CN109111381A - A kind of preparation method of cilastatin - Google Patents
A kind of preparation method of cilastatin Download PDFInfo
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- CN109111381A CN109111381A CN201811277337.1A CN201811277337A CN109111381A CN 109111381 A CN109111381 A CN 109111381A CN 201811277337 A CN201811277337 A CN 201811277337A CN 109111381 A CN109111381 A CN 109111381A
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- cilastatin
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- sodium hydroxide
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- 229960004912 cilastatin Drugs 0.000 title claims abstract description 67
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000011347 resin Substances 0.000 claims abstract description 22
- 229920005989 resin Polymers 0.000 claims abstract description 22
- 229960003716 cilastatin sodium Drugs 0.000 claims abstract description 17
- JSAKRLDIZOGQTN-UHFFFAOYSA-M 4-[(2-hydroxynaphthalen-1-yl)diazenyl]naphthalene-1-sulfonate Chemical compound OC1=C(C2=CC=CC=C2C=C1)N=NC1=CC=C(C2=CC=CC=C12)S(=O)(=O)[O-] JSAKRLDIZOGQTN-UHFFFAOYSA-M 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 238000001694 spray drying Methods 0.000 claims abstract description 15
- 239000002250 absorbent Substances 0.000 claims abstract description 12
- 230000002745 absorbent Effects 0.000 claims abstract description 12
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229960001305 cysteine hydrochloride Drugs 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 117
- 238000010828 elution Methods 0.000 claims description 35
- 239000007788 liquid Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000000376 reactant Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 6
- 230000000384 rearing effect Effects 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 3
- 150000001944 cysteine derivatives Chemical class 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 239000000796 flavoring agent Substances 0.000 claims description 3
- 235000019634 flavors Nutrition 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000012976 tarts Nutrition 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 7
- 238000009826 distribution Methods 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000002245 particle Substances 0.000 abstract description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 4
- 229960002182 imipenem Drugs 0.000 description 4
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 4
- 229960002433 cysteine Drugs 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- -1 2- amino -2- carboxy ethyl Chemical group 0.000 description 1
- YURNCBVQZBJDAJ-UHFFFAOYSA-N 2-heptenoic acid Chemical compound CCCCC=CC(O)=O YURNCBVQZBJDAJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to cilastatin technical fields; and disclose a kind of preparation method of cilastatin; include the following steps; 1) in the environment of 0~70 DEG C; alkali and reaction dissolvent are mixed to get aqueous slkali, the chloro- 2- of (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali; and cysteine hydrochloride is added in the environment of -5~70 DEG C, reaction obtains the reaction solution of cilastatin in the environment of 25~80 DEG C.The preparation method of the cilastatin; the chloro- 2- of remaining compound (Z) -7- ((S) -2; 2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid content even 0 less than 0.3%; macroporous absorbent resin technology is preferable separating and purifying technology; the effect isolated and purified is more preferable; reaction process is relatively complete; and then lower impurity, yield and the higher product of purity are obtained, the spray drying process of use can be by the particle size of Cilastatin Sodium and size distribution control within the scope of suitable.
Description
Technical field
The present invention relates to cilastatin technical field, specially a kind of preparation method of cilastatin.
Background technique
Entitled [R- [R*, S* (Z)]] -7- [(2- amino -2- carboxy ethyl) the sulphur] -2- [[(2,2- of chemistry of cilastatin
Dimethvlcvclopropvl) carbonyl] amino] -2- heptenoic acid, molecular formula C12H26N2O5S, molecular weight 380.4, by its sodium salt with
Carbapenem antibiotics imipenem is used in combination, and can inhibit degradation of the dehydropeptidase of kidney to Imipenem, increases uropoiesis
The concentration of Imipenem in system reduces its renal toxicity, Imipenem/Cilastatin Sodium to improve the activity of Imipenem
It listed, is widely used in 1985 as a kind of extensive pedigree antibiotic.
According to a kind of method for preparing Cilastatin Sodium announced in Chinese invention CN 101307015A, the preparation west department
The method of his fourth sodium is suitble to industrialized production, but this prepares the method preparation of Cilastatin Sodium in the actual use process
Obtained finished product purity is not high, and product quality cannot ensure, drug effect is difficult to achieve the desired results, so propose a kind of Xi Sita
The preparation method of fourth solves the problems, such as above-mentioned propose.
Summary of the invention
(1) the technical issues of solving
In view of the deficiencies of the prior art, the present invention provides a kind of preparation methods of cilastatin, have finished product purity is high
The advantages of, solve that a kind of finished product purity that the method for preparing Cilastatin Sodium is prepared is not high, and product quality cannot protect
Barrier, drug effect are difficult to the problem of achieving the desired results.
(2) technical solution
To realize above-mentioned finished product purity is high purpose, the invention provides the following technical scheme: a kind of preparation side of cilastatin
Method, comprising the following steps:
1) in the environment of 0~70 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -
2,2- Dimethvlcvclopropvl formoxyls) -2- heptenoic acid is added in aqueous slkali, and half Guang ammonia is added in the environment of -5~70 DEG C
Acid hydrochloride, reaction obtains the reaction solution of cilastatin in the environment of 25~80 DEG C；
2) reaction solution of cilastatin obtained in step 1) is pure by macroporous absorbent resin in the environment of 5~45 DEG C
Change, then successively through water and elution, collect elution feed liquid, then elute feed liquid be successively concentrated, growing the grain and spraying dry
Dry step, elution feed liquid are concentrated into the chloro- 2- of raw material in step 1) (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptan
Organic solution is added in the reactant obtained after concentration for 1.5~10 times of olefin(e) acid quality, carries out growing the grain, and growing the grain temperature is -30
~30 DEG C, rearing crystal time is 4~16 hours, is spray-dried the moisture content < 3% into obtained cilastatin, drying
Inlet air temperature is 120~200 DEG C, and outlet temperature is 80~120 DEG C, obtains compound cilastatin；
3) sodium hydroxide and water are mixed, stirs 5~20min, whipping temp is 0~60 DEG C, is added what step 2) obtained
Cilastatin stirs 20~40min, is adjusted pH to 1.6~3.5 using sodium hydroxide solution, in sodium hydroxide solution, hydrogen-oxygen
The weight ratio for changing sodium and water is 0.5~2.5:2~20, obtains compound Cilastatin Sodium.
Preferably, the aqueous slkali be inorganic base or organic alkali solution, selected from sodium hydroxide, potassium hydroxide, sodium carbonate and
Sodium methoxide, reaction temperature are 30~90 DEG C, base amount and the chloro- 2- of (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2-
The mass ratio of heptenoic acid is 1: 3~1: 1.
Preferably, the reaction dissolvent is water, methanol or ethyl alcohol, and the macroporous absorbent resin is selected from low pole macroporous absorption
Resin.
Preferably, the organic solvent is selected from acetone, cyclohexanone, butanone and acetonitrile, and wherein acetone is best, described organic molten
The weight ratio of agent and concentrate is 9~12: 1.
Preferably, the method for concentration is to be evaporated under reduced pressure, and the cysteine hydrochloride is white crystals, and there have to be slight special
Smell tart flavour.
(3) beneficial effect
Compared with prior art, the present invention provides a kind of preparation method of cilastatin, have it is following the utility model has the advantages that
The preparation method of the cilastatin, by the environment of 0~70 DEG C, alkali and reaction dissolvent are mixed to get alkali
The chloro- 2- of (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali by solution, and -5
Cysteine hydrochloride is added in the environment of~70 DEG C, reaction obtains the reaction solution of cilastatin in the environment of 25~80 DEG C,
Shorten the reaction time, the reaction solution of cilastatin passes through purification with macroreticular resin in the environment of 5~45 DEG C, then successively passes through
Water and elution, collect elution feed liquid, then elute feed liquid be successively concentrated, growing the grain and spray drying step, elution
Feed liquid is concentrated into the chloro- 2- of raw material in step 1) (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid quality
1.5~10 times, organic solution is added in the reactant obtained after concentration, carries out growing the grain, growing the grain temperature is -30~30 DEG C, is supported
The brilliant time is 4~16 hours, is spray-dried the moisture content < 3% into obtained cilastatin, dry inlet air temperature
It is 120~200 DEG C, outlet temperature is 80~120 DEG C, obtains compound cilastatin, sodium hydroxide and water is mixed, stirring 5
~20min, whipping temp are 0~60 DEG C, and cilastatin is added, stirs 20~40min, is adjusted pH using sodium hydroxide solution
To 1.6~3.5, in sodium hydroxide solution, the weight ratio of sodium hydroxide and water is 0.5~2.5:2~20, obtains compound west department
His fourth sodium, the content of the chloro- 2- of remaining compound (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid are less than
0.3% even 0, macroporous absorbent resin technology is preferable separating and purifying technology, and the effect isolated and purified is more preferable, reaction process
It is relatively complete, and then lower impurity, yield and the higher product of purity are obtained, the spray drying process of use can be by Cilastatin Sodium
Particle size and size distribution control within the scope of suitable, improve the uniformity of ingredient in tablets.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution in the embodiment of the present invention is clearly and completely retouched
It states, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the present invention
In embodiment, every other implementation obtained by those of ordinary skill in the art without making creative efforts
Example, shall fall within the protection scope of the present invention.
Embodiment one:
A kind of preparation method of cilastatin, comprising the following steps:
1) in the environment of 0 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -2,2-
Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali, and cysteine hydrochloric acid is added in the environment of -5 DEG C
Salt, reaction obtains the reaction solution of cilastatin in the environment of 25 DEG C；
2) reaction solution of cilastatin obtained in step 1) is passed through to purification with macroreticular resin in the environment of 5 DEG C,
Elution feed liquid successively is collected through water and elution again, then elution feed liquid is successively concentrated, growing the grain and spray drying walk
Suddenly, elution feed liquid is concentrated into the chloro- 2- of raw material in step 1) (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid
Organic solution is added in the reactant obtained after concentration for 1.5 times of quality, carries out growing the grain, and growing the grain temperature is -30 DEG C, growing the grain
Time is 4 hours, is spray-dried the moisture content < 3% into obtained cilastatin, and dry inlet air temperature is 120
DEG C, outlet temperature is 80 DEG C, obtains compound cilastatin；
3) sodium hydroxide and water being mixed, stirs 5min, whipping temp is 0 DEG C, the cilastatin that step 2) obtains is added,
20min is stirred, is adjusted pH to 1.6 using sodium hydroxide solution, in sodium hydroxide solution, the weight ratio of sodium hydroxide and water is
0.5:2 obtains compound Cilastatin Sodium.
Aqueous slkali is inorganic base or organic alkali solution, is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and sodium methoxide, reaction
Temperature is 30~90 DEG C, the quality of base amount and the chloro- 2- of (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid
Than being 1: 3~1: 1, reaction dissolvent is water, methanol or ethyl alcohol, and macroporous absorbent resin is selected from low pole macroporous absorbent resin, organic
Solvent is selected from acetone, cyclohexanone, butanone and acetonitrile, and wherein acetone is best, and the weight ratio of organic solvent and concentrate is 9: 1, dense
Contracting method is to be evaporated under reduced pressure, and cysteine hydrochloride is white crystals, there is slight special odor tart flavour, by 0 DEG C of environment
Under, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -
2- heptenoic acid is added in aqueous slkali, and cysteine hydrochloride is added in the environment of -5 DEG C, is reacted in the environment of 25 DEG C
The reaction solution of cilastatin is obtained, the reaction time is shortened, the reaction solution of cilastatin passes through macroporous absorption in the environment of 5 DEG C
Purifying resin, then successively through water and elution, collect elution feed liquid, then elute feed liquid be successively concentrated, growing the grain and
Spray drying step, elution feed liquid are concentrated into raw material in step 1) (Z) -7- chloro- 2- ((S) -2,2- Dimethvlcvclopropvl formyl
Base) 1.5 times of -2- heptenoic acid quality, organic solution is added in the reactant obtained after concentration, carries out growing the grain, growing the grain temperature
Be -30 DEG C, rearing crystal time is 4 hours, is spray-dried moisture content < 3% into obtained cilastatin, it is dry into
Air temperature is 120 DEG C, and outlet temperature is 80 DEG C, obtains compound cilastatin, and sodium hydroxide and water are mixed, and stirs 5min,
Whipping temp is 0 DEG C, and cilastatin is added, and stirs 20min, is adjusted pH to 1.6 using sodium hydroxide solution, sodium hydroxide is molten
In liquid, the weight ratio of sodium hydroxide and water is 0.5:2, obtains compound Cilastatin Sodium, the chloro- 2- of remaining compound (Z) -7-
The content of ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is even 0 less than 0.3%, macroporous absorbent resin technology
For preferable separating and purifying technology, the effect isolated and purified is more preferable, and reaction process is relatively complete, so obtain impurity it is lower, receive
The spray drying process of rate and the higher product of purity, use can close the particle size of Cilastatin Sodium and size distribution control
Within the scope of suitable, the uniformity of ingredient in tablets is improved.
