CN101307015B - Process for preparing cilastatin sodium - Google Patents
Process for preparing cilastatin sodium Download PDFInfo
- Publication number
- CN101307015B CN101307015B CN 200710099332 CN200710099332A CN101307015B CN 101307015 B CN101307015 B CN 101307015B CN 200710099332 CN200710099332 CN 200710099332 CN 200710099332 A CN200710099332 A CN 200710099332A CN 101307015 B CN101307015 B CN 101307015B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- dimethyl
- heptenoic acid
- cilastatin
- 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.)
- Active
Links
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
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing a compound called cilastatin sodium shown as a formula (I). Cilastatin is prepared by crystallizing and purifying (Z)-7-chlorine-2((S)-2, 2-dimethyl c-pr carbamoyl)-2-heptenoic acid and the cilastatin sodium is prepared by purifying the cilastatin through microporous resin, thereby improving the purity quotient and the yield coefficient of the cilastatin sodium.
Description
Technical field
The present invention relates to a kind of preparation method of compound, relate in particular to a kind of method for preparing cilastatin sodium (Cilastain Sodium Salt).
Background technology
The chemistry of cilastatin sodium is called [R-[R
*, S
*(Z)] [(2-amino-2-carboxy ethyl) sulphur]-2-[[(2,2-dimethyl-cyclopropyl) carbonyl] amino]-2-heptenoic acid sodium]-7, its chemical structure is suc as formula (I), and molecular formula is C
12H
25N
2NaO
5S, molecular weight are 380.44.Cilastatin sodium and β-carbapenem antibiotic such as imipenum (imipenem) compatibility uses, and can suppress the degraded of kidney dehydrogenation pepx to imipenum, increases the concentration in ampere south, the urinary tract Central Asia, thereby improves the activity of imipenum, reduces its renal toxicity.Imipenum/cilastatin sodium is widely used as a kind of broad spectrum antimicrobicide.
Existing at present a lot of reports about the cilastatin sodium preparation method.EP48301B1 begins to prepare cilastatin sodium after disclosing employing 1-bromo-5-chloropentane and Grignard reagent (Grignard Rx) reaction generation 7-chloro-2-oxoheptanoate; Donald W.Graham etc. discloses with 1,3-two thiophenes-2-ethyl formate as initial reactant prepare cilastatin sodium (Donald W.Graham etc., J.Med.Chem, 1987,30:1074), reactions step is following:
Through 7-chloro-2-oxoheptanoate (III) with (S)-2,2-diformazan basic ring propyl formamide prepared in reaction gets formula (IV) compound (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid ethyl ester.
Because in step 2 preparation formula (IV) compound (Z)-7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-reaction of 2-heptenoic acid ethyl ester in; A small amount of (about 10%~13%) E formula isomer (E)-7-chloro-2 ((S)-2 are arranged; 2-dimethyl-cyclopropyl carboxamide base)-and 2-heptene ethyl ester (VII) generation, E formula isomer can further degraded production (VIII) compound (E)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid in the reaction of step 3.
In order to overcome the problems referred to above; Attempt to add halfcystine reaction production (IX) compound (E)-7-(L-amino-2-propyloic) sulphur-2-((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid through acidizing crystal or in above-mentioned steps 3 gained reaction solns, acidifying heating isomery is removed impurity then; But find formula V compound (Z)-7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid crystallization yield is still very low, because in the reaction of step 3, generated by product (E)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (VIII); The acidifying of step 4 heating further causes not clear impurity (XI) and (S)-2; 2-dimethyl-cyclopropyl carboxamide (XII) generates, and makes the isolating difficulty of purification increase, and reaction process is following:
In order to address this problem; The PCT/WO2006/022511A1 application discloses following method: hydrolyzing type under alkaline condition (IV) compound (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid ethyl ester transfers to neutrality with reacting solution pH value; Then it is used the organic solvent crystallization; Prepare formula (XIII) compound (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid metal-salt, thereby removed formula V compound 7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-and the E formula isomer of 2-heptenoic acid, stoped next step reaction to generate the E formula isomer impurities of cilastatin (VI); Then with formula (XIII) compound (Z)-7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid metal-salt and halfcystine reaction; Through cationic exchange resin adsorption, the ammoniacal liquor elution, concentrate the back add alcohol refining formula (XIV) compound cilastatin ammonium; The sodium hydroxide solution of cilastatin ammonium (XIV) base exchange through Zeo-karb is prepared cilastatin sodium (I), and its reactions step is following:
But in the aforesaid method of PCT/WO2006/022511A1, because in carrying out the alkali swap operation process of Zeo-karb, the acid-base reaction liberated heat can cause that cilastatin (VI) decomposes on a small quantity and reduces the yield and the purity of product; In addition, loaded down with trivial details through the process operation of cilastatin ammonium (XIV) preparation cilastatin sodium (I), do not reach economic requirement, so still be not the method that a good industrialized is produced cilastatin sodium (I).
