CN103113373B - 1 beta-methyl carbapenem compound and synthetic process thereof - Google Patents
1 beta-methyl carbapenem compound and synthetic process thereof Download PDFInfo
- Publication number
- CN103113373B CN103113373B CN201310075658.4A CN201310075658A CN103113373B CN 103113373 B CN103113373 B CN 103113373B CN 201310075658 A CN201310075658 A CN 201310075658A CN 103113373 B CN103113373 B CN 103113373B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- volume
- synthesis technique
- beta
- 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
- 0 C[C@@]1*CC2(CC2)C1 Chemical compound C[C@@]1*CC2(CC2)C1 0.000 description 4
- XSPVFGSHRULRON-MSOLQXFVSA-N COc1cc(N(C[C@@H](C2)S)[C@@H]2C(OCc2ccccc2)=O)ccc1 Chemical compound COc1cc(N(C[C@@H](C2)S)[C@@H]2C(OCc2ccccc2)=O)ccc1 XSPVFGSHRULRON-MSOLQXFVSA-N 0.000 description 1
- XGMKPTHUVRWONE-WMZOPIPTSA-N COc1cc(N(C[C@H](C2)O)[C@@H]2C(OCc2ccccc2)=O)ccc1 Chemical compound COc1cc(N(C[C@H](C2)O)[C@@H]2C(OCc2ccccc2)=O)ccc1 XGMKPTHUVRWONE-WMZOPIPTSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a 1 beta-methyl carbapenem compound and a synthetic process thereof. A compound is wide in antibacterial spectrum and high in antimicrobial activity, and is used for stabilizing beta-lactamase; trans-hydroxyproline and methyl carbapenem nuclear parent which are easily obtained are used as raw materials; and the raw materials are reacted in eight steps to obtain a target compound. Compared with the existing synthetic process, the synthetic method has the advantages of easily availability of synthetic raw materials, high yield, mild reaction conditions, easiness for control, easiness for controlling a separation purifying method, and suitability for large-scale industrial preparation.
Description
Technical field
The present invention relates to a kind of carbapenem compound and new synthetic process thereof, belong to antibiotic medicine field.
Background technology
Carbapenem antibiotic is the class beta-lactam compound that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stablizes β-lactamase, and receives much concern.Its constructional feature is compared with the parent nucleus 6-APA of penicillin, and the sulphur atom of 4 is replaced by carbon, and 2 have double bond, is compounded with the effect of the five-ring of penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.Carbapenem itself has good anti-microbial activity, and also can suppress β-lactamase, therefore, it becomes the focus of Recent study simultaneously.Wherein mesomethylene carbon penem is proved to be has good restraining effect to the β-lactamase of category-A and C class.It is the most important structural modification position of carbapenem compound that 3-position replaces, most kind has the side chain of sulfur-bearing and has the pyrrolidine ring of different substituents in 3-position, some is also containing amino, imino-etc., and typical medicine is as sulfomycin, imipenum, meropenem, panipenem etc.The substituting groups such as 4-position introducing methyl can improve the stability to DHP-I.2-position is connected to hydroxyl usually.
Represent medicine meropenem (mero β enem) and within 1994, start listing.Within 2003, included by American Pharmacopeia, this medicine be first can be individually dosed 4-methyl carbapenem antibiotic, it is stronger than imipenum (imipenem) and panipenem (panipenem) 2-8 times to gram negative bacilli vitro antibacterial activity, is more better than cynnematin and Penicillin antibiotics.
The present invention, in order to overcome the deficiencies in the prior art, on the basis of the carbapenem compound now used clinically, devises series compound of the present invention, and provides the synthesis technique of this series compound, be applicable to a large amount of synthesis.
Summary of the invention
The object of this invention is to provide a kind of such as formula the one 1 Beta-methyl carbapenem compound shown in (I) and synthesis technique thereof, its synthesis general formula as shown in Figure 1.With the easy trans oxyproline that is easy to get and methyl carbon mould parent nucleus for raw material is obtained by reacting target compound through 8 steps, the advantage of this synthesis technique is: adopt the linked reaction of Pd catalysis to build proline(Pro) N position aromatic nucleus skeleton; Adopt the configuration reversal in mesyloxy alkyl process to introduce S and replace position chiral centre; By controlling the pH value of hydrogenation, synthesis final product.Compared with existing synthesis technique, synthetic method synthesis material of the present invention easily obtains, yield is higher, reaction conditions is gentle and easily control, separation purification method easily operate, and is applicable to industrial a large amount of preparation.
The technical solution adopted for the present invention to solve the technical problems is:
The invention provides a kind of 1 Beta-methyl carbapenem compound, its general structure as shown in (I),
R can be positioned at 3 or 4 of aromatic nucleus, is respectively methoxyl group, oxyethyl group, isopropoxy.
Numbering is that respective compound adds-1 to-6, specifically sees embodiment.
The invention provides the synthesis technique such as formula 1 Beta-methyl carbapenem compound shown in (I), it synthesizes general formula as shown in Figure 1:
Fig. 1
Reactions steps is:
1) compound 1 first protects 2 carbonyls and 4 hydroxyls respectively with benzyl and TIPS, obtains compound 3;
2) compound 3 and fragrant bromo-derivative 4 obtain compound 5 through linked reaction;
3) compound 5 remove silicon ether protection after, 4 hydroxyl methylsulfonyls are activated, then with thioacetic acid nak response, build thioether, through hydrolysis obtain key intermediate 8;
4) compound 8 and carbapenem parent nucleus 9 reacting generating compound 10 in the presence of base;
5) compound 10 removes PNB and benzyl protecting group through hydrogenation, obtains target product 11.
In synthesis technique provided by the invention, step 2) in:
The solvent of linked reaction can be selected from toluene, tetrahydrofuran (THF), methylene dichloride any one;
The catalyzer of linked reaction can be selected from Pd (dba) Cl
2, Pd (PPh
3)
4, PdCl
2(dppf), Pd (OAc)
2any one;
The alkali of linked reaction can select any one of triethylamine, pyridine, N dimethylamine yl pyridines, salt of wormwood, cesium carbonate.
In synthesis technique provided by the invention, step 3) in:
The reaction conditions of methylsulfonyl activation is: drip methylsulfonyl chloride under frozen water cooling, and control temperature, at 0 ~ 10 DEG C, is preferably 8 DEG C;
The reaction solvent building thioether is 1: 1 ~ 3: 1 mixing by volume of DMF/ toluene, and temperature of reaction is 60 ~ 80 DEG C; Being preferably DMF/ volume of toluene ratio is 2: 1, and temperature of reaction is 70 DEG C;
The purifying process of key intermediate 8 is completed by conventional silica gel column chromatography, and eluent is that petrol ether/ethyl acetate mixes by 3: 1 to 6: 1 volume ratio, and being preferably petrol ether/ethyl acetate volume ratio is 5: 1.
In synthesis technique provided by the invention, step 5) in
The pH value of hydrogenation is 6.0-7.2, is preferably 7.0;
The purifying process of target product 11 adds acetone soln in the filtrate after washed with diethylether, and rear ethanol/water or isopropanol/water be 1: 1 ~ 5: 1 recrystallization by volume, is preferably ethanol/water volume ratio 3: 1.
Accompanying drawing explanation
Fig. 1 is the synthesis general formula of target product.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
The preparation of embodiment, compound 11-1 (R is methoxyl group)
1, the preparation of compound 2
13.1g compound 1,15mL benzylalcohol and 50g tosic acid are dissolved in 200mL toluene, are heated to 100 DEG C, azeotropic 3 hours, is cooled to room temperature, and decompression steams toluene, cooling crystallization, obtains white solid 24.5g, yield 62.3%.
2, the preparation of compound 3
(2S，4S)-benzyl4-((triisopropylsilyl)oxy)pyrrolidine-2-carboxylate
Be dissolved in 200mL methylene dichloride by 20.5g compound 2 and 10.2g imidazoles, icy salt solution is cooled to less than 0 DEG C, drips 11.6g TIPSCl, keeps thermotonus 1 hour, rises to stirred overnight at room temperature.Reaction solution uses the saturated NaHCO of 200mL successively
3with saturated common salt water washing, anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain 17.9g colorless oil, be directly used in next step.
The preparation of 3, compound 5-1 (2S, 4S)-benzyl-1-(3-methoxyphenyl)-4-(tri isopropyl siloxany) pyrroles-2-carbonic ether
By compound 3,0.8g Pd (dba) Cl of step preparation on 17.9g
2with 19.2g CsCO
3under nitrogen protection, be dissolved in 200mL THF, add 11.2g compound 4-1, stirred at ambient temperature 3 hours.By in reaction solution impouring 150mL saturated ammonium chloride solution, dichloromethane extraction (150mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry.Crude product column chromatography purification, petrol ether/ethyl acetate (6/1, v/v) is washed, and obtains 12.1g colorless oil compounds 5-1, yield 39.7% (two steps add up to).
4, the preparation of compound 6-1
10.5g compound 5-1 is dissolved in 150mL THF, under frozen water cooling, drips the THF solution of the TBAF of 50mL1.0Mol/L, react 2 hours under room temperature.By in reaction solution impouring 150mL saturated sodium bicarbonate solution, dichloromethane extraction (150mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry.Crude product column chromatography purification, petrol ether/ethyl acetate (3/1, v/v) is washed, and obtains 7.5g colorless oil compounds 6-1, yield 92.0%.
5, the preparation of compound 7-1
Be dissolved in 150mL methylene dichloride by 7.0g compound 6-1 and 10.8g triethylamine, frozen water cooling is lower drips 3.7g methylsulfonyl chloride, and control temperature, below 10 DEG C, drips and finishes, rise to stirred overnight at room temperature.By in reaction solution impouring 150mL saturated sodium bicarbonate solution, dichloromethane extraction (150mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry, is directly used in next step reaction.
6, the preparation of compound 8-1
The compound 7-1 upper step prepared is dissolved in the mixing solutions of 200mL DMF/ toluene (1/1, v/v), adds 2.9g AcSK, is heated to 70 DEG C, stirs 5 hours.Be cooled to room temperature, add 80mL saturated ammonium chloride solution, use 100mL diluted ethyl acetate, separate organic phase, aqueous phase extracts 2 times by 150mL ethyl acetate again, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain pale yellow oil.
Pale yellow oil is dissolved in 200mL methyl alcohol, adds the sodium hydroxide solution of 30g10%, reflux 2 hours.Be cooled to room temperature, by reaction solution impouring 150mL saturated sodium bicarbonate solution, dichloromethane extraction (150mL*2), merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry.Column chromatography purification, petrol ether/ethyl acetate (5/1, v/v) is washed, and obtains 2.7g compound as white solid 8-1, yield 37.6% (two steps merge).
7, the preparation of compound 10-1
0.61g compound 9 is dissolved in 20mL acetonitrile, under nitrogen protection, adds the acetonitrile solution that 0.23g ethyl diisopropyl amine and 10mL are dissolved with 0.34g compound 8-1 successively, room temperature for overnight.Reaction solution 50mL diluted ethyl acetate, 30mL saturated sodium bicarbonate solution washs, and merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, filters, is evaporated to dry, obtains pale yellow oil.Column chromatography purification, petrol ether/ethyl acetate (6/1, v/v) is washed, and obtains 0.26g faint yellow solid compound 10-1, yield 37.1%.
8, the preparation of compound 11-1
2.6g compound 10-1 is dissolved in 40mL pH be 7.0 phosphoric acid buffer and THF (1/1, v/v) in, add 0.3g Pd/C, the H of 50psi
2under pressure, react 2 hours.Filter, washed with diethylether twice, adds acetone soln 20mL in filtrate, separates out faint yellow solid, with ethanol/water (3/1, v/v) recrystallization, obtains white solid 0.48g, yield 28%.
Claims (5)
1. a synthesis technique for 1 Beta-methyl carbapenem compound, the general structure of this compounds is as shown in (I):
In formula: R can be positioned at 3 or 4 of aromatic nucleus, is selected from methoxyl group, oxyethyl group, isopropoxy;
It is characterized in that, its synthesis general formula is shown below, and comprises the following steps:
1) compound 1 first protects 2 carboxyls and 4 hydroxyls respectively with benzyl and TIPS, obtains compound 3;
2) compound 3 and the coupling of fragrant bromo-derivative 4 obtain compound 5;
3) compound 5 remove silicon ether protection after, 4 hydroxyl methylsulfonyls are activated, then with thioacetic acid nak response, build thioether, through hydrolysis obtain compound 8;
4) compound 8 and carbapenem parent nucleus 9 reacting generating compound 10 in the presence of base;
5) PNB and benzyl protecting group are removed in compound 10 hydrogenation, obtain compound 11;
Wherein, described step 2) in:
The solvent of described linked reaction can be selected from toluene, tetrahydrofuran (THF), methylene dichloride any one;
The catalyzer of described linked reaction can be selected from Pd (dba) Cl
2, Pd (PPh
3)
4, PdCl
2(dppf), Pd (OAc)
2any one;
The alkali of described linked reaction can select any one of triethylamine, pyridine, N dimethylamine yl pyridines, salt of wormwood, cesium carbonate.
2. synthesis technique according to claim 1, is characterized in that, described step 3) in
The reaction conditions of described methylsulfonyl activation is: drip methylsulfonyl chloride under frozen water cooling, control temperature is at 0 ~ 10 DEG C;
The reaction solvent building thioether is 1: 1 ~ 3: 1 mixing by volume of DMF/ toluene, and temperature of reaction is 60 ~ 80 DEG C;
The purifying process of compound 8 is completed by conventional silica gel column chromatography, and eluent is that petrol ether/ethyl acetate mixes by 3: 1 to 6: 1 volume ratio.
3. synthesis technique according to claim 2, is characterized in that, described step 3) in
The reaction conditions of described methylsulfonyl activation is: drip methylsulfonyl chloride under frozen water cooling, control temperature is at 8 DEG C;
The reaction solvent building thioether is 2: 1 mixing by volume of DMF/ toluene, and temperature of reaction is 70 DEG C;
The purifying process of compound 8 is completed by conventional silica gel column chromatography, and eluent is that petrol ether/ethyl acetate mixes by 5: 1 volume ratios.
4. synthesis technique according to claim 1, is characterized in that, described step 5) in
The pH value of described hydrogenation is 6.0-7.2;
The purifying process of compound 11 adds acetone soln in the filtrate after washed with diethylether, and ethanol/water or isopropanol/water be 1: 1 ~ 5: 1 recrystallization by volume.
5. synthesis technique according to claim 4, is characterized in that, described step 5) in
The pH value of described hydrogenation is 7.0;
The purifying process of compound 11 adds acetone soln in the filtrate after washed with diethylether, and ethanol/water is 3: 1 recrystallizations by volume.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310075658.4A CN103113373B (en) | 2013-03-11 | 2013-03-11 | 1 beta-methyl carbapenem compound and synthetic process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310075658.4A CN103113373B (en) | 2013-03-11 | 2013-03-11 | 1 beta-methyl carbapenem compound and synthetic process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103113373A CN103113373A (en) | 2013-05-22 |
| CN103113373B true CN103113373B (en) | 2015-05-20 |
Family
ID=48411793
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310075658.4A Active CN103113373B (en) | 2013-03-11 | 2013-03-11 | 1 beta-methyl carbapenem compound and synthetic process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103113373B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101328180B (en) * | 2007-06-15 | 2010-12-15 | 山东轩竹医药科技有限公司 | Sulfhydryl oxo heterocycle substituted penem derivates |
| CN101570537A (en) * | 2009-06-18 | 2009-11-04 | 浙江师范大学 | Preparation method of panipenem |
| CN102249972A (en) * | 2011-05-27 | 2011-11-23 | 菏泽睿智科技开发有限公司 | Method for synthesizing novel chiral lateral chain of meropenem |
-
2013
- 2013-03-11 CN CN201310075658.4A patent/CN103113373B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103113373A (en) | 2013-05-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2006290416B2 (en) | An improved process for the preparation of beta-lactam antibiotic | |
| CN104672225A (en) | Method for preparing dihydropyrimidine derivative and intermediate of dihydropyrimidine | |
| HU199473B (en) | Process for producing chrystalline carbapenem derivative and pharmaceutical compositions comprising same as active ingredient | |
| CN101628914A (en) | Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem | |
| CN102558181A (en) | Preparation method of carbapenems | |
| CA1284500C (en) | Carbapenem antibiotics | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN103113374B (en) | Carbapenem antibiotic and new synthetic process thereof | |
| CN103113373B (en) | 1 beta-methyl carbapenem compound and synthetic process thereof | |
| CA1246546A (en) | 2-alkylthiopenem derivatives | |
| CN101481346B (en) | Preparation of carbapenem antibiotic side chain | |
| CN101848911A (en) | Acid addition salts of synthetic intermediates for carbapenem antibiotics and processes for preparing the same | |
| CN103059046B (en) | Preparation method of faropenem | |
| CN113929684B (en) | Meropenem intermediate and preparation method thereof | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN103012406B (en) | A kind of preparation method of antibacterials | |
| KR101142757B1 (en) | Process for preparing meropenem trihydrate | |
| CN105037348B (en) | A kind of Retapamulin synthetic method | |
| CN101367830B (en) | Synthesis of sulfomycin derivant | |
| KR20120007331A (en) | An improved process for the preparation of carbapenem compounds | |
| KR100476672B1 (en) | THIOL DERIVATIVES AND 1-β-METHYL-CARBAPENEM DERIVATIVES WITH THE SAME | |
| DE69816095T2 (en) | PRODUCTION OF BETA MEHTYLCARBAPENEM INTERMEDIATE PRODUCTS | |
| KR100848752B1 (en) | Thienamycin solvate and its process | |
| CN105566392A (en) | Bacterial protein synthesis inhibitor preparation method | |
| CN116462693A (en) | Preparation method and application of tedizolid phosphate intermediate |
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 | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 123000 No. 1, Chemical Road, Fuxin Road, Haizhou District, Liaoning Patentee after: Liaoning Tianhua Biological Pharmaceutical Co. Ltd. Address before: 123000 No. 1, Chemical Road, Fuxin Road, Haizhou District, Liaoning Patentee before: Liaoning Tianhua Chemical Co., Ltd. |