CN104649948A - Cilastatin calcium crystal, preparation method and application thereof - Google Patents
Cilastatin calcium crystal, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a cilastatin calcium crystal, a preparation method and an application thereof. Under X-ray powder diffraction, the cilastatin calcium crystal has main characteristic peaks at positions with 2[theta] being 5.2+/-0.1 degree, 10.3+/-0.1 degree, 15.9+/-0.1 degree, 18.9+/-0.1 degree, 20.7+/-0.1 degree and 22.4+/-0.1 degree. The preparation method of the cilastatin calcium crystal includes following steps: (1) adding calcium chloride to an aqueous solution containing cilastatin or/and cilastatin salt; (2) regulating the pH value to 5-9 with an inorganic acid or an inorganic alkali; (3) adding an organic solvent which is mix-dissolvable with water to the system to perform stir-crystallization; and (4) filtering and drying an obtained crystal. By means of the cilastatin calcium crystal provided in the invention, cilastatin sodium being higher than 99.0% in HPLC purity can be conveniently prepared. The preparation method is simple in operation, is high in yield, is easy to carry out in large scale, and can provide an effective approach for preparing the cilastatin sodium being high in purity and stable in quality industrially in large scale.
Description
Technical field
The present invention relates to a kind of cilastatin calcium xln and its preparation method and application, belongs to technical field of organic chemistry.
Background technology
Cilastatin sodium (cilastatin sodium) is researched and developed by Merck company, and be a kind of kidney dehydrogenation pepx specific inhibitor efficiently, its chemical structure is such as formula shown in I.Cilastatin sodium can block the metabolism of carbapenem antibiotics imipenem in human kidney, alleviates the renal toxicity of medicine, increases the concentration of imipenum, heightens the effect of a treatment.The injection that cilastatin sodium and imipenum form with the part by weight of 1:1 has played vital role in anti-infectious treatment.
Current most document adopts 7 – halogen-2-oxoheptanoates or 7 – halogen-2-oxo-heptanoic acids to be starting raw material synthesis cilastatin sodium, and concrete synthetic route is as follows:
EP0028778, US5147868 and EP0048301 discloses with 7-chloro-2-oxoheptanoate (4) as raw material, pass through successively and S-(+)-2,2-dimethyl-cyclopropane carboxamide (8) and the obtained cilastatin sodium of Cys (7) reaction, have employed Dowex Zeo-karb purifying and freeze-drying process in this technique, total recovery only has 50%.Especially, owing to all there being a certain proportion of E formula isomer to generate in every single step reaction, these impurity how are removed most important.This technique is in order to remove the E formula isomer of cilastatin, the mode adjusting pH to 3.0 also to heat is adopted to make E formula isomer be converted into cilastatin, although E formula isomer can be controlled effectively, but high temperature causes degradation impurity and other impurity to generate, these impurity are difficult to purifying in subsequent technique, so that have impact on the quality of the finished product.In addition, the freeze-drying process of this technique is also unfavorable for suitability for industrialized production.
The purifying process of cilastatin is disclosed: first rough cilastatin solution regulated pH to 0.5 ~ 1.5 and be heated to 85-95 DEG C in Chinese patent literature CN1592737A, E formula isomer is made to be converted into cilastatin, again through purification with macroreticular resin, concentrated to obtain cilastatin, total recovery 37.6%.The problem that this technique exists and US5147868 is similar, has the generations such as degradation impurity in the process of heating isomerization reaction, be difficult to through resin column purifying, and yield is lower.
WO2006022511 has carried out some on the basis of above-mentioned technique to be improved: 1) in the preparation of 7-chloro-2 ((S)-2,2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid sodium (2), adopt acetonitrile crystallization to obtain the product of Z formula isomer/E formula isomer >20/1; 2) react at (2) and Cys (7) and terminate to adopt cationic exchange resin adsorption, obtain pure cilastatin amine salt or ammonium salt with ammoniacal liquor or amine wash-out, crystallization; Finally again obtain cilastatin sodium through Zeo-karb purifying, freeze-drying, from 7-chloro-2-oxoheptanoate to the yield of cilastatin ammonium be 35 ~ 47%.Chloro-2 ((S)-2 of 7-in this technique, 2-Dimethvlcvclopropvl formamido-) yield of-2-heptenoic acid sodium (2) is low by only 55%, and the E formula isomer still containing 5% in product affects subsequent reactions, whole technique uses Zeo-karb and freeze drying technology for twice, and process complexity is unfavorable for industrialization.
Chloro-2 ((S)-2 of 7-in technique disclosed in Chinese patent literature CN101792410A, 2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid sodium (2) and Cys (7) carry out condensation reaction, reaction solution is after acidifying, extraction, concentrating, loading carries out purifying to macroporous adsorptive resins, directly with sodium hydroxide solution wash-out, freeze-drying obtains cilastatin sodium solid, total recovery 31%.Chloro-2 ((S)-2 of 7-that this technique adopts the method for acetonitrile crystallization to obtain, 2-Dimethvlcvclopropvl formamido-) E formula isomer still containing 1-2% in-2-heptenoic acid sodium (2) affects subsequent reactions, and in the process to the 40 degree of high temperature decolourings of cilastatin sodium solution, have the generations such as degradation impurity, affect the quality of product.
Following improvement is had: 1) adopt methylene dichloride/toluene or dioxane/hexanaphthene crystallization to remove E formula isomer the 7-halogen-2 obtained ((S)-2,2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid (2) oily matter in technique disclosed in Chinese patent literature CN101307015A; 2) to react with Cys (7) at 7-halogen-2 ((S)-2,2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid (2) and terminate to adopt macroporous adsorbent resin HP-20 purifying to obtain cilastatin; 3) in the cilastatin aqueous solution, add sodium hydroxide, freeze-drying obtains cilastatin sodium, total recovery 30-32%.Can degradation impurity be produced in the process of this technique concentrated aqueous solution after resin purification and affect end product quality.
The technique that Chinese patent literature CN101386588A adopts is: by the double bond isomeric mixture of chloro-for 7-2 ((S)-2,2-Dimethvlcvclopropvl formamido-)-2-heptenoate under strongly acidic conditions isomerization obtain pure Z formula isomer (3); 2) methyl alcohol/acetonitrile crystallization is adopted to obtain cilastatin, total recovery 34% at (Z)-7-chloro-2 ((S)-2,2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid sodium (2) after reacting with Cys (7).The extremely sad filter of the cilastatin jelly that this technique produces in methyl alcohol/acetonitrile crystallisation process, is unfavorable for that industrialization is amplified.
Process characteristic disclosed in WO2011061609A is: 1) adopt isopropyl ether/normal hexane crystallization purifying 7-halogen-2 ((S)-2,2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid (2); 2) pure cilastatin ammonium salt is prepared; 3) adopt cation exchange resin column Indion-225 that cilastatin ammonium is converted into cilastatin, then react to obtain cilastatin sodium with sodium hydroxide, total recovery is low by only 22%.This technique is by preparing cilastatin ammonium removing impurity, and whole reaction process complex process is unfavorable for amplifying.
Chinese patent literature CN101200434A discloses (Z) chloro-2 ((S)-2 of-7-, 2-Dimethvlcvclopropvl formamido-) purification process of-2-heptenoic acid (2): first by chloro-for 7-2 ((S)-2,2-Dimethvlcvclopropvl formamido-) E formula isomer selective hydrolysis in acid condition in-2-heptenoate, then in the basic conditions to the hydrolysis of Z formula isomer and through ethyl acetate/normal hexane crystallization, obtain pure chloro-2 ((S)-2 of (Z)-7-, 2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid (2), yield 56%.
Following improvement has been made: 1) by chloro-for 7-2 ((S)-2 in technique disclosed in WO2007054771A2,2-Dimethvlcvclopropvl formamido-) there is isomerization under strongly acidic conditions and with hexane/isopropyl ether crystallization, obtain the Z formula isomer (2) of 99% purity in the double bond isomeric mixture of-2-heptenoic acid; 2) at chloro-2 ((S)-2 of 7-, 2-Dimethvlcvclopropvl formamido-)-2-heptenoic acid (2) and Cys (7) react and terminate to adopt that C4 ~ C8 alcoholic solvent extracts, crystallization obtains cilastatin crude product, then obtain pure cilastatin through water/dichloromethane/ethyl acetate crystallization; 3) cilastatin is dissolved in ethanol/triethylamine, adds 2 ethyl hexanoic acid sodium, separate out cilastatin sodium.This technique does not report yield.Due to the alcoholic solvent that cilastatin is insoluble in except methyl alcohol, this technique yield losses in extraction process is more, is also unfavorable for suitability for industrialized production.