Summary of the invention
Therefore in order to remedy the deficiency of prior art, make the preparation of cilastatin sodium be fit to suitability for industrialized production, the invention provides a kind of novel method for preparing cilastatin sodium.
The present invention realizes through following technical scheme:
A kind of preparation chemical structural formula is (I), and chemical name is [R-[R
*, S
*(Z)] method of [(2-amino-2-carboxy ethyl) sulphur]-2-[[(2,2-dimethyl-cyclopropyl) carbonyl] amino]-2-heptenoic acid sodium]-7 comprises following step:
The crystallisate of 1) preparation formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl formyl radical)-2-heptenoic acid;
2) with crystallisate and the halfcystine or cysteine hydrochloride prepared in reaction formula (VI) the compound cilastatin of formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl formyl radical)-2-heptenoic acid;
3) with step 2) formula (VI) the compound cilastatin of preparation is through neutral purification with macroreticular resin;
4) with the formula behind the purifying (VI) compound cilastatin and alkaline sodium salt solution reaction, preparation cilastatin sodium (I) solid;
Wherein X is a halogen atom.
Wherein the preparation method of the crystallisate of the described formula of step 1) (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl formyl radical)-2-heptenoic acid comprises:
A) with 7-X-2-oxoheptanoate and (+)-(S)-2,2-dimethyl-cyclopropane carboxamide prepared in reaction formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid;
B) prepare step a) to such an extent that formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl formyl radical)-2-heptenoic acid crystallization in methylene dichloride and toluene obtains the crystallisate of formula (XV) compound;
Wherein X is a chlorine or bromine.
Wherein the preparation method of the crystallisate of the described formula of step 1) (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl formyl radical)-2-heptenoic acid comprises:
A1) with 7-X-2-oxoheptanoate and (+)-(S)-2,2-dimethyl-cyclopropane carboxamide prepared in reaction formula (XV) compound (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid;
B1) prepare step a) to such an extent that formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl formyl radical)-2-heptenoic acid crystallization in dioxane and hexanaphthene obtains the crystallisate of formula (XV) compound;
Wherein X is a chlorine or bromine.
Wherein said neutral macroporous adsorbent resin is the HP-10 resin column, and elutriant is the mixing solutions of water, first alcohol and water.
The methyl alcohol in wherein said methyl alcohol and the water mixed solution and the weight ratio of water are 1:9.
Wherein the described alkaline sodium salt of step 4) is a sodium hydroxide.
Aforesaid method is prepared into highly purified formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid through crystallization, can effectively stop the E formula isomer of formula (VI) cilastatin to generate; Cilastatin solution is purified through neutral macroporous resin, reduced thermolysis and generated other impurity, thereby improved the purity and the yield of cilastatin sodium (I).
Embodiment
Further describe the present invention through the following example, make the present invention more clear be more readily understood.
The preparation of step 1 (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV)
(Z)-7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) according to the EP48301B1 reported method with 247.8g7-chloro-2-oxoheptanoate (III); 135.6g (+)-S-2,2-dimethyl-cyclopropane carboxamide and 1.6g tosic acid are synthetic in 1200mL toluene, concentrate to reclaim toluene; Get the 359.3g brown viscous liquid, product is not done to separate and directly is used for next step reaction.
Last single step reaction gained 359.3g brown viscous liquid is added in the sodium hydroxide solution of 600mL ethanol and 720g10%, be heated to 45~50 ℃, insulated and stirred makes its reaction, and HPLC monitors reaction process, and reaction in about 10 hours finishes; Add tertbutyl ether washing reaction liquid then three times, add tertbutyl ether 1000mL at every turn, discard organic layer; Enriching hcl acidifying in water layer is regulated pH to 3~3.5, adds the ethyl acetate extraction acidizing fluid three times; Each amount that adds ETHYLE ACETATE is 1000mL, abandons water-yielding stratum, adds anhydrous sodium sulfate drying to ethyl acetate layer; Filter then, concentrating under reduced pressure filtrating is also reclaimed ETHYLE ACETATE, obtains 312.2 brown viscous liquids.
The preparation of step 2 (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid solid (IV) can have following two kinds of methods:
Under method one room temperature with 200g (Z)-7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-brown viscous liquid of 2-heptenoic acid (IV) is dissolved in the 500mL methylene dichloride, adds 1350mL toluene then, after stirring with gained solution place 0 ℃ static 12 hours; Collect a large amount of solids of separating out in the solution; Vacuum-drying gets white (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) solid 98.5g.Be evaporated to constant weight with getting mother liquor after the crystallization simultaneously, get the brown viscous solution of 85g, according to aforesaid method; At room temperature the brown viscous solution of 85g is added 200mL methylene dichloride and 500mL toluene; 0 ℃ was descended freezing 12 hours, collected the solid of separating out in the solution, vacuum-drying; Obtain white (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) solid 19.2g.Front and back obtain (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) solid 117.7g twice altogether, and it is 98.7% that HPLC measures its purity, and yield is 56%.
Method two refluxes and down 200g is contained (Z)-7-chloro-2 ((S)-2; 2-dimethyl-cyclopropyl carboxamide base)-the brown viscous liquid solution 600mL dioxane of 2-heptenoic acid (IV) in, add the 1260mL hexanaphthene then, after stirring gained solution placed and left standstill under the room temperature 12 hours; A large amount of solids that collection is separated out; Vacuum-drying gets white (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) solid 123.5g; It is 98.7% that HPLC measures its purity, and yield is 59%.
The preparation of step 3 cilastatin (VI)
Under the ice bath, 164.3g white (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) solids are added in the sodium hydroxide solution of 1200g10%; Controlled temperature is less than or equal to 10 ℃; Stir and also to feed nitrogen, treat that (Z)-7-chloro-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid (IV) solid is all after the dissolving; Add 105.3g cysteine hydrochloride monohydrate, controlled temperature is less than or equal to 10 ℃ simultaneously; After adding, in about 5 ℃, continue to stir 0.5 hour, be warming up to 55~60 ℃ then, insulated and stirred makes its reaction, HPLC monitoring reaction process, and reaction in about 8 hours finishes; After question response finishes, will react liquid cooling and go to room temperature, and add washed with dichloromethane 3 times, add methylene dichloride is 600mL at every turn, discards organic layer, adds the long-pending water of reaction solution monoploid, adds strong brine regulator solution pH value to 2.5~3.0 then; In solution, add the washed with dichloromethane reaction solution 4 times after the acidifying, each methylene dichloride that adds is 800mL, discards organic layer; 55 ℃ are evaporated to the half the of liquor capacity to original volume, and gained solution is added the HP-10 resin column, use earlier water elution; After the sodium-chlor wash-out that generates in the question response finishes, use the methanol/water solution wash-out of 10/90 (wt/wt) again, collect the cilastatin solution of gained; 55 ℃ are concentrated into driedly, and vacuum-drying is to constant weight, light yellow cilastatin solid (VI) 127.8g; It is 98.5% that HPLC measures its purity, and yield is 59.5%.
The preparation of step 4 cilastatin sodium (I)
150g cilastatin (VI) solid that step 3 is prepared adds in the 500mL water, stirs, and sodium hydroxide to the pH value that under ice bath, slowly is added dropwise to 2.08mol/L (16.6g sodium hydroxide is dissolved in the 200mL water) is 7.0; Stop the dropping of sodium hydroxide solution, continue to stir 0.5 hour, treat pH value of solution value and temperature-stable after; In solution, add the 3.5g activated carbon; 40 ℃ are stirred decolouring 15 minutes down, with 0.45 μ m millipore filtration suction filtration, with gained filtrating warp 0.20 μ m filter core press filtration to sterilisable chamber; Collect filtrating with the filtrating refrigerator tray of packing into; Lyophilize gets white aseptic cilastatin sodium (I) lyophilized powder 143.3g, and it is 98.8% that HPLC measures its purity, and yield is 90%.
Above embodiment does not all limit the present invention going up in all senses, if of the present invention these are revised with modification belongs within the scope of claim of the present invention and equivalent technologies thereof, and then the present invention also is intended to comprise these changes and modification interior.
Claims (3)
1. one kind prepares chemical structural formula for (I), and chemical name is the method for [R-[R*, S* (Z)]]-7 [(2-amino-2-carboxy ethyl) sulphur]-2-[[(2,2-dimethyl-cyclopropyl) carbonyl] amino]-2-heptenoic acid sodium, comprises following step:
The crystallisate of 1) preparation formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid;
2) with crystallisate and the halfcystine or cysteine hydrochloride prepared in reaction formula (VI) the compound cilastatin of formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid;
3) with step 2) formula (VI) the compound cilastatin of preparation is through HP-10 resin column purifying, and elutriant is the mixing solutions of water, first alcohol and water;
4) with the formula behind the purifying (VI) compound cilastatin and alkaline sodium salt solution reaction, preparation formula (I) compound cilastatin sodium solid;
Wherein X is a halogen atom,
Wherein the preparation method of the crystallisate of the described formula of step 1) (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid comprises:
A) with 7-X-2-oxoheptanoate and (+)-(S)-2, the reaction of 2-dimethyl-cyclopropane carboxamide obtains brown viscous liquid, does not do to separate in the sodium hydroxide solution of direct adding ethanol and 10%, is heated to 45~50 ℃; Insulated and stirred reaction 10 hours adds the tertbutyl ether washing then, discards organic layer; Enriching hcl acidifying in water layer is regulated pH to 3~3.5, adds ethyl acetate extraction; Discard water layer, ethyl acetate layer is dry, filters; Concentrating under reduced pressure, preparation formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid;
B) step a) is prepared formula (XV) compound (Z)-7-X-2 ((S)-2,2-dimethyl-cyclopropyl carboxamide base)-2-heptenoic acid crystallization in methylene dichloride and toluene or in dioxane and hexanaphthene and obtain the crystallisate of formula (XV) compound.
2. the method for claim 1, the methyl alcohol in wherein said methyl alcohol and the water mixed solution and the weight ratio of water are 1: 9.
3. the method for claim 1, wherein the described alkaline sodium salt of step 4) is a sodium hydroxide.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200710099332 CN101307015B (en) | 2007-05-16 | 2007-05-16 | Process for preparing cilastatin sodium |
PCT/CN2008/000947 WO2008138228A1 (en) | 2007-05-16 | 2008-05-15 | A process for the preparation of cilastatin sodium |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200710099332 CN101307015B (en) | 2007-05-16 | 2007-05-16 | Process for preparing cilastatin sodium |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101307015A CN101307015A (en) | 2008-11-19 |
CN101307015B true CN101307015B (en) | 2012-06-13 |
Family
ID=40001686
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 200710099332 Active CN101307015B (en) | 2007-05-16 | 2007-05-16 | Process for preparing cilastatin sodium |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101307015B (en) |
WO (1) | WO2008138228A1 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102675175B (en) * | 2011-03-08 | 2014-02-19 | 深圳市海滨制药有限公司 | Method for separating and purifying cilastatin |
CN102702051B (en) * | 2011-03-26 | 2016-04-13 | 山东新时代药业有限公司 | A kind of preparation method of cilastatin sodium |
CN104649948B (en) * | 2013-11-19 | 2017-05-24 | 江苏迪赛诺制药有限公司 | Cilastatin calcium crystal, preparation method and application thereof |
CN106518741B (en) * | 2016-10-21 | 2018-11-16 | 深圳市海滨制药有限公司 | A kind of preparation method of Cilastatin Sodium bulk pharmaceutical chemicals |
CN107522642A (en) * | 2017-08-14 | 2017-12-29 | 新乡海滨药业有限公司 | A kind of process for purification of cilastatin |
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 |
CN110845354B (en) * | 2018-08-21 | 2020-08-25 | 鲁南制药集团股份有限公司 | Preparation method of cilastatin sodium intermediate |
CN109111381A (en) * | 2018-10-30 | 2019-01-01 | 雅本化学股份有限公司 | A kind of preparation method of cilastatin |
CN115108934B (en) * | 2022-07-08 | 2024-02-06 | 珠海联邦制药股份有限公司 | Preparation method of cilastatin intermediate sodium |
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 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1592737A (en) * | 2001-08-24 | 2005-03-09 | 兰贝克赛实验室有限公司 | Process for the preparation of cilastatin |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE48301T1 (en) * | 1980-09-24 | 1983-01-20 | Merck & Co., Inc., 07065 Rahway, N.J. | 2- (CYCLOPROPANCARBOXAMIDO) -2-ALKO ACIDS, THEIR ESTERS AND SALTS AND THE EXISTING BACTERIAL INHIBITING COMPOSITIONS WITH A TYPE THIENAMYCINE COMPOUND. |
KR100638471B1 (en) * | 2004-08-25 | 2006-10-25 | 동국제약 주식회사 | Novel Process for Preparing Cilastatin Sodium Salt |
-
2007
- 2007-05-16 CN CN 200710099332 patent/CN101307015B/en active Active
-
2008
- 2008-05-15 WO PCT/CN2008/000947 patent/WO2008138228A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1592737A (en) * | 2001-08-24 | 2005-03-09 | 兰贝克赛实验室有限公司 | Process for the preparation of cilastatin |
Non-Patent Citations (1)
Title |
---|
陈扬.西司他丁钠及其E构型异构体的合成.《陈扬学位论文》.2007,22,29-32. * |
Also Published As
Publication number | Publication date |
---|---|
WO2008138228A1 (en) | 2008-11-20 |
CN101307015A (en) | 2008-11-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101307015B (en) | Process for preparing cilastatin sodium | |
CN103450225B (en) | The preparation method of cefoxitin sodium | |
CN102775364A (en) | Preparation method of cross linking agent triallyl isocyanurate | |
CN101619069A (en) | Preparation method of cefotiam hexetil hydrochloride | |
CN103360410B (en) | Ofloxacine USP 23 preparation method | |
CN111004162B (en) | A kind of method and device for preparing L-selenocystine with sodium triacetoxyborohydride as reducing agent | |
CN109096129B (en) | Preparation method of L-carnitine tartrate | |
CN1679586A (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
CN109836424B (en) | Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt | |
CN115991655B (en) | Synthesis method and product of m-hydroxylamine bitartrate and key intermediate enantiomer thereof | |
CN106279207A (en) | A kind of synthetic method of cefdinir | |
CN117304049A (en) | Preparation method of N,2, 3-trimethyl-2-isopropyl butyramide cooling agent | |
CN101612551B (en) | Preparation of medical sodium benzoate | |
CN105017287B (en) | A kind of preparation method of cephamycin intermediate | |
CN109912625B (en) | Process method for reducing ceftazidime impurity H | |
CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
CN102702051A (en) | Preparation method of cilastatin sodium | |
CN100398507C (en) | DL-amygdalic acid preparing method | |
CN100383114C (en) | Nateglinide preparing process | |
CN114315703B (en) | Preparation method of high-purity vitamin B6 | |
CN104710437A (en) | Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation | |
CN112679361B (en) | Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde | |
CN109053797A (en) | A kind of improvement synthetic method of oxygen phosphoric acid-l-tyrosine | |
CN108484669B (en) | Preparation method of thiotepa | |
CN102675175A (en) | Method for separating and purifying cilastatin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |