06 | 盐野义制药株式会社 | Cephem compound having pseudo-catechol group |
| WO2016025813A1 (en) * | 2014-08-15 | 2016-02-18 | Merck Sharp & Dohme Corp. | Intermediates in the synthesis of cephalosporin compounds |
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2016
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|---|---|---|---|---|
| US4929612A (en) * | 1987-04-17 | 1990-05-29 | Eisai Co., Ltd. | Thiadiazolylacetamide cephem derivatives |
| JPH04364189A (en) * | 1990-03-08 | 1992-12-16 | Fujisawa Pharmaceut Co Ltd | New cefem compound |
| CN1708502A (en) * | 2002-10-30 | 2005-12-14 | 安斯泰来制药有限公司 | Cephem compounds |
| CN102918047A (en) * | 2010-04-05 | 2013-02-06 | 盐野义制药株式会社 | Cephem compound having pseudo-catechol group |
| WO2016025813A1 (en) * | 2014-08-15 | 2016-02-18 | Merck Sharp & Dohme Corp. | Intermediates in the synthesis of cephalosporin compounds |
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