As from the foregoing, prior art all can not meet the industrialization production requirements of cilastatin sodium well.
Summary of the invention
For the problems referred to above that prior art exists, the present invention aims to provide a kind of cilastatin calcium xln and preparation method thereof and is preparing the application in cilastatin sodium with this xln, prepares high purity, stay-in-grade cilastatin sodium to realize industrial mass.
For achieving the above object, the technical solution used in the present invention is as follows:
Cilastatin calcium xln of the present invention, under powder x-ray diffraction, is 5.2 ° ± 0.1 ° at angle of diffraction 2 θ, 10.3 ° ± 0.1 °, 15.9 ° ± 0.1 °, 18.9 ° ± 0.1 °, 20.7 ° ± 0.1 °, 22.4 ° ± 0.1 ° place has main characteristic peak.
Furtherly, cilastatin calcium xln of the present invention, under powder x-ray diffraction, it is 5.2 ° ± 0.1 ° at angle of diffraction 2 θ, 10.3 ° ± 0.1 °, 11.7 ° ± 0.1 °, 14.3 ° ± 0.1 °, 15.9 ° ± 0.1 °, 18.9 ° ± 0.1 °, 19.8 ° ± 0.1 °, 20.7 ° ± 0.1 °, 21.2 ° ± 0.1 °, 22.4 ° ± 0.1 ° place has characteristic peak.
Furtherly, cilastatin calcium xln of the present invention, has the powder x-ray diffraction spectrogram shown in Fig. 1.
Prepare a method for cilastatin calcium xln of the present invention, comprise the steps:
A) to containing cilastatin or/and add calcium chloride in the aqueous solution of cilastatin salt;
B) pH to 5 ~ 9 are regulated with mineral acid or mineral alkali;
C) add in system and can carry out stirring and crystallizing by the organic solvent miscible with water;
D) filter, dry, obtain described cilastatin calcium xln.
Step a) described in cilastatin salt comprise at least one in the sodium salt of cilastatin, ammonium salt and dimethylamine salt.
Step a) in calcium chloride add-on be that cilastatin is or/and 0.2 ~ 5 equivalent of cilastatin salt.
Step b) described in mineral acid comprise at least one in hydrochloric acid, sulfuric acid and phosphoric acid, described mineral alkali comprises at least one in sodium hydroxide and potassium hydroxide.
Step c) described in organic solvent comprise at least one in acetone, methyl alcohol, ethanol, Virahol, n-propyl alcohol, acetonitrile and tetrahydrofuran (THF).
Steps d) described in drying be 20 ~ 70 DEG C of vacuum-dryings.
Apply the method that cilastatin calcium xln of the present invention prepares cilastatin sodium, comprise the steps:
1. the cilastatin calcium xln by described is water-soluble, regulates pH=2 ~ 4, adopts HP20 type resin column purifying, obtained cilastatin acid;
2. in dehydrated alcohol, add cilastatin acid, drip organic bases clearly molten to system, after activated carbon decolorizing, drip the ethanol solution of 2 ethyl hexanoic acid sodium, filter, dry, obtain cilastatin sodium.
Step 2. in organic bases be preferably triethylamine, the dripping quantity of organic bases and 2 ethyl hexanoic acid sodium is 0.5 ~ 1.5 equivalent of cilastatin acid.
Compared with prior art; the present invention is by providing high purity, stable cilastatin calcium xln; obtain high purity (HPLC purity is greater than 99.0%) cilastatin sodium easily; and preparation technology is simple to operate; yield is high; be easy to realize mass-producing, prepare high purity for realizing industrial mass, stay-in-grade cilastatin sodium provides effective way.
Accompanying drawing explanation
Fig. 1 is the powder x-ray diffraction spectrogram of cilastatin calcium xln of the present invention;
Fig. 2 is the DSC spectrogram of cilastatin calcium xln of the present invention;
Fig. 3 is the TG spectrogram of cilastatin calcium xln of the present invention;
Fig. 4 is cilastatin calcium xln of the present invention
1h-NMR spectrogram;
Fig. 5 is cilastatin calcium xln of the present invention
13c-NMR spectrogram.
Embodiment
Below in conjunction with drawings and Examples, technical scheme of the present invention is described in further detail.
The preparation method of cilastatin raw material used in embodiment can refer to EP0028778, US5147868, EP0048301, CN1592737A, WO2006022511, CN101792410A, CN101307015A, CN101386588A, WO2011061609A, CN101200434A, WO2007054771A2, Journal of Medicinal Chemistry.1987, described in the documents such as 30 (6): 1074-1090.
Analytical instrument model used in embodiment and condition determination as follows:
1, powder x-ray diffraction analysis
Instrument: Dedye-Scherrer INEL CPS-120 powder x-ray diffraction; The condition of scanning: source of radiation α
1(wavelength
), α
2(wavelength
), strength ratio α
1/ α
2be 0.5, Cu (40KV, 30mA).
2, DSC condition determination
In encloses container, logical 50mL/min nitrogen gas stream, at 20 ~ 320 DEG C of temperature, heating rate is 10 DEG C/min, uses DSC Q2000 (TA company of the U.S.) equipment.
3, TGA condition determination
In encloses container, the nitrogen gas stream of logical 100mL/min, at 20 ~ 320 DEG C of temperature, heating rate is 10 DEG C/min, uses SDT Q600 (TA company of the U.S.) equipment.
4,
1h-NMR analyzes
Instrument: Brooker,Switzerland AV400,400MHz nmr analysis instrument; Measure solvent: D
2o.
5,
13c-NMR analyzes
Instrument: Brooker,Switzerland AV400,100MHz nmr analysis instrument; Measure solvent: D
2o.
6, HPLC purity testing
Instrument: Agilent1200/Waters2695;
Chromatographic column: Apex ODS, 250*4.6mm, 5 μm;
Chromatographic condition: F=2.0ml/min, T=50 DEG C, λ=210nm;
Working time: 56min.
Moving phase:
A) acetonitrile: 0.1%H
3pO
4=300:700;
B）0.1%H
3PO
4
| Time (min) | A(%) | B(%) |
| 0 | 15 | 85 |
| 30 | 100 | 0 |
| 46 | 100 | 0 |
| 56 | 15 | 85 |
Embodiment 1
Under argon shield, 10.0g cilastatin (purity is 97%) is dissolved in the purified water of 200mL, in stirred at ambient temperature to clearly molten; Add 3.2g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N NaOH solution to regulate pH to 7, drip 1000mL acetone; Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the acetone of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 8.5g white solid is cilastatin calcium xln, and molar yield is 80%, HPLC purity is 99.5%.
The powder x-ray diffraction spectrogram of gained cilastatin calcium xln is as shown in Figure 1: the peaks being 5.2 ° of places at angle of diffraction 2 θ are by force 100%; Be 5.2 ° ± 0.1 ° at angle of diffraction 2 θ, 10.3 ° ± 0.1 °, 11.7 ° ± 0.1 °, 14.3 ° ± 0.1 °, 15.9 ° ± 0.1 °, 18.9 ° ± 0.1 °, 19.8 ° ± 0.1 °, 20.7 ° ± 0.1 °, 21.2 ° ± 0.1 °, there is characteristic peak at 22.4 ° ± 0.1 ° place.
The DSC spectrogram of gained cilastatin calcium xln is as shown in Figure 2: 100 ~ 180 DEG C, have obvious absorption peak between 190 ~ 210 DEG C and 260 ~ 300 DEG C.
The TG spectrogram of gained cilastatin calcium xln is as shown in Figure 3: lose the weight of 4.6% at 129 ~ 189 DEG C, and illustrating containing 2 molecular waters in its molecule, is dihydrate.
Gained cilastatin calcium xln
1h-NMR spectrogram is as shown in Figure 4:
1H-NMR(D
2O，400MHz)δ0.78(dd，1H，J=4.8，J=7.6，cyclopropylC
H 2)；δ0.92(t，1H，J=5.2，cyclopropylC
H 2)；δ1.05(s，3H，cyclopropylC
H 3)；δ1.11(s，3H，cyclopropyl C
H 3)；δ1.45(m，2H，J=7.2，C=CH-CH
2-C
H 2)；δ1.55(m，2H，J=7.2，S-CH
2-C
H 2)；δ1.60(dd，1H，J=6.0，J=7.8，cyclopropyl C
H)；δ2.03(dt，2H，J=7.6，J=14.8，C=CH-C
H 2 )；δ2.53(t，2H，J=6.8，S-C
H 2)；δ2.94(dd，1H，J=8.0，J=16.0，NH
2-CH-C
H 2)；δ3.05(dd，1H，J=4.0，J=14.8，NH
2-CH-C
H 2)；δ3.82(dd，1H，J=4.4，J=7.6，NH
2-C
H)；δ6.38(t，1H，J=7.6，C=C
H)。
Gained cilastatin calcium xln
13c-NMR spectrogram is as shown in Figure 5:
13C-NMR(D2O，100MHz)δ18.71(cyclopropyl
CH
2)；δ19.21(cyclopropyl
CH
2)；δ21.74(cyclopropyl
CH
3)；δ25.96(cyclopropyl
CH
3)；δ26.65(S-CH
2-
CH
2)；δ27.05(C=CH-CH
2-
CH
2)；δ28.30(C=CH-
CH
2)；δ28.64(cyclopropyl
CH)；δ31.16(S-
CH
2-CH
2)；δ32.07(S-
CH
2-CH-NH
2)；δ53.65(
CH-NH
2)；δ130.50(
C=CH)；δ135.93(C=
CH)；δ172.11(=C-
COO
-)；δ172.94(CH(NH
2)-
COOH)；δ173.83(NH-
CO)。
Embodiment 2
Under argon shield, 10.0g cilastatin (purity is 96%) is dissolved in the purified water of 300mL, in stirred at ambient temperature to clearly molten; Add 1.6g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N KOH solution to regulate pH to 8, drip 1000mL methyl alcohol; Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the methyl alcohol of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 9.0g white solid is cilastatin calcium xln, and molar yield is 85%, HPLC purity is 99.4%.
The present embodiment gained cilastatin calcium xln also has shown in the powder x-ray diffraction spectrogram shown in Fig. 1, the DSC spectrogram shown in Fig. 2, the TG spectrogram shown in Fig. 3, Fig. 4
1shown in H-NMR spectrogram and Fig. 5
13c-NMR spectrogram.
Embodiment 3
Under argon shield, 10.0g cilastatin (purity is 96%) is dissolved in the purified water of 400mL, in stirred at ambient temperature to clearly molten; Add 4.8g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N NaOH solution to regulate pH to 6, drip 1000mL ethanol; Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the ethanol of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 8.7g white solid is cilastatin calcium xln, and molar yield is 82%, HPLC purity is 99.4%.
The present embodiment gained cilastatin calcium xln also has shown in the powder x-ray diffraction spectrogram shown in Fig. 1, the DSC spectrogram shown in Fig. 2, the TG spectrogram shown in Fig. 3, Fig. 4
1shown in H-NMR spectrogram and Fig. 5
13c-NMR spectrogram.
Embodiment 4
Under argon shield, 10.0g cilastatin (purity is 96%) is dissolved in the purified water of 200mL, in stirred at ambient temperature to clearly molten; Add 1.6g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N KOH solution to regulate pH to 7, drip 1000mL n-propyl alcohol; Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the n-propyl alcohol of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 8.6g white solid is cilastatin calcium xln, and molar yield is 81%, HPLC purity is 99.3%.
The present embodiment gained cilastatin calcium xln also has shown in the powder x-ray diffraction spectrogram shown in Fig. 1, the DSC spectrogram shown in Fig. 2, the TG spectrogram shown in Fig. 3, Fig. 4
1shown in H-NMR spectrogram and Fig. 5
13c-NMR spectrogram.
Embodiment 5
Under argon shield, 10.0g cilastatin (purity is 96%) is dissolved in the purified water of 300mL, in stirred at ambient temperature to clearly molten; Add 1.6g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N NaOH solution to regulate pH to 7, drip 1000mL Virahol; Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the Virahol of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 8.6g white solid is cilastatin calcium xln, and molar yield is 81%, HPLC purity is 99.5%.
The present embodiment gained cilastatin calcium xln also has shown in the powder x-ray diffraction spectrogram shown in Fig. 1, the DSC spectrogram shown in Fig. 2, the TG spectrogram shown in Fig. 3, Fig. 4
1shown in H-NMR spectrogram and Fig. 5
13c-NMR spectrogram.
Embodiment 6
Under argon shield, 10.0g cilastatin (purity is 96%) is dissolved in the purified water of 400mL, in stirred at ambient temperature to clearly molten; Add 1.6g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N KOH solution to regulate pH to 7, drip 1000mL acetonitrile; Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the acetonitrile of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 9.2g white solid is cilastatin calcium xln, and molar yield is 87%, HPLC purity is 99.3%.
The present embodiment gained cilastatin calcium xln also has shown in the powder x-ray diffraction spectrogram shown in Fig. 1, the DSC spectrogram shown in Fig. 2, the TG spectrogram shown in Fig. 3, Fig. 4
1shown in H-NMR spectrogram and Fig. 5
13c-NMR spectrogram.
Embodiment 7
Under argon shield, 10.0g cilastatin (purity is 96%) is dissolved in the purified water of 200mL, in stirred at ambient temperature to clearly molten; Add 1.6g Calcium Chloride Powder Anhydrous, be stirred to clearly molten; Adopt 10N NaOH solution to regulate pH to 7, drip 1000mL tetrahydrofuran (THF); Drip and finish, stir 2h; Filter, be the mixed solvent washing leaching cake that the tetrahydrofuran (THF) of 5:1 and water are formed by 60mL volume ratio, finally in 50 DEG C of vacuum-dryings, gained 9.0g white solid is cilastatin calcium xln, and molar yield is 85%, HPLC purity is 99.3%.
The present embodiment gained cilastatin calcium xln also has shown in the powder x-ray diffraction spectrogram shown in Fig. 1, the DSC spectrogram shown in Fig. 2, the TG spectrogram shown in Fig. 3, Fig. 4
1shown in H-NMR spectrogram and Fig. 5
13c-NMR spectrogram.
Embodiment 8
Under argon shield, 5.0g cilastatin calcium (purity is 99.3%) is dissolved in 250mL purified water, clearly molten in stirred at ambient temperature; drip hydrochloric acid and regulate pH=3, loading, to HP20 resin column, is washed to not having calcium ion to flow out by purified water; washed with methanol is adopted to collect product; in 40 DEG C of vacuum concentration except desolventizing, with acetone making beating, filter; in 40 DEG C of vacuum-dryings; gained 4.3g white solid is cilastatin acid, and molar yield is 91%, HPLC purity is 99.3%.
Under argon shield, in 75mL dehydrated alcohol, add 3.0g cilastatin acid (purity is 99.3%) in 25-30 DEG C, drip 0.87g triethylamine, stir clearly molten; Add 0.15g gac and 2.25g diatomite carries out decolouring 20min, the 15mL ethanol solution containing 1.65g2-Sodium Ethylhexanoate is dripped after membrane filtration, filter after stirring 2h, successively through ethanol and washing with acetone, in 40 DEG C of vacuum-dryings, gained 2.6g white solid is cilastatin sodium, and molar yield is 82%, HPLC purity is 99.2%.
Finally be necessary to herein means out: above embodiment is only for being described further technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. a cilastatin calcium xln, is characterized in that: under powder x-ray diffraction, is 5.2 ° ± 0.1 ° at angle of diffraction 2 θ, 10.3 ° ± 0.1 °, 15.9 ° ± 0.1 °, 18.9 ° ± 0.1 °, 20.7 ° ± 0.1 °, 22.4 ° ± 0.1 ° place has main characteristic peak.
2. cilastatin calcium xln as claimed in claim 1, it is characterized in that: under powder x-ray diffraction, is 5.2 ° ± 0.1 ° at angle of diffraction 2 θ, 10.3 ° ± 0.1 °, 11.7 ° ± 0.1 °, 14.3 ° ± 0.1 °, 15.9 ° ± 0.1 °, 18.9 ° ± 0.1 °, 19.8 ° ± 0.1 °, 20.7 ° ± 0.1 °, 21.2 ° ± 0.1 °, 22.4 ° ± 0.1 ° place has characteristic peak.
3. prepare a method for cilastatin calcium xln according to claim 1, it is characterized in that, comprise the steps:
A) to containing cilastatin or/and add calcium chloride in the aqueous solution of cilastatin salt;
B) pH to 5 ~ 9 are regulated with mineral acid or mineral alkali;
C) add in system and can carry out stirring and crystallizing by the organic solvent miscible with water;
D) filter, dry, obtain described cilastatin calcium xln.
4. method as claimed in claim 3, is characterized in that: step a) described in cilastatin salt comprise at least one in the sodium salt of cilastatin, ammonium salt and dimethylamine salt.
5. method as claimed in claim 3, is characterized in that: step a) in calcium chloride add-on be that cilastatin is or/and 0.2 ~ 5 equivalent of cilastatin salt.
6. method as claimed in claim 3, is characterized in that: step b) described in mineral acid comprise at least one in hydrochloric acid, sulfuric acid and phosphoric acid, described mineral alkali comprises at least one in sodium hydroxide and potassium hydroxide.
7. method as claimed in claim 3, is characterized in that: step c) described in organic solvent comprise at least one in acetone, methyl alcohol, ethanol, Virahol, n-propyl alcohol, acetonitrile and tetrahydrofuran (THF).
8. method as claimed in claim 3, is characterized in that: steps d) described in drying be 20 ~ 70 DEG C of vacuum-dryings.
9. application rights requires that the cilastatin calcium xln described in 1 prepares a method for cilastatin sodium, it is characterized in that, comprises the steps:
1. the cilastatin calcium xln by described is water-soluble, regulates pH=2 ~ 4, adopts HP20 type resin column purifying, obtained cilastatin acid;
2. in dehydrated alcohol, add cilastatin acid, drip organic bases clearly molten to system, after activated carbon decolorizing, drip the ethanol solution of 2 ethyl hexanoic acid sodium, filter, dry, obtain cilastatin sodium.
10. method as claimed in claim 9, is characterized in that: step 2. in organic bases be triethylamine, the dripping quantity of organic bases and 2 ethyl hexanoic acid sodium is 0.5 ~ 1.5 equivalent of cilastatin acid.
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|---|---|---|---|
| CN201310583452.2A CN104649948B (en) | 2013-11-19 | 2013-11-19 | Cilastatin calcium crystal, preparation method and application thereof |
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| CN110305033A (en) * | 2018-03-20 | 2019-10-08 | 鲁南制药集团股份有限公司 | A kind of purification process of cilastatin sodium intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006022511A1 (en) * | 2004-08-25 | 2006-03-02 | Dong Kook Pharm. Co., Ltd. | Novel process for the preparation of cilastatin sodium salt |
| CN101307015A (en) * | 2007-05-16 | 2008-11-19 | 深圳市海滨制药有限公司 | Process for preparing cilastatin sodium |
| WO2010005175A2 (en) * | 2008-07-09 | 2010-01-14 | (주)하이텍팜 | Novel crystalline cilastatin ammonium salts and preparation method thereof |
| WO2011061609A2 (en) * | 2009-11-19 | 2011-05-26 | Ranbaxy Laboratories Limited | Processes for the preparation of cilastatin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006022511A1 (en) * | 2004-08-25 | 2006-03-02 | Dong Kook Pharm. Co., Ltd. | Novel process for the preparation of cilastatin sodium salt |
| CN101307015A (en) * | 2007-05-16 | 2008-11-19 | 深圳市海滨制药有限公司 | Process for preparing cilastatin sodium |
| WO2010005175A2 (en) * | 2008-07-09 | 2010-01-14 | (주)하이텍팜 | Novel crystalline cilastatin ammonium salts and preparation method thereof |
| WO2011061609A2 (en) * | 2009-11-19 | 2011-05-26 | Ranbaxy Laboratories Limited | Processes for the preparation of cilastatin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305033A (en) * | 2018-03-20 | 2019-10-08 | 鲁南制药集团股份有限公司 | A kind of purification process of cilastatin sodium intermediate |
| CN110305033B (en) * | 2018-03-20 | 2020-08-28 | 鲁南制药集团股份有限公司 | Purification method of cilastatin sodium intermediate |
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