CN110305033A - A kind of purification process of cilastatin sodium intermediate - Google Patents
A kind of purification process of cilastatin sodium intermediate Download PDFInfo
- Publication number
- CN110305033A CN110305033A CN201810227932.8A CN201810227932A CN110305033A CN 110305033 A CN110305033 A CN 110305033A CN 201810227932 A CN201810227932 A CN 201810227932A CN 110305033 A CN110305033 A CN 110305033A
- Authority
- CN
- China
- Prior art keywords
- heptenoate
- added
- halogenated
- dimethyl
- purification process
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical synthesis fields, specifically disclose a kind of purification process of Cilastatin Sodium intermediate, the present invention is by ((S) -2 of (E-Z) -7- halogenated -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate is added in acetone, stirring, a certain amount of Organic Alcohol is added, then purified water is added dropwise, pH is adjusted with acid after being added dropwise to 4-6, it is cooled to 0-10 DEG C, insulated and stirred 3-4h, is filtered, obtaining solid is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate.The HPLC purity of product Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate is made to reach 99.0% or more by technical solution of the present invention, E configuration impurity is reduced to 0.1% or less.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of purification process of cilastatin sodium intermediate.
Background technique
Cilastatin sodium (Z) -7- [(2R)-(2- amino -2- shuttle base ethyl) sulphur]-[(1s) -2,2- dimethylcyclopropane first
Amide groups] -2- heptenoic acid sodium, it and Imipenem combination are wide spectrum beta-Lactam antibiotics, can kill most of Grain-positive
With Gram negative aerobic and anaerobic pathogen bacterial and to the drug resistant bacterial strain of the antibiotic of most of beta-lactams.Control drug resistance
Important function has been played in the treatment of bacterium, zymogenic bacteria infection and immune deficient patients' infection, has been that clinical evaluation is very high anti-heavy
One of disease infection medicine.Structure is as follows:
At present about cilastatin sodium synthesis report it is more, be all mostly by synthesize 7- chloro-2-oxoheptanoate,
Then as Material synthesis target compound cilastatin sodium such as patent EP48301, CN101851186A,
CN102702051A, CN102875433 etc. in all these synthesis steps, can be related to reacting as follows:
In this reaction process, due to the generation of double bond, isomer impurities E-7- chloro -2 is inevitably introduced
((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, and content reaches 10% or more, with reaction into
Row, which eventually generates the isomer impurities of cilastatin sodium, and can generate other many unknown impurity in centre, most
Cause product impurity content exceeded eventually.
In terms of document report, patent US5147868, CN02821284.3 etc., which discloses heating in acid condition, makes E type
The method that isomers is isomerizated into cilastatin, but cilastatin, to thermo-responsive, isomerization process can equally generate a certain amount of
Impurity.
Patent CN101307015A application discloses a kind of method, is removed by the method for methylene chloride and re crystallization from toluene
Isomer impurities, step is firstly the need of hydrolysis 7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoic acid second
Ester obtains 7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoic acid acetic acid, then again with related solvents weight
Crystallization, in this opertions engineering, hydrolysis time 10 hours, time of repose 12 hours in recrystallization process, required time compared with
It is long, and be possible to will lead to the production of other impurities in hydrolytic process, cost is increased in industrial production, does not meet energy conservation
Emission reduction reduces the production requirement of cost.
Patent CN101792410A application discloses a kind of method, also need first to hydrolyze 7- chloro -2 ((S) -2,
2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, obtain ((S) -2,2- dimethyl-cyclopropane carboxamide of 7- chloro -2
Base) -2- heptenoic acid, aqueous slkali is then added, then acid is adjusted to the form of metal salt, operating process is cumbersome, reduces total
Body yield, hydrolytic process 8h, extends the process time, is unfavorable for industrialized production.
Patent CN102030674A refers to a kind of purification process of the intermediate, by ((S) -2,2- diformazan of 7- chloro -2
Basic ring cyclopropane carboxamide base) -2- heptenoate hydrolyzes to obtain corresponding acid, is then adjusted to corresponding salt with lye, passes through
Recrystallization improves compound purity repeatedly, is finally being adjusted with acid as corresponding acid.Although it is preferable that purity can be obtained in the method
Midbody compound, but hydrolysis and repeated recrystallize decline the yield of compound, technological operation is many and diverse, is unfavorable for dropping
Low cost and plant operations.
A kind of method that patent CN102875433A refers to purifying also first hydrolyzes relevant ester, then with dense
Hydrochloric acid is at 25-30 DEG C.Under the conditions of stir 3-6 hours, then use toluene and water washing, use mix reagent (n-hexane/bis- under low temperature
Isopropyl ether volume ratio is 1/3), to be slowly cooled to 0-5 DEG C, filters and is simultaneously washed with normal heptane, this process solvent dosage is big, when operation
Between it is long, complex steps are unfavorable for industrialized production.
It is acid that method in summary, which is all by ester hydrolysis mostly, either refines its corresponding salt by purification acid and reaches
To the purpose of purifying, but all there is hydrolytic process overlong times, and produce the possibility of new impurity, and operate more numerous
It is trivial.Therefore, a kind of new purification process is explored, providing new path for the removal of cilastatin sodium impurity and industrialized production is
It is highly desirable.
Summary of the invention
In order to make up the defect and deficiency of the prior art, the present invention provides a kind of purifying sides of cilastatin sodium intermediate
The technical solution of method, this method is as follows:
(E-Z) -7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate is added to acetone
In, stirring is added a certain amount of Organic Alcohol, purified water is then added dropwise, pH to 4-6 is adjusted with acid after being added dropwise, is cooled to 0-10
DEG C, insulated and stirred 3-4h is filtered, and obtaining solid is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2-
Heptenoate.
Preferably, (E-Z) -7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate and third
The mass volume ratio of ketone is 1:1~2, and wherein quality is in terms of g, and volume is in terms of ml.
Preferably, the Organic Alcohol is selected from one or more of methanol, ethyl alcohol, isopropanol and tert-butyl alcohol；(E-Z)-
The mass volume ratio of ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate of 7- halogenated -2 and Organic Alcohol is 1:1
~2, wherein quality is in terms of g, and volume is in terms of ml.
Preferably, ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate of (E-Z) -7- halogenated -2 with it is pure
The mass volume ratio for changing water is 1:5~10, and wherein quality is in terms of g, and volume is in terms of ml.
Preferably, adjusting acid used in pH is one of acetic acid, sulfuric acid or hydrochloric acid；Adjust the quality point of acid used in pH
Number is 1~5%.
Preferably, in (E-Z) -7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate
Halogenated is chloro, bromo or fluoro.
Make product Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base)-by technical solution of the present invention
The HPLC purity of 2- heptenoate reaches 99.0% or more, and E configuration impurity is reduced to 0.1% or less.
Technical solution of the present invention step is simple, and impurity removal process is not performed under heating conditions, and it is new to reduce production
A possibility that impurity, and be not necessarily to (E-Z) -7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoic acid
Ethyl ester is hydrolyzed to corresponding acid or salt and can refine, and reduces in hydrolytic process, E configuration impurity is converted into other impurities
Possibility, while operating process is simplified, agents useful for same is cheap and easy to get, and relevant operation is easy, is the removal and industrialization of impurity
Production, provides effective thinking.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, it is thus understood that these embodiments are only used for
The purpose of illustration, does not limit the scope of the invention, at the same those of ordinary skill in the art done according to the present invention it is apparent
Change and modification be also contained within the scope of the invention.
The present invention does not limit crude product source, (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2-
Heptenoate can use EP48301, CN101851186A, CN102702051A, prepared by the methods of CN102875433.
(E-Z) -7- bromo -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate can be used such as lower section
Method preparation:
Using 7- bromo -2- oxoheptanoate as raw material, preparation method is the same as -2 ((S) -2,2- dimethyl of (E-Z) -7- chloro
Cyclopropanecarbonyl amido) -2- heptenoate.
