CN102757449A - Preparation method of anhydrous penicillin sulfoxide - Google Patents
Preparation method of anhydrous penicillin sulfoxide Download PDFInfo
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- CN102757449A CN102757449A CN2012102201788A CN201210220178A CN102757449A CN 102757449 A CN102757449 A CN 102757449A CN 2012102201788 A CN2012102201788 A CN 2012102201788A CN 201210220178 A CN201210220178 A CN 201210220178A CN 102757449 A CN102757449 A CN 102757449A
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Abstract
The invention discloses a preparation method of anhydrous penicillin sulfoxide. According to the preparation method, an N-oxygen compound is added in the reaction, and molecular oxygen (O2) is directly adopted to oxidize a thioether compound to obtain anhydrous penicillin sulfoxide under the catalyzing of the N-oxygen compound. Water is not introduced in the oxidizing process, thus, the generation of crystal water compound in the product is avoided. The preparation method is mild in reaction, and easy to operate, and has high yield; and the catalyst is out of leakage, and easy to separate, and can be recycled. The reaction method is especially suitable for the reaction for synthesizing sulfoxide by oxidizing penicillin and derivates thereof.
Description
Technical field
The invention belongs to the reaction method of organic thioether compound oxidation, particularly the synthetic preparation method who does not contain the sulfoxide compound of crystal water of oxidation penicillium mould and verivate thereof.
Background technology
Penicillin G sulfoxide normally is that starting raw material gets through oxidation with the penicillin G.It can synthesize various Cephalosporanic acids through the ring expansion rearrangement reaction, like 7-ADCA (7-amino removes acetoxyl group), GCLE (7-phenyl acetylaminohydroxyphenylarsonic acid 3-chloromethyl cephalosporin olefin(e) acid is to methoxy benzyl ester), GCLH (7-phenyl acetylaminohydroxyphenylarsonic acid 3-chloromethyl cephalosporin olefin(e) acid phenylbenzene methyl esters).Penicillin G sulfoxide has the unique molecular structure of beta-lactam, and the instability of bringing down a fever forms hydrogen bond with solvent in the aqueous solution, thus when product is separated out in the aqueous solution easily formation contain 2 water molecules xln.Because the ring expansion rearrangement reaction is anhydrous response, the content of the moisture in the processing requirement penicillin G sulfoxide can not surpass 0.2%, and foreign matter content can not be higher than 1%, otherwise, the yield of Cephalosporanic acid and obviously reduction of content.Thereby the penicillin G sulfoxide that contains crystal water is unfavorable for using and storing, and in many compound methods that oneself knows, generally adopts H
2O
2Reach other superoxide and make oxygenant, with V or VIb family metal-salt or oxide compound, like Na
2WO, Na
2MoO, V
2O
5Deng making catalyzer.But this type oxygenant is easy to make the sulfoxide over oxidation to change into sulfone owing to himself strong excessively oxidisability, and causes the danger of exploding in addition.For this reason, people are constantly seeking gentle more oxygenant, and from environmental protection, safety considers with economic angle, receive people's attention with air just widely as the substitute of superoxide.In (J.Mol.Cat. A108 (1996) 57-62) document of people such as Maria M, disclose a kind of in molecular oxygen branched chain aldehyde system; With Co (acac) 2, Co (AAEMA) 2, Fe (AAEMA) 3 transition metal complexes such as grade are made the catalyst oxidation organic sulfide; But reactant only is confined to micromolecular compound simple in structure; And for the macromole organic sulfide of structure more complicated, or transformation efficiency is very low, or just simply can not be oxidized.At people (Hideo Tanaka such as the Hideo of Japan Tanaka; Ryo Kikuchi; Sigeru Torri. Tetrahedron 52 (7): 2343-2348,1996) a kind of method with atmospheric oxidation penicillium mould and the synthetic sulfoxide of verivate thereof is disclosed in the document.They bore (III) (Co (acac) 3) with methyl ethyl diketone and make catalyzer, in the presence of isobutyric aldehyde, and blowing air in acetonitrile or ethylene dichloride medium, stirring at room can make the penicillin G-methoxy-benzyl ester is changed into corresponding sulfoxide in 3 hours, and productive rate can reach 94%.But a separation problem that disadvantage is a reaction system of this method, they adopt chromatography separated product and catalyzer.Because this method is very loaded down with trivial details, and wants the time and the eluent of labor,, be difficult to realize industriallization so cost is very high.Reuse with selectivity and catalyzer for improving reactive activity, in the reaction of atmospheric oxidation organic sulfide, also the someone attempt catalyzer is carried out immobilized, as at N, N in N-N
2Under the protection, 50 ℃ are stirred Co (AAEMA), N, and N-DMAA and N, N '-methylene diacrylamine obtains immobilized Co (AAEMA)
2(J. Mol. Cat. A l08 (1996) 57-62); Can be used in the air oxidation reaction of small molecules thioether; But this method is immobilized on polymer catalyzer, along with the prolongation of duration of service, and the instability that polymer can become; Thereby cause catalyzer to be revealed, so the immobilized catalyst life of this method is shorter.People (J.Mol.Cat.A l08 (1996) l53-160) such as Hanan Sertchook once reported with immobilized rhodium, the iridium complex that is used for isomerization reaction of sol-gel technique.Its whole process will be carried out under nitrogen atmosphere or vacuum, and reaction conditions is relatively harsher, not easy to operate, and cost is high.All these methods have all adopted the more serious heavy metal of environmental pollution as catalyzer, and perhaps reaction process is inevitably introduced water, causes the appearance of crystal water compound.Therefore, need try to explore to obtain a kind of preparation method of penicillin G sulfoxide of non-aqueous system,, help improving the yield and the content of Cephalosporanic acid in the ring expansion rearrangement reaction simultaneously to improve the stability of penicillin G sulfoxide.
Summary of the invention
The object of the present invention is to provide a kind of anhydrous penicillin sulfoxide preparation method, this technology under non-aqueous system, the N-oxide compound of non-heavy metal is as catalyzer, air method direct oxidation penicillium mould becomes the penicillin sulfoxide compounds.Present method can not produce the crystal water compound, the stability that helps improving the yield and the content of Cephalosporanic acid in the ring expansion rearrangement reaction and improve penicillin G sulfoxide simultaneously; Adopt organic catalyst to avoid the pollution of heavy metal; Air oxidation reaction avoids the use of strong oxidizers such as superoxide, and reaction can be carried out in very gentle condition, and is safe and reliable; Catalyzer is not revealed, and is easily separated, and reusable.
In order to realize the foregoing invention purpose, the technical scheme that the present invention adopts is following:
A kind of anhydrous penicillin sulfoxide preparation method, carry out according to following steps:
(1) catalyzer of thio-ether type compounds, N-oxygen compound and hexalin being formed is dissolved into after by following mixed and obtains mixture in the cosolvent, wherein: thioether: N-oxygen compound=10～5:1; Thioether: hexalin=1:1～10, the consumption of cosolvent can make whole system become homogeneous phase and get final product.
(2) said mixture is stirred, under the normal pressure 45-65 ℃, continue bubbling air oxidizing reaction 6-24 hour;
(3) solvent is fallen in the reaction solution underpressure distillation of (2) step reaction gained, add absolute ethyl alcohol, crystallization is filtered, washing, and drying under reduced pressure promptly obtains sulfoxide compound to constant weight.
What step (3) adopted is that the reaction solution that conventional steps reacts gained to (2) carries out subsequent disposal; Here; If use methanol crystallization, then mainly be the crystal water compound that forms band a part methyl alcohol, and the present invention adopt ethanol; Alcohols such as ethanol can not form the crystal water compound, can use ETHYLE ACETATE and the hexanaphthene mixed solution crystallization according to 2:8 yet.Certainly, along with using the different of oxidising agent, its crystallization dissolving also can change.