Embodiment two:
A kind of preparation method of cilastatin, comprising the following steps:
1) in the environment of 35 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -2,
2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali, and cysteine salt is added in the environment of 32.5 DEG C
Hydrochlorate, reaction obtains the reaction solution of cilastatin in the environment of 52.5 DEG C；
2) reaction solution of cilastatin obtained in step 1) is passed through to purification with macroreticular resin in the environment of 25 DEG C,
Elution feed liquid successively is collected through water and elution again, then elution feed liquid is successively concentrated, growing the grain and spray drying walk
Suddenly, elution feed liquid is concentrated into the chloro- 2- of raw material in step 1) (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid
Organic solution is added in the reactant obtained after concentration for 5.75 times of quality, carries out growing the grain, and growing the grain temperature is 0 DEG C, when growing the grain
Between be 10 hours, be spray-dried moisture content < 3% into obtained cilastatin, dry inlet air temperature is 160 DEG C,
Outlet temperature is 100 DEG C, obtains compound cilastatin；
3) sodium hydroxide and water are mixed, stirs 12.5min, whipping temp is 30 DEG C, and the west department that step 2) obtains is added
His fourth stirs 30min, is adjusted pH to 2.55 using sodium hydroxide solution, in sodium hydroxide solution, the weight of sodium hydroxide and water
Amount obtains compound Cilastatin Sodium than being 1.5:11.
By in the environment of 35 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -
2,2- Dimethvlcvclopropvl formoxyls) -2- heptenoic acid is added in aqueous slkali, and cysteine is added in the environment of 32.5 DEG C
Hydrochloride, reaction obtains the reaction solution of cilastatin in the environment of 52.5 DEG C, shortens the reaction time, the reaction of cilastatin
Liquid collects elution feed liquid, then through water and elution by purification with macroreticular resin, then successively in the environment of 25 DEG C
Elution feed liquid is successively concentrated, growing the grain and spray drying step, elution feed liquid are concentrated into the chloro- 2- of raw material in step 1) (Z) -7-
5.75 times of ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid quality are added in the reactant obtained after concentration
Organic solution carries out growing the grain, and growing the grain temperature is 0 DEG C, and rearing crystal time is 10 hours, is spray-dried into obtained cilastatin
Moisture content < 3%, dry inlet air temperature be 160 DEG C, outlet temperature be 100 DEG C, compound cilastatin is obtained, by hydrogen
22.5min is stirred in sodium oxide molybdena and water mixing, and whipping temp is 30 DEG C, and cilastatin is added, stirs 30min, uses sodium hydroxide
Solution adjusts pH to 2.55, and in sodium hydroxide solution, the weight ratio of sodium hydroxide and water is 1.5:11, obtains compound west department
His fourth sodium, the content of the chloro- 2- of remaining compound (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid are less than
0.3% even 0, macroporous absorbent resin technology is preferable separating and purifying technology, and the effect isolated and purified is more preferable, reaction process
It is relatively complete, and then lower impurity, yield and the higher product of purity are obtained, the spray drying process of use can be by Cilastatin Sodium
Particle size and size distribution control within the scope of suitable, improve the uniformity of ingredient in tablets.
Except it is above it is different in addition to, the present embodiment two it is other identical as above-described embodiment one, and the present embodiment two is same
Has the advantages that such as above-described embodiment one, this is no longer going to repeat them.
Embodiment three:
A kind of preparation method of cilastatin, comprising the following steps:
1) in the environment of 70 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -2,
2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali, and cysteine hydrochloric acid is added in the environment of 70 DEG C
Salt, reaction obtains the reaction solution of cilastatin in the environment of 80 DEG C；
2) reaction solution of cilastatin obtained in step 1) is passed through to purification with macroreticular resin in the environment of 45 DEG C,
Elution feed liquid successively is collected through water and elution again, then elution feed liquid is successively concentrated, growing the grain and spray drying walk
Suddenly, elution feed liquid is concentrated into the chloro- 2- of raw material in step 1) (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid
Organic solution is added in the reactant obtained after concentration for 10 times of quality, carries out growing the grain, and growing the grain temperature is 30 DEG C, when growing the grain
Between 16 hours, be spray-dried moisture content < 3% into obtained cilastatin, dry inlet air temperature is 200 DEG C, out
Mouth temperature is 120 DEG C, obtains compound cilastatin；
3) sodium hydroxide and water are mixed, stirs 20min, whipping temp is 60 DEG C, and the Xi Sita that step 2) obtains is added
Fourth stirs 40min, is adjusted pH to 3.5 using sodium hydroxide solution, in sodium hydroxide solution, the weight of sodium hydroxide and water
Than obtaining compound Cilastatin Sodium for 2.5:20.
By in the environment of 70 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -
2,2- Dimethvlcvclopropvl formoxyls) -2- heptenoic acid is added in aqueous slkali, and cysteine salt is added in the environment of 70 DEG C
Hydrochlorate, reaction obtains the reaction solution of cilastatin in the environment of 80 DEG C, shortens the reaction time, the reaction solution of cilastatin exists
By purification with macroreticular resin in the environment of 45 DEG C, then successively elution feed liquid is collected, is then eluted through water and elution
Feed liquid is successively concentrated, growing the grain and spray drying step, elution feed liquid are concentrated into the chloro- 2- of raw material in step 1) (Z) -7-
10 times of ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid quality, being added in the reactant obtained after concentration has
Machine solution carries out growing the grain, and growing the grain temperature is 30 DEG C, and rearing crystal time is 16 hours, is spray-dried into obtained cilastatin
Moisture content < 3%, dry inlet air temperature be 200 DEG C, outlet temperature be 120 DEG C, compound cilastatin is obtained, by hydrogen
20min is stirred in sodium oxide molybdena and water mixing, and whipping temp is 60 DEG C, and cilastatin is added, and stirs 40min, molten using sodium hydroxide
Liquid adjusts pH to 3.5, and in sodium hydroxide solution, the weight ratio of sodium hydroxide and water is 2.5:20, obtains compound Xi Sita
The content of fourth sodium, the chloro- 2- of remaining compound (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is less than
0.3% even 0, macroporous absorbent resin technology is preferable separating and purifying technology, and the effect isolated and purified is more preferable, reaction process
It is relatively complete, and then lower impurity, yield and the higher product of purity are obtained, the spray drying process of use can be by Cilastatin Sodium
Particle size and size distribution control within the scope of suitable, improve the uniformity of ingredient in tablets.
Except it is above it is different in addition to, the present embodiment three it is other identical as above-described embodiment one, and the present embodiment three is same
Has the advantages that such as above-described embodiment one, this is no longer going to repeat them.
The beneficial effects of the present invention are:
By in the environment of 0~70 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7-
((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali, and is added in the environment of -5~70 DEG C
Cysteine hydrochloride, reaction obtains the reaction solution of cilastatin in the environment of 25-80 DEG C, shortens the reaction time, west department
The reaction solution of his fourth is collected by purification with macroreticular resin, then successively through water and elution in the environment of 5-45 DEG C
Feed liquid is eluted, then elution feed liquid is successively concentrated, growing the grain and spray drying step, elution feed liquid are concentrated into step 1) Central Plains
1.5-10 times for expecting the chloro- 2- of (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid quality, obtains after concentration
Reactant in be added organic solution, carry out growing the grain, growing the grain temperature is -30~30 DEG C, and rearing crystal time is 4-16 hour, is done by spraying
Moisture content < 3% in dry to obtained cilastatin, dry inlet air temperature are 120-200 DEG C, outlet temperature 80-
120 DEG C, compound cilastatin is obtained, sodium hydroxide and water are mixed, stirs 5-20min, whipping temp is 0-60 DEG C, is added
Cilastatin stirs 20-40min, is adjusted pH to 1.6-3.5 using sodium hydroxide solution, in sodium hydroxide solution, hydroxide
The weight ratio of sodium and water is 0.5~2.5:2~20, obtains compound Cilastatin Sodium, the chloro- 2- of remaining compound (Z) -7-
The content of ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is even 0 less than 0.3%, macroporous absorbent resin technology
For preferable separating and purifying technology, the effect isolated and purified is more preferable, and reaction process is relatively complete, so obtain impurity it is lower, receive
The spray drying process of rate and the higher product of purity, use can close the particle size of Cilastatin Sodium and size distribution control
Within the scope of suitable, the uniformity of ingredient in tablets is improved.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (5)
1. a kind of preparation method of cilastatin, which comprises the following steps:
1) in the environment of 0~70 DEG C, alkali and reaction dissolvent are mixed to get aqueous slkali, by the chloro- 2- of (Z) -7- ((S) -2,2-
Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is added in aqueous slkali, and cysteine salt is added in the environment of -5~70 DEG C
Hydrochlorate, reaction obtains the reaction solution of cilastatin in the environment of 25~80 DEG C；
2) reaction solution of cilastatin obtained in step 1) is passed through to purification with macroreticular resin in the environment of 5~45 DEG C,
Elution feed liquid successively is collected through water and elution again, then elution feed liquid is successively concentrated, growing the grain and spray drying walk
Suddenly, elution feed liquid is concentrated into the chloro- 2- of raw material in step 1) (Z) -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid
Organic solution is added in the reactant obtained after concentration for 1.5~10 times of quality, carries out growing the grain, and growing the grain temperature is -30~30
DEG C, rearing crystal time is 4~16 hours, is spray-dried the moisture content < 3% into obtained cilastatin, dry air inlet
Temperature is 120~200 DEG C, and outlet temperature is 80~120 DEG C, obtains compound cilastatin；
3) sodium hydroxide and water are mixed, stirs 5~20min, whipping temp is 0~60 DEG C, and the west department that step 2) obtains is added
His fourth stirs 20~40min, is adjusted pH to 1.6~3.5 using sodium hydroxide solution, in sodium hydroxide solution, sodium hydroxide
Weight ratio with water is 0.5~2.5:2~20, obtains compound Cilastatin Sodium.
2. a kind of preparation method of cilastatin according to claim 1, which is characterized in that the aqueous slkali is inorganic base
Or organic alkali solution, be selected from sodium hydroxide, potassium hydroxide, sodium carbonate and sodium methoxide, reaction temperature be 30~90 DEG C, base amount with
(Z) mass ratio of the chloro- 2- of -7- ((S) -2,2- Dimethvlcvclopropvl formoxyl) -2- heptenoic acid is 1: 3~1: 1.
3. a kind of preparation method of cilastatin according to claim 1, which is characterized in that the reaction dissolvent be water,
Methanol or ethyl alcohol, the macroporous absorbent resin are selected from low pole macroporous absorbent resin.
4. a kind of preparation method of cilastatin according to claim 1, which is characterized in that the organic solvent is selected from third
Ketone, cyclohexanone, butanone and acetonitrile, wherein acetone is best, and the weight ratio of the organic solvent and concentrate is 9~12: 1.
5. a kind of preparation method of cilastatin according to claim 1, which is characterized in that the method for concentration is decompression
Evaporation, the cysteine hydrochloride is white crystals, there is slight special odor tart flavour.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115260067A (en) * | 2022-08-26 | 2022-11-01 | 同舟纵横（厦门）流体技术有限公司 | Method for purifying cilastatin mother liquor |
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| 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 |
| CN106518741A (en) * | 2016-10-21 | 2017-03-22 | 深圳市海滨制药有限公司 | Preparation method of cilastatin sodium active pharmaceutical ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN106518741A (en) * | 2016-10-21 | 2017-03-22 | 深圳市海滨制药有限公司 | Preparation method of cilastatin sodium active pharmaceutical ingredient |
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