(E-Z) -7- fluoro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate can be used such as lower section
Method preparation:
Using 7- fluoro -2- oxoheptanoate as raw material, preparation method is the same as -2 ((S) -2,2- dimethyl of (E-Z) -7- chloro
Cyclopropanecarbonyl amido) -2- heptenoate.
Embodiment 1
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with the hydrochloric acid that mass fraction is 1% after being added dropwise, is then cooled to 5 DEG C, insulated and stirred 3h, filters,
Obtaining solid 8.4g is Z-7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, and HPLC is pure
Degree 99.5%, E configuration impurity 0.06%.
Embodiment 2
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
20ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml isopropanol is added in stirring, is added dropwise
50ml purified water adjusts pH6 with the acetic acid that mass fraction is 5% after being added dropwise, is then cooled to 10 DEG C, insulated and stirred 3h,
It filters, obtaining solid 8.2g is Z-7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate,
HPLC purity 99.1%, E configuration impurity 0.09%.
Embodiment 3
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
15ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then the 20ml tert-butyl alcohol is added in stirring, is added dropwise
80ml purified water adjusts pH5 with the sulfuric acid that mass fraction is 1% after being added dropwise, is then cooled to 0 DEG C, insulated and stirred 3h, takes out
Filter, obtaining solid 8.5g is Z-7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, HPLC
Purity 99.0%, E configuration impurity 0.10%.
Embodiment 4
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, is added dropwise
100ml purified water adjusts pH6 with the acetic acid that mass fraction is 2% after being added dropwise, is then cooled to 5 DEG C, insulated and stirred 3h,
It filters, obtaining solid 8.3g is Z-7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, pure
Degree 99.1%, E configuration impurity 0.10%.
Embodiment 5
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
20ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 20ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with the hydrochloric acid that mass fraction is 5% after being added dropwise, is then cooled to 5 DEG C, insulated and stirred 3h, filters,
Obtaining solid 8.0g is Z-7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, and HPLC is pure
Degree 99.3%, E configuration impurity 0.07%.
Embodiment 6
Weigh (E-Z) -7- bromo -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with the hydrochloric acid that mass fraction is 1% after being added dropwise, is then cooled to 5 DEG C, insulated and stirred 3h, filters,
Obtaining solid 8.4g is Z-7- bromo -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, and HPLC is pure
Degree 99.4%, E configuration impurity 0.06%.
Embodiment 7
Weigh (E-Z) -7- fluoro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with the hydrochloric acid that mass fraction is 1% after being added dropwise, is then cooled to 5 DEG C, insulated and stirred 3h, filters,
Obtaining solid 8.5g is Z-7- fluoro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, and HPLC is pure
Degree 99.3%, E configuration impurity 0.06%.
Comparative example 1
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml butanone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with 1% dilute hydrochloric acid after being added dropwise, is then cooled to 5 DEG C, insulated and stirred 3h finally obtains oily liquid
Body can not filter, purification effect is not achieved.
Comparative example 2
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethylene glycol is added in stirring, is added dropwise
50ml purified water adjusts pH4 with 1% dilute hydrochloric acid after being added dropwise, and is then cooled to 5 DEG C, insulated and stirred 3h, filters, consolidate
Body 7.2g is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, HPLC purity
92.2%, E configuration impurity 1.6%.
Comparative example 3
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH1 with 1% dilute hydrochloric acid after being added dropwise, and is then cooled to 5 DEG C, insulated and stirred 3h, filters, obtains solid
7.8g is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, HPLC purity 94.2%,
E configuration impurity 0.7%.
Comparative example 4
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 40ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with 1% dilute hydrochloric acid after being added dropwise, and is then cooled to 20 DEG C, insulated and stirred 3h, filters, obtains solid
4.8g is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, HPLC purity 96.7%,
E configuration impurity 1.7%.
Comparative example 5
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
40ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 50ml is added dropwise
Purified water adjusts pH4 with 1% dilute hydrochloric acid after being added dropwise, and is then cooled to 5 DEG C, insulated and stirred 3h, filters, obtains solid
5.8g is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, HPLC purity 98.0%,
E configuration impurity 0.16%.
Comparative example 6
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10ml acetone is added in 10.0g (HPLC purity 85%, E configuration impurity 12%), then 10ml ethyl alcohol is added in stirring, and 20ml is added dropwise
Purified water adjusts pH4 with 1% dilute hydrochloric acid after being added dropwise, and is then cooled to 5 DEG C, insulated and stirred 3h, filters, obtains solid
6.8g is Z-7- halogenated -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate, HPLC purity 97.6%,
E configuration impurity 0.22%.
Comparative example 7
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
15.0g (HPLC purity 85%, E configuration impurity 12%), addition 30ml10% sodium hydroxide solution, HPLC monitoring reaction course,
It is reacted 8 hours at 30-45 DEG C.Toluene 10ml is added every time in hydrolysis gained reaction solution, washing reaction liquid is three times repeatedly.It discards
Organic phase is added concentrated hydrochloric acid acidification, adjusts the pH to 3.5 of water phase.The feed liquid layer is extracted three times with 25ml toluene, discards water phase,
After organic phase is dried over anhydrous sodium sulfate, filters and be evaporated under reduced pressure.45ml dehydrated alcohol is added in concentrate, is sufficiently stirred molten
Solution, is filtered to remove insoluble impurities.It is slowly added to 30% sodium hydroxide solution into above-mentioned filtrate, adjusts pH value to 7.0, stops
Sodium hydroxide solution is added dropwise, continues stirring 1.0 hours, reaction solution is concentrated under reduced pressure after pH stablizes.Concentrate is stood under low temperature
Crystallization, is collected by filtration a large amount of solids being precipitated in solution, is dried in vacuo ((S) -2,2- dimethylcyclopropane of (Z) -7- chloro -2
Formamido) -2- heptenoic acid sodium solid 7.7g, HPLC purity 97.2%, E configuration impurity 0.8%.
Comparative example 8
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
37.0g (HPLC purity 85%, E configuration impurity 12%), is cooled to 5-10 DEG C of addition 15g sodium hydroxide and 50ml water, in 25-30
Continue stirring 8 hours at DEG C, until ester layer disappears, separation of methylbenzene, water layer is washed with toluene, is adjusted water layer pH with 6N hydrochloric acid and is arrived
4.0-4.5, and extracted with 100ml toluene, chloro containing 7- -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoic acid
Toluene layer 100ml water washing, layering, in this reaction solution, isomer proportion is that Z:E is 90:10%, what above-mentioned steps obtained
Toluene layer with 100ml concentrated hydrochloric acid in 25-30 DEG C of stirring 3-6 hours until E isomer disappears, toluene layer 100ml water and 100ml
Salt water washing, after 20g sodium sulphate is dry, decompression lower volume is concentrated to 50%, be added at 50 DEG C 100ml mix reagent (just oneself
Alkane/diisopropyl ether volume ratio is 1/3), to be slowly cooled to 0-5 DEG C, filters and is washed with 20ml n-hexane, is dried in vacuo to obtain Z-7-
Chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoic acid 16.8g white solid, HPLC purity 97.7%, E structure
Type impurity is 0.6%.
Comparative example 9
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
36.0g (HPLC purity 85%, E configuration impurity 12%) is added in 60mL ethyl alcohol and the sodium hydroxide solution of 72g10%, heating
To 45-50 DEG C, insulated and stirred makes its reaction, and TLC monitors reaction process, about 10 hours end of reaction；Then tertbutyl ether is added
Washing reaction liquid three times, every time be added tertbutyl ether 100ml, discard organic layer, into water layer enriching hydrochloric acid be acidified, adjust pH to
Ethyl acetate extraction acidifying solution is added three times in 3-3.5, and the amount that ethyl acetate is added every time is 100ml, water-yielding stratum is abandoned, to acetic acid
Anhydrous sodium sulfate drying is added in methacrylate layer, then filters, and filtrate is concentrated under reduced pressure and simultaneously recycles ethyl acetate, it is viscous to obtain 31.2g brown
Thick liquid.
At room temperature by the brown of 20g (Z) -7- chloro- 2 ((S) -2,2- Dimethvlcvclopropvl formamido) -2- heptenoic acid (W)
Thick liquid is dissolved in 50ml methylene chloride, and 140ml toluene is then added, acquired solution is placed in 0 DEG C of standing after mixing evenly
12 hours, a large amount of solids being precipitated in solution are collected, vacuum drying obtains white chloro- 2 ((S) -2,2- dimethyl cyclopropyl of (Z) -7-
Base formamido) -2- heptenoic acid (W) solid 9.8g.Mother liquor being obtained after crystallization simultaneously and being concentrated under reduced pressure into constant weight, it is viscous to obtain 8.5g brown
According to the above method 20ml methylene chloride and 50ml toluene is added at room temperature in 8.5g viscous brown solution by thick solution, and 0 DEG C
Lower freezing 12 hours, collects the solid being precipitated in solution, and vacuum drying obtains white chloro- 2 ((S) -2,2- dimethyl of (Z) -7-
Cyclopropyl carboxamide base) -2- heptenoic acid (W) solid 1.9g.Front and back obtains ((S) -2,2- diformazan basic ring of (Z) -7- chloro- 2 altogether twice
Cyclopropylmethylamide base) -2- heptenoic acid (W) solid 10.7g, HPLC purity be 98.7%, E configuration impurity be 0.82%.
Comparative example 10
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
37.0g (HPLC purity 85%, E configuration impurity 12%), is added 50ml water and 15.1g sodium hydroxide, at 20-25 DEG C, by 24
The stirring of hour, must take isomer (Z) -7- chloro- 2- ((S) -2,2- dimethylcyclopropane of (E) form containing 10-13%
Ester amine base) -2- heptenoic acid sodium-salt aqueous solution.
To the chloro- 2- of (E, Z) -7- (S) -2,2- dimethylcyclopropane amide groups) it is added in -2- heptenoic acid sodium-salt aqueous solution
PH is adjusted to 3 with chloric acid aqueous solution by the toluene of 150ml.After layering, carried out after organic solvent layer is added in anhydrous magnesium sulfate
Filter.In extraction raffinate, the n-propylamine of 8.93g is added and turns round toluene distillation after stirring 1 hour, obtains the chloro- 2- of 40g (E, Z) -7-
((S) -2,2- dimethylcyclopropane amide groups) -2- heptenoic acid n-propylamine sodium salt.
The ethyl acetate of 250ml is added to the chloro- 2- of (E, Z) -7- ((S) -2,2- dimethylcyclopropane amide groups) -2- heptan
In olefin(e) acid n-propyl amine salt, heating makes to melt completely, is cooled back to 0 DEG C, forms crystallization, then filters, in 40 DEG C of progress vacuum
It is dry, obtain the chloro- 2- of 25g (Z) -7- ((S) -2,2- dimethylcyclopropane amide groups) -2- heptenoic acid tert-butylamine salt, HPLC purity
It is 95.8%.The process that above-mentioned 25g crystallization is recrystallized using the ethyl acetate of 250ml again must be taken repeatedly twice
The chloro- 2- of 21g (Z) -7- ((S) -2,2- dimethylcyclopropane amide groups) -2- heptenoic acid n-propylamine sodium salt, HPLC purity are
99.0%.It is completely dissolved the crystallization that the above-mentioned HPLC purity of 21g is 99.1% with the water of 200ml, pH is adjusted to 3 with chloric acid, filtering
Crystal is generated, by vacuum drying, obtains the chloro- 2- of (Z) -7- ((S) -2,2- dimethylcyclopropane amide groups) -2- heptene of 17.1g
Acid, HPLC purity are 99.2%, E configuration impurity 0.5%.
Comparative example 11
Weigh (E-Z) -7- chloro -2 ((S) -2,2- dimethyl-cyclopropane carboxamide base) -2- heptenoate crude product
10.0g (HPLC purity 85%, E configuration impurity 12%), with concentrated hydrochloric acid tune pH to 0.5 later by reaction mixture at 85-90 DEG C
Lower heating 30 minutes to obtain product HPLC purity 94.4%, E configuration impurity residue 0.7% for corresponding E structure body alienation.
Claims (8)
1. a kind of purification process of cilastatin sodium intermediate, which is characterized in that this method comprises the following steps: by (E-Z) -7-
Halogenated -2 ((S) -2,2- dimethylcyclopropane first phthalein amido) -2- heptenoate is added in acetone, and stirring is added a certain amount of
Then purified water is added dropwise in Organic Alcohol, pH to 4-6 is adjusted with acid after being added dropwise, and is cooled to 0-10 DEG C, insulated and stirred 3-4h, takes out
Filter, obtaining solid is Z-7- halogenated -2 ((S) -2,2- dimethylcyclopropane first phthalein amido) -2- heptenoate.
2. purification process according to claim 1, which is characterized in that ((S) -2,2- diformazan basic ring of (E-Z) -7- halogenated -2
Propane first phthalein amido) mass volume ratio of -2- heptenoate and acetone is 1:1~2, wherein quality is in terms of g, and volume is with ml
Meter.
3. purification process according to claim 1, which is characterized in that the Organic Alcohol is selected from methanol, ethyl alcohol, isopropanol
One or more of with the tert-butyl alcohol.
4. purification process according to claim 1, which is characterized in that ((S) -2,2- diformazan basic ring of (E-Z) -7- halogenated -2
Propane first phthalein amido) mass volume ratio of -2- heptenoate and Organic Alcohol is 1:1~2, wherein quality is in terms of g, and volume is with ml
Meter.
5. purification process according to claim 1, which is characterized in that ((S) -2,2- diformazan basic ring of (E-Z) -7- halogenated -2
Propane first phthalein amido) mass volume ratio of -2- heptenoate and purified water is 1:5~10, wherein quality in terms of g, volume with
Ml meter.
6. purification process according to claim 1, which is characterized in that adjusting acid used in pH is acetic acid, sulfuric acid or hydrochloric acid
One of.
7. purification process according to claim 1, which is characterized in that adjust the mass fraction of acid used in pH for 1~
5%.
8. purification process according to claim 1, which is characterized in that ((S) -2,2- diformazan basic ring of (E-Z) -7- halogenated -2
Propane first phthalein amido) it is halogenated for one of chloro, bromo or fluoro in -2- heptenoate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810227932.8A CN110305033B (en) | 2018-03-20 | 2018-03-20 | Purification method of cilastatin sodium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810227932.8A CN110305033B (en) | 2018-03-20 | 2018-03-20 | Purification method of cilastatin sodium intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110305033A true CN110305033A (en) | 2019-10-08 |
| CN110305033B CN110305033B (en) | 2020-08-28 |
Family
ID=68073302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810227932.8A Active CN110305033B (en) | 2018-03-20 | 2018-03-20 | Purification method of cilastatin sodium intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110305033B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111562333A (en) * | 2020-04-16 | 2020-08-21 | 丽珠集团新北江制药股份有限公司 | Preparation method of cilastatin sodium impurity C |
Citations (9)
| 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 |
| CN101386588A (en) * | 2008-08-28 | 2009-03-18 | 珠海联邦制药股份有限公司 | Method for preparing cilastatin acid |
| CN101792410A (en) * | 2009-12-29 | 2010-08-04 | 浙江工业大学 | Preparation method of cilastatin sodium |
| CN102702051A (en) * | 2011-03-26 | 2012-10-03 | 山东省新时代药业有限公司 | Preparation method of cilastatin sodium |
| CN102875433A (en) * | 2012-10-29 | 2013-01-16 | 江西金顿香料有限公司 | Preparation method of cilastatin acid |
| US20150126523A1 (en) * | 2013-11-01 | 2015-05-07 | Merial Limited | Antiparisitic and pesticidal isoxazoline compounds |
| CN104649948A (en) * | 2013-11-19 | 2015-05-27 | 江苏迪赛诺制药有限公司 | Cilastatin calcium crystal, preparation method and application thereof |
| CN107778331A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of method of purification of picoplatin |
-
2018
- 2018-03-20 CN CN201810227932.8A patent/CN110305033B/en active Active
Patent Citations (9)
| 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 |
| CN101386588A (en) * | 2008-08-28 | 2009-03-18 | 珠海联邦制药股份有限公司 | Method for preparing cilastatin acid |
| CN101792410A (en) * | 2009-12-29 | 2010-08-04 | 浙江工业大学 | Preparation method of cilastatin sodium |
| CN102702051A (en) * | 2011-03-26 | 2012-10-03 | 山东省新时代药业有限公司 | Preparation method of cilastatin sodium |
| CN102875433A (en) * | 2012-10-29 | 2013-01-16 | 江西金顿香料有限公司 | Preparation method of cilastatin acid |
| US20150126523A1 (en) * | 2013-11-01 | 2015-05-07 | Merial Limited | Antiparisitic and pesticidal isoxazoline compounds |
| CN104649948A (en) * | 2013-11-19 | 2015-05-27 | 江苏迪赛诺制药有限公司 | Cilastatin calcium crystal, preparation method and application thereof |
| CN107778331A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of method of purification of picoplatin |
Non-Patent Citations (2)
| Title |
|---|
| 仲崇超: "西司他丁中间体合成工艺研究", 《中国优秀硕士学位论文全文数据库（电子期刊）工程科技I辑》 * |
| 陈扬: "西司他丁钠及其E构型异构体的合成", 《中国优秀硕士学位论文全文数据库（电子期刊）工程科技I辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111562333A (en) * | 2020-04-16 | 2020-08-21 | 丽珠集团新北江制药股份有限公司 | Preparation method of cilastatin sodium impurity C |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110305033B (en) | 2020-08-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109761867B (en) | Vitamin D production by using lanolin as raw material3Is a new method for industrialization | |
| CN105330609B (en) | A kind of method for preparing LCZ696 | |
| CN105399754B (en) | A kind of preparation method of Cefamandole Nafate | |
| CN109678744B (en) | Method for continuously preparing glycine | |
| CN107963993A (en) | A kind of preparation method of high-purity ethiprole | |
| CN111170892B (en) | Synthesis method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) | |
| CN101792410A (en) | Preparation method of cilastatin sodium | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN110305033A (en) | A kind of purification process of cilastatin sodium intermediate | |
| CN101386588A (en) | Method for preparing cilastatin acid | |
| CN108084213B (en) | Preparation method of cefazedone sodium compound | |
| CN106588888B (en) | Method for preparing high-purity L-sunitinib malate | |
| CN110845354B (en) | Preparation method of cilastatin sodium intermediate | |
| CN109761868B (en) | Synthesis method of optically pure chlorprostenol | |
| CN106565776A (en) | Separating and purifying method for 4-(methyl hydroxyl phosphoryl)-2-carbonyl butyric acid | |
| CN108017658B (en) | Synthesis method of cefprozil | |
| CN111285781B (en) | Preparation method of cilastatin sodium key intermediate | |
| CN110642722A (en) | Method for preparing N, N-tetramethyl decamethylene diamine | |
| CN104649948B (en) | Cilastatin calcium crystal, preparation method and application thereof | |
| CN102491915B (en) | Method for preparing ubenimex hydrolysis intermediates | |
| CN109680016A (en) | A kind of preparation method of Prohexadione calcium | |
| CN110818679B (en) | Synthetic method of 4-bromobenzo [ b ] thiophene | |
| CN114957130B (en) | Purification method and application of high-purity 5-benzylidene hydantoin | |
| CN110872322B (en) | Preparation method of cefaloside acetate monohydrate and intermediate thereof | |
| CN110183355B (en) | Refining method of high-purity o-chloro mandelonitrile |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |