CN101186614A - Preparation method of methoxybenzyl ester - Google Patents
Preparation method of methoxybenzyl ester Download PDFInfo
- Publication number
- CN101186614A CN101186614A CNA2007101916335A CN200710191633A CN101186614A CN 101186614 A CN101186614 A CN 101186614A CN A2007101916335 A CNA2007101916335 A CN A2007101916335A CN 200710191633 A CN200710191633 A CN 200710191633A CN 101186614 A CN101186614 A CN 101186614A
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- CN
- China
- Prior art keywords
- carrying
- penicillin
- reaction
- sulfinic acid
- sulfoxide
- 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.)
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- -1 methoxybenzyl ester Chemical class 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 229930182555 Penicillin Natural products 0.000 claims abstract description 7
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 7
- 229940049954 penicillin Drugs 0.000 claims abstract description 7
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- JEHKKBHWRAXMCH-UHFFFAOYSA-M benzenesulfinate Chemical compound [O-]S(=O)C1=CC=CC=C1 JEHKKBHWRAXMCH-UHFFFAOYSA-M 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 235000002639 sodium chloride Nutrition 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- JEHKKBHWRAXMCH-UHFFFAOYSA-N benzenesulfinic acid Chemical compound O[S@@](=O)C1=CC=CC=C1 JEHKKBHWRAXMCH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005868 electrolysis reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 2
- 238000007098 aminolysis reaction Methods 0.000 abstract 1
- 239000012320 chlorinating reagent Substances 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 1
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a preparation method of methoxybenzyl ester, which comprises the steps of using penicillin as a raw material, carrying out oxidation reaction to obtain penicillosulfoxide, carrying out esterification to form Kenyycin sulfoxide ester, then carrying out reaction with benzene sulfinate, carrying out ring opening to generate an aza-butanone sulfinic acid intermediate, then electrolyzing the saturated saline solution containing sulfuric acid, carrying out chlorination by using a chlorinating agent generated by the generated penicillin, and finally carrying out aminolysis ring closing to form GCLE.
Description
Technical field
The present invention relates to a kind of preparation method of industrial chemicals, especially a kind of preparation method of methoxy benzyl ester.
Background technology
7 one phenylacetyl ammonia, one 3 one chloromethyl cephalosporin alkyl olefin(e) acids are a kind of medicine intermediates to methoxy benzyl ester (being called for short GCLE), especially be used for synthesizing cephalosporins, the present domestic existing minority produced in small quantities GCLE of producer, but production technique still has problems, production cost is higher, quality product is relatively poor, domestic synthesizing at it is raw material with the potassium salt of penicillin mainly, through esterification, and oxidation, ring expansion, reduction and chlorine make, and crucial last chlorination reaction can be synthetic with chlorine method and t-butyl hypochlorate method, but the chlorine method uses chlorine dangerous strong, t-butyl hypochlorate method cost is too high, all is not suitable for suitability for industrialized production.
Summary of the invention
The present invention is directed to the defective of prior art, a kind of methoxy benzyl ester preparation method of practicality is provided.
To achieve these goals, the present invention takes following measure to realize:
A kind of preparation method of methoxy benzyl ester, comprise raw material, contain the vitriolic saturated aqueous common salt, it is characterized in that with penicillin being raw material, get mould rope sulfoxide through oxidizing reaction, after esterification forms and agree the mycin sulfoxide esters, with the benzene sulfinic acid reactant salt, open loop generates azepine butanone-sulfinic acid intermediate again, and electrolysis contains the vitriolic saturated aqueous common salt then, chlorizating agent with its generation carries out chlorination, and last ammonia is separated the method that closed loop forms GCLE.
The present invention has following characteristics with respect to prior art: the present invention has product yield height, purity height, low, the measured advantage of matter of cost, and adopts the electrolysis closed loop to carry out chlorination in generative process, guarantees to react safety.
Embodiment
Concrete steps are as follows:
1. oxidation: adopt 30g potassium salt of penicillin and 18.2gNaIO
4Solution at room temperature reacts 1h, gets penicillin sulfoxide acid.
2. esterification: in 100ml eggplant type bottle, add potassium salt of penicillin 11.6g (0.03mol), new distillatory N, dinethylformamide 50ml and new distillatory cylite 4.28ml (0.03mol), at room temperature stir 4h, filter, filtrate is poured in the 150ml frozen water, after stirring is left standstill, discard milk, gained oily matter is esterification products.
3. open loop and chlorination reaction: in next step electrolytic process; should there be a group can protect the sulphur hydrocarbon of C-4 position; make it not participate in reaction; this group is left away than being easier to again in last closed loop procedure; therefore; select the reaction of benzene sulfinate and penicillin sulfoxide ester for use, but open loop generates azepine butanone-sulfinic acid intermediate.
Chlorination: electrolysis contains the vitriolic saturated aqueous common salt, chlorizating agent with its generation carries out chlorination, detailed process is as follows: the azepine butanone-sulfinic acid intermediate of getting 0.2mmol is dissolved in the 5ml chloroform, be filled in the cell that two platinum electrodes are housed with containing 0.14ml vitriolic saturated aqueous common salt, electric current transfers to 10mA/cm
2, at 7-12 ℃ of reaction 1.3h, reaction is isolated organic layer after finishing, washing.
4. ammonia is separated the synthetic GCLE of closed loop: get the above-mentioned chlorizate of 0.1mmol, with 0.5mlN, dinethylformamide is a solvent, logical people 0.3mmolNH
3Carry out ammonia and separate, at 20-30 ℃ of reaction 1h, this closed loop procedure need be carried out under alkaline condition.
5.GCLE purifying: in the pyriform flask of 1L, add 600ml methyl alcohol, be cooled to 3 ℃, use 120mlN, dinethylformamide dissolving 120g buttery GCLE dropwise splashes into this mixing solutions in the abundant chilled methyl alcohol, stir 30min, GCLE is separated out with crystallized form, and precipitate is filtered in underpressure distillation, uses methanol wash, decompression is dry down, obtains the GCLE crystal.
In the reality, GCLE is the novel parent nucleus intermediate feed of synthetic cephalosporins medicine, is used for synthetic 7 one different side chains, and the cephalosporins medicine of 3 one different substituent methyls has the yield height, low cost, advantage such as quality is good.
Claims (2)
1. the preparation method of a methoxy benzyl ester, comprise raw material, contain the vitriolic saturated aqueous common salt, it is characterized in that with penicillin being raw material, get mould rope sulfoxide through oxidizing reaction, after esterification forms and agree the mycin sulfoxide esters, with the benzene sulfinic acid reactant salt, open loop generates azepine butanone-sulfinic acid intermediate again, and electrolysis contains the vitriolic saturated aqueous common salt then, chlorizating agent with its generation carries out chlorination, and last ammonia is separated the method that closed loop forms GCLE.
2. according to claim 1, in open loop and chlorination reaction process, select the reaction of benzene sulfinate and penicillin sulfoxide ester for use, but open loop generates azepine butanone-sulfinic acid intermediate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101916335A CN101186614A (en) | 2007-12-13 | 2007-12-13 | Preparation method of methoxybenzyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101916335A CN101186614A (en) | 2007-12-13 | 2007-12-13 | Preparation method of methoxybenzyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101186614A true CN101186614A (en) | 2008-05-28 |
Family
ID=39479264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101916335A Withdrawn CN101186614A (en) | 2007-12-13 | 2007-12-13 | Preparation method of methoxybenzyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101186614A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344459A (en) * | 2011-07-27 | 2012-02-08 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102690243A (en) * | 2012-05-25 | 2012-09-26 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN102863460A (en) * | 2012-09-29 | 2013-01-09 | 广东省石油化工研究院 | Preparation method of cephalosporin antibiotic parent nucleus GCLE (7-phenylacetamido-3-cephem-4-carboxylic p-methoxybenzyl ester) |
-
2007
- 2007-12-13 CN CNA2007101916335A patent/CN101186614A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344459A (en) * | 2011-07-27 | 2012-02-08 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102344459B (en) * | 2011-07-27 | 2014-08-06 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102690243A (en) * | 2012-05-25 | 2012-09-26 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN102690243B (en) * | 2012-05-25 | 2014-07-16 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN102863460A (en) * | 2012-09-29 | 2013-01-09 | 广东省石油化工研究院 | Preparation method of cephalosporin antibiotic parent nucleus GCLE (7-phenylacetamido-3-cephem-4-carboxylic p-methoxybenzyl ester) |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C04 | Withdrawal of patent application after publication (patent law 2001) | ||
| WW01 | Invention patent application withdrawn after publication |