Described N-oxygen compound is N-hydroxyphthalimide (NHPI) or N-methyl oxygen morpholine.
Thioether in the step (1): N-oxygen compound: hexalin=1:0.1:5.
Cosolvent in the step (1) is to make whole system become the homogeneous organic solvent.
Cosolvent is acetonitrile, benzyl cyanide or THF.
Compared with prior art, the invention has the beneficial effects as follows:
(1) nonaqueous phase reaction can not produce the crystal water compound, the stability that helps improving the yield and the content of Cephalosporanic acid in the ring expansion rearrangement reaction and improve penicillin G sulfoxide simultaneously.
(2) because the organic catalyst that adopts has been avoided the pollution problem of heavy metal.
(3) air oxidation reaction has been avoided strong oxidizers such as use superoxide, and reaction can be carried out in very gentle condition, and is safe and reliable.
(4) catalyzer is not revealed, and is easily separated, and reusable.
Description of drawings
Fig. 1 is the infared spectrum of the product penicillin G ester sulfoxide among the embodiment 1;
Fig. 2 is the 7-ADCA infared spectrum among the embodiment 2;
Fig. 3 is the mass spectrum of the 7-ADCA among the embodiment 2.
Embodiment
Below in conjunction with embodiment foregoing invention content of the present invention is done further to describe in detail.
But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.Not breaking away under the above-mentioned technological thought situation of the present invention, according to ordinary skill knowledge and customary means, make various replacements and change, all should comprise within the scope of the invention.
Embodiment 1
Present embodiment is preparation embodiment:
A kind of anhydrous penicillin sulfoxide preparation method, carry out according to following steps:
(1) preparation sulfide compound: add the 5.0g potassium penicillin G in the 100ml there-necked flask, 30mL exsiccant DMF, 2.9g is to the nitro bromobenzyl;
(2) be heated to 45 ℃ of reactions, thin layer tracks to reaction and finishes the about 6.0h of reaction (acetonitrile: water=7:3).System is cooled to 10 ℃.Add about 200mL pure water, stirred crystallization is removed supernatant, and solid washs separatory once with the 20mL pure water then with the dissolving of the methylene dichloride of 30mL, with the saturated common salt water washing separatory of 20mL once.Obtain the dichloromethane solution of about 30mL carboxylate.Through anhydrous sodium sulfate drying 12h, filter, filter cake is with the washed with dichloromethane of 10mL, and the filtrate decompression evaporate to dryness is subsequent use.
The oxidation of sulfide compound: add the NHPI of 0.5g and the hexalin of 25g (penicilline g potassium 5 times) in the above-mentioned penicillium mould carboxylate and be dissolved in the anhydrous nitrile; Temperature rising reflux; With thin layer detection reaction concluding time (ETHYLE ACETATE: normal hexane=7:3), continue bubbling air backflow 12h;
(3) after reaction finished, reaction solution cooled to room temperature, and acetonitrile is fallen in underpressure distillation; Up to bath temperature is 35 degree, and vacuum pump can't further be extracted out till the solvent, on this basis; The ethanol that adds 10ml; Dissolving 10min distills all ethanol, then till vacuum pump can't be extracted solvent out under this temperature under 35 degree.(the use ethanol here is to use for the distillatory dehydration)
The absolute ethyl alcohol and stirring dissolving crystallized 12h of solid about with 25mL filters, and filter cake washs the sulfoxide midbody 5.6 that solid must dewater in 30 ℃ of following vacuum-dryings with the cold acetone of 10mL.Yield is 85%, and measuring fusing point is 149～151 ℃, and the infrared analysis result sees Fig. 1.
Present embodiment is for estimating embodiment:
The dry penicillin G sulfoxide ester (purity is greater than 97% for 4.85g, 0.01mol) that in the 250mL four-hole bottle, adds above-mentioned direct preparation; Toluene 65 mL; Under the nitrogen protection, (5.2g is 0.0125mol) with ring expansion catalyzer pyridine derivate-hydrobromate 0.004mol to add exsiccant hexamethyl silicon urea; Be warming up to about 105 ℃ of refluxed reaction 2.5h rapidly, in the reaction process with the generation situation of HPLC monitoring feedstock conversion situation and ring expansion product and decarboxylation by product.After the basic end of reaction, toluene is fallen in underpressure distillation, moisture 20% of adding 30ml phenol in the above-mentioned solid, the about 4h of stirring at room reaction, the H of the about 50ml of adding after reaction finishes
2O, stirred crystallization 8h, 0 ℃ leaves standstill 0.5h, and suction filtration gets thick product 3.0g, mass yield 90%, infared spectrum and mass spectrometric detection result see Fig. 2 and Fig. 3.
Embodiment 3
Present embodiment is preparation embodiment:
A kind of anhydrous penicillin sulfoxide preparation method, carry out according to following steps:
(1) weighing 1.1g penicilline g potassium, the hexalin of the NHPI of 0.1g and 5.5g (penicilline g potassium 5 times) are dissolved in the nitrile ℃;
(2) heat up 65 ℃, reflux, with thin layer detection reaction concluding time (ETHYLE ACETATE: normal hexane=7:3), continue bubbling air backflow 12h;
(3) after reaction finishes; Reaction solution cools to room temperature; Acetonitrile is fallen in underpressure distillation, the H2O stirring and dissolving of solid about with 10mL, and using the hydrochloric acid soln of 1mol/L to regulate pH is 2 crystallization 8h; The cold water washing of filter cake about with 10ml, the sulfoxide midbody 0.93g that solid must dewater in 30 ℃ of following vacuum-dryings.Yield is 90%, and measuring fusing point is 163～164 ℃.
Embodiment 4
Present embodiment is preparation embodiment:
A kind of anhydrous penicillin sulfoxide preparation method, carry out according to following steps:
(1) weighing 1.0g penicillium mould, the NHPI of 0.1g and the hexalin of 5.0g are dissolved in the nitrile;
(2) heat up 65 ℃, reflux, with thin layer detection reaction concluding time (ETHYLE ACETATE: normal hexane=7:3), continue bubbling air backflow 24h;
(3) after reaction finished, reaction solution cooled to room temperature, and acetonitrile is fallen in underpressure distillation; The ethanol stirring and dissolving crystallization 12h of solid about with 10mL; Filter, the cold acetonitrile of filter cake about with 10ml washs the sulfoxide midbody 0.94g that solid must dewater in 30 ℃ of following vacuum-dryings.Yield is 90%, and measuring fusing point is 163～164 ℃.
Embodiment 5
Present embodiment is the evaluation embodiment of embodiment 3 and 4:
The dry penicillin G sulfoxide (purity is greater than 97% for 7.2g, 0.02mol) that in the 250mL four-hole bottle, adds above-mentioned direct preparation; Toluene 65 mL under the nitrogen protection, add exsiccant hexamethyl silicon urea (17.4g; 0.05mol), react 2h down at about 50 ℃, carboxyl is carried out the estersil protection.Add ring expansion catalyzer pyridine derivate-hydrobromate 0.004mol then, be warming up to about 105 ℃ of refluxed reaction 2.5h rapidly, in the reaction process with the generation situation of HPLC monitoring feedstock conversion situation and ring expansion product and decarboxylation by product.After the basic end of reaction, reaction system is cooled to 60 ℃, adds about 50 ℃ of deionized water 25mL; Under 50 ℃, add 3M sulfuric acid and transfer pH to be about 2, be cooled to restir 0.5h under the room temperature; 0 ℃ leaves standstill 0.5h, and suction filtration gets thick product 6.1g, mass yield 90%; The product and the embodiment 2 of preparation are identical, and infared spectrum and mass spectrometric detection result and embodiment 2 are identical, see Fig. 2 and Fig. 3.
Claims (5)
1. anhydrous penicillin sulfoxide preparation method is characterized in that carrying out according to following steps:
(1) catalyzer of thio-ether type compounds, N-oxygen compound and hexalin being formed obtains mixture by being dissolved into after (weight) mixed as follows in the cosolvent, wherein: thioether: N-oxygen compound=10～5:1; Thioether: hexalin=1:1～10, the consumption of cosolvent can make whole system become homogeneous phase and get final product;
(2) said mixture is stirred, under the normal pressure 45-65 ℃, continue bubbling air oxidizing reaction 6-24 hour;
(3) solvent is fallen in the reaction solution underpressure distillation of (2) step reaction gained, add absolute ethyl alcohol, crystallization is filtered, washing, and drying under reduced pressure promptly obtains sulfoxide compound to constant weight.
2. anhydrous penicillin sulfoxide preparation method according to claim 1 is characterized in that: described N-oxygen compound is N-hydroxyphthalimide or N-methyl oxygen morpholine.
3. anhydrous penicillin sulfoxide preparation method according to claim 1 is characterized in that: thioether in the step (1): N-oxygen compound: hexalin=1:0.1:5.
4. anhydrous penicillin sulfoxide preparation method according to claim 1 is characterized in that: the cosolvent in the step (1) is to make whole system become the homogeneous organic solvent.
5. anhydrous penicillin sulfoxide preparation method according to claim 4 is characterized in that: the cosolvent in the step (1) is acetonitrile, benzyl cyanide or THF.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985003294A1 (en) * | 1984-01-19 | 1985-08-01 | La Trobe University | Preparation of penicillin sulfoxide |
| EP0659742A1 (en) * | 1993-12-27 | 1995-06-28 | Lupin Laboratories Limited | An improved method for the preparation of 2-chloro sulfinyl azetidin-4-one |
| CN1397533A (en) * | 2001-04-18 | 2003-02-19 | 河北工业大学 | Reaction process for oxidization of organic sulfide in air |
| CN101974017A (en) * | 2010-10-11 | 2011-02-16 | 天津大学 | Method for preparing penicillin-G-1-(S)-oxide |
-
2012
- 2012-06-29 CN CN2012102201788A patent/CN102757449A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985003294A1 (en) * | 1984-01-19 | 1985-08-01 | La Trobe University | Preparation of penicillin sulfoxide |
| EP0659742A1 (en) * | 1993-12-27 | 1995-06-28 | Lupin Laboratories Limited | An improved method for the preparation of 2-chloro sulfinyl azetidin-4-one |
| CN1397533A (en) * | 2001-04-18 | 2003-02-19 | 河北工业大学 | Reaction process for oxidization of organic sulfide in air |
| CN101974017A (en) * | 2010-10-11 | 2011-02-16 | 天津大学 | Method for preparing penicillin-G-1-(S)-oxide |
Non-Patent Citations (3)
| Title |
|---|
| HIDEO TANAKA，等: "Chemoselective Aerobic Oxidation of Penicillin and Cephalosporin Derivatives into Sulfoxides", 《TETRAHEDRON》, vol. 52, no. 7, 31 December 1996 (1996-12-31) * |
| TAKAHIRO IWAHAMA，等: "Selective Oxidation of Sulfides to Sulfoxides with Molecular Oxygen Catalyzed by N-Hydroxyphthalimide (NHPI) in the Presence of Alcohols", 《TETRAHEDRON LETTERS》, vol. 39, no. 49, 31 December 1998 (1998-12-31), XP004141002, DOI: doi:10.1016/S0040-4039(98)02054-1 * |
| 杨莉，等: "青霉素G亚砜的合成", 《精细化工中间体》, vol. 37, no. 6, 31 December 2007 (2007-12-31) * |
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Application publication date: 20121031 |