CN102766181A - Preparation method of 6-o-substituted erythromycin derivative - Google Patents
Preparation method of 6-o-substituted erythromycin derivative Download PDFInfo
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- CN102766181A CN102766181A CN2011101173305A CN201110117330A CN102766181A CN 102766181 A CN102766181 A CN 102766181A CN 2011101173305 A CN2011101173305 A CN 2011101173305A CN 201110117330 A CN201110117330 A CN 201110117330A CN 102766181 A CN102766181 A CN 102766181A
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Abstract
The invention relates to the technical field of a preparation method of a 6-o-substituted erythromycin derivative. According to the preparation method of the 6-o-substituted erythromycin derivative, under the action of strong base, a erythromycin derivative compound as shown in the formula (VI) reacts with 3-(3-quinolyl)-2-propenyl-1-halide. By the adoption of the novel preparation method of the 6-o-substituted erythromycin derivative (V), the erythromycin derivative compound as shown in the formula (V) can be conveniently obtained by one-step reaction. The condition is easy to control. In addition, the preparation method is simple to operate and is suitable for industrial production at large scale.
Description
Technical field
The present invention relates to preparing method's technical field of the substituted erythromycin derivatives of 6-O-.
Background technology
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-11,12-cyclic carbamate-3-ketone group Erythromycin A (match Oxacyclotetradecane,erythromycin deriv) is in E.P patent 0929563A1, to disclose effective macrolide antibiotics.
Prepare the method for matching Oxacyclotetradecane,erythromycin deriv and generally be to use seven footworks of erythromycin A-9 oxime as raw material:
Step 1: with 2 ', 4 " and 9 hydroxyls protect;
Step 2: 6 hydroxyls are carried out alkylation and 9 hydroxyl deprotections;
Step 3: 9 oximes are changed into ketone;
Step 4: 11 and 12 hydroxyl is changed into cyclic carbamate;
Step 5: 3 glycosyls are sloughed;
Step 6: 3 hydroxyl oxygens are changed into ketone;
Step 7: with 4 " position hydroxyl deprotection.
In aforesaid method, the alkylation that step 2 is 6 needs under the catalysis of palladium, to make the compound reaction of erythromycin derivatives and following formula:
The several different methods of preparation match Oxacyclotetradecane,erythromycin deriv has been described in the document.Match Oxacyclotetradecane,erythromycin deriv can be through with 6-O-allyl group-4 "-benzoyl--11,12-cyclic carbamate-3-ketone group Erythromycin A under the catalysis of palladium with the reaction of three bromoquinolines, slough 4 again " the position protection is basic and make (EP0929563A1).Match Oxacyclotetradecane,erythromycin deriv can also pass through Erythromycin A 9-oxime 2 ' .4 ", 6 hydroxy alkylateds of 9-three benzoic ethers make (WO0078773A2) through a few step reactions again.
In the known references of preparation match Oxacyclotetradecane,erythromycin deriv, the alkylation of 6 hydroxyls of erythromycin derivatives all needs the participation of palladium catalyst, and reaction conditions requires also relatively stricter, and production cost is higher.Yet, also do not have catalytic 6 alkylations of palladium about match Oxacyclotetradecane,erythromycin deriv synthetic.
Summary of the invention
The object of the invention just is to address the above problem, and a kind of preparation method of the new substituted erythromycin derivatives of 6-O-is provided, and this method does not need the participation of palladium catalyst, and reaction conditions is gentle.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is following:
The preparation method of the substituted erythromycin derivatives of 6-O-(V), this method are that under the highly basic effect, formula (VI) erythromycin derivatives compound and 3-(3-quinolyl)-2-propylene-1-halides is reacted
Wherein, R represents 1-isopropoxy cyclohexyl, benzoyl-, ethanoyl or trimethyl silicon based; R
1Be meant benzoyl-, ethanoyl or trimethyl silicon based.
Said alkaline object lesson comprises potassium tert.-butoxide and sodium methylate.
The preparation method of the substituted erythromycin derivatives of above-mentioned 6-O-(V), temperature of reaction be preferably at-15 ℃-35 ℃, most preferably-15 ℃-10 ℃.
Its Chinese style (VI) erythromycin derivatives compound is selected from 2 '; 4 "-O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime, 2 ', 4 "-O-two (benzoyl-) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime, 2 ', 4 "-O-two (ethanoyl) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime, 2 '; 4 " The trimethyl silicon based Erythromycin A 9-of 9-oxime, 2 ', 4 ", 9-tri-benzoyl Erythromycin A 9-oxime and 2 '; 4 ", 9-triacetyl Erythromycin A 9-oxime.Formula (VI) compound can obtain through prior art, prepares like the method among the document EP0929563A1.
The object lesson of 3-(3-quinolyl)-2-propylene-1-halides comprises 3-(3-quinolyl)-2-propylene-1-bromo-derivative, 3-(3-quinolyl)-2-propylene-1-iodo thing, 3-(3-quinolyl)-2-propylene-1-chloro thing.
The structure of 3-(3-quinolyl)-2-propylene-1-halides is shown below:
Wherein, X represents bromine, chlorine or iodine.
3-(3-quinolyl)-2-propylene-1-halides can prepare through following method: with formula III compound 3-(3-quinolyl)-2-propylene-1-alcohol and halide reaction
The preparation method of above-mentioned 3-(3-quinolyl)-2-propylene-1-halides, said halogenide is selected from phosphorus tribromide, phosphorus triiodide, phosphorus trichloride, N-bromo-succinimide, N-iodo succimide and N-chlorosuccinimide.
The preparation method of above-mentioned 3-(3-quinolyl)-2-propylene-1-halides, temperature of reaction be preferably at-15 ℃-35 ℃, most preferably-15 ℃-10 ℃.
The preparation method of above-mentioned 3-(3-quinolyl)-2-propylene-1-halides, when halogenide was N-halogenated succinimide imide, preferable scheme was to add dimethyl sulphide in the reaction solution.
Formula (III) but method among preparing method's reference US2003199696A1 of compound makes formula (III) compound by formula (I) compound:
Also can adopt other existing method to obtain.
Beneficial effect of the present invention:
The invention provides the substituted erythromycin derivatives of a kind of new 6-O-(V) preparation method; The inventive method is under the highly basic effect; Through type (VI) erythromycin derivatives compound and 3-(3-quinolyl)-2-propylene-1-halides single step reaction promptly obtains formula V erythromycin derivatives compound very easily; Condition is controlled easily, and is simple to operate, is fit to large-scale industrialization production.
Embodiment
The embodiment that provides is used for describing the application of preferred embodiment and the inventive method, rather than is used for limiting the present invention, only if in accompanying claims, state.
Reaction scheme
In solvent, under about-15 ℃ to 35 ℃ temperature, under the highly basic effect, erythromycin derivatives formula (VI) compound and 3-(3-quinolyl)-2-propylene-1-halides reaction makes the formula V compound.
The preparation of embodiment 1:3-(3-quinolyl)-2-propylene-1-bromo-derivative
Add 2g compound III 3-(3-quinolyl)-2-propylene-1-alcohol in the 100ml reaction flask, add anhydrous THF 35ml, cryosel is bathed and is cooled to-10 ℃ to-15 ℃, drips the 10mlTHF solution of 1.4g phosphorus tribromide then; 30min drips off, and keeps-10 ℃ to-15 ℃ reaction 1h, and raw material reaction is complete, after reaction solution dilutes with 50ml ETHYLE ACETATE; With the 40ml washing, use the 40ml saturated sodium bicarbonate more successively, the 40ml saturated sodium-chloride is washed; Behind the anhydrous sodium sulfate drying, concentrate, obtain solid (1.8g).
The preparation of embodiment 2:3-(3-quinolyl)-2-propylene-1-bromo-derivative
Add 2.92g N-bromo-succinimide (NBS) in the 100ml reaction flask, anhydrous methylene chloride 20ml, ice-water bath are cooled to 0-5 ℃; Add dimethyl sulphide 1.02g, behind the stirring 15min, drip the dichloromethane solution (2g is dissolved in the 30ml methylene dichloride) of compound III 3-(3-quinolyl)-2-propylene-1-alcohol; After 30min drips off, room temperature reaction 2h, raw material reaction is complete; Reaction solution, is washed with the 50ml saturated sodium bicarbonate with the 50ml washing with the dilution of 20ml methylene dichloride again; The 50ml saturated sodium-chloride is washed, and behind the anhydrous sodium sulfate drying, concentrates and obtains solid (3g).
The preparation of embodiment 3:3-(3-quinolyl)-2-propylene-1-chloro thing
Add 2.92g N-chlorosuccinimide (NCS) in the 100ml reaction flask, anhydrous methylene chloride 20ml, ice-water bath are cooled to 0-5 ℃; Add dimethyl sulphide 1.02g, behind the stirring 15min, drip the dichloromethane solution (2g is dissolved in the 30ml methylene dichloride) of compound 3; After 30min drips off, room temperature reaction 2h, raw material reaction is complete; Reaction solution, is washed with the 50ml saturated sodium bicarbonate with the 50ml washing with the dilution of 20ml methylene dichloride again; The 50ml saturated sodium-chloride is washed, and behind the anhydrous sodium sulfate drying, concentrates and obtains solid (2.3g).
Embodiment 4
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 "-preparation of O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime:
Add 2 ' in the 100ml reaction flask; 4 "-O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime (according to the preparation of the method among the EP0929563A1) 2g; Add 10ml DMSO and 10ml THF, add 3-(3-quinolyl)-2-propylene-1-bromo-derivative 0.54g, be cooled to 0 ℃; Behind the 5min, drip the 10ml DMSO of potassium tert.-butoxide (1M 4ml) and the solution among the 10ml THF.This reaction mixture is dissolved in the ETHYLE ACETATE, water and salt washing, the vacuum concentration organic phase obtains foam-like compound (2.5g).
Embodiment 5
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 "-preparation of O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime
Add 2 ' in the 100ml reaction flask; 4 "-O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime (according to the preparation of the method among the EP0929563A1) 2g; Add 10ml DMSO and 10ml THF, add 3-(3-quinolyl)-2-propylene-1-bromo-derivative 0.54g, be cooled to-10 ℃; Behind the 5min, drip the 10ml DMSO of potassium tert.-butoxide (1M 4ml) and the solution among the 10ml THF.This reaction mixture is dissolved in the ETHYLE ACETATE, water and salt washing, the vacuum concentration organic phase obtains foam-like compound (2.48g).
Embodiment 6
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 "-preparation of O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime
Add 2 ' in the 100ml reaction flask; 4 "-O-two (TMS) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime (according to the preparation of the method among the EP0929563A1) 2g; Add 10ml DMSO and 10ml THF; Add 3-(3-quinolyl)-2-propylene-1-bromo-derivative 0.54g, room temperature drips the 10ml DMSO of potassium tert.-butoxide (1M 4ml) and the solution among the 10ml THF, keeps temperature to be no more than 35 ℃.This reaction mixture is dissolved in the ETHYLE ACETATE, water and salt washing, the vacuum concentration organic phase obtains foam-like compound (2.49g).
Embodiment 7
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 "-preparation of O-two (benzoyl-) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime
Add 2 ' in the 100ml reaction flask; 4 "-O-two (benzoyl-) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime 2g; Add 10ml DMSO and 10ml THF, add 3-(3-quinolyl)-2-propylene-1-bromo-derivative 0.57g, be cooled to 0 ℃; Behind the 5min, drip the 10ml DMSO of potassium tert.-butoxide (1M 4ml) and the solution among the 10ml THF.This reaction mixture is dissolved in the ETHYLE ACETATE, water and salt washing, the vacuum concentration organic phase obtains foam-like compound (2.49g).
Embodiment 8
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 "-preparation of O-two (ethanoyl) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime
Add 2 ' in the 100ml reaction flask; 4 "-O-two (ethanoyl) Erythromycin A 9-(O-isopropoxy cyclohexyl ketal) oxime 2g; Add 10ml DMSO and 10ml THF, add 3-(3-quinolyl)-2-propylene-1-bromo-derivative 0.51g, be cooled to 0 ℃; Behind the 5min, drip the 10ml DMSO of potassium tert.-butoxide (1M 4ml) and the solution among the 10ml THF.This reaction mixture is dissolved in the ETHYLE ACETATE, water and salt washing, the vacuum concentration organic phase obtains foam-like compound (2.39g).
Embodiment 9
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 ", the preparation of the trimethyl silicon based Erythromycin A 9-of 9-oxime
Add 2 ' in the 100ml reaction flask; 4 ", the trimethyl silicon based Erythromycin A 9-of 9-oxime 2g adds 10ml DMSO and 10ml THF; Add 3-(3-quinolyl)-2-propylene-1-bromo-derivative 0.50g; Be cooled to 0 ℃, behind the 5min, drip the 10ml DMSO of potassium tert.-butoxide (1M 4ml) and the solution among the 10ml THF.This reaction mixture is dissolved in the ETHYLE ACETATE, water and salt washing, the vacuum concentration organic phase obtains foam-like compound (2.36g).
Embodiment 10
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 ", the preparation of 9-tri-benzoyl Erythromycin A 9-oxime
With 2 ', 4 ", 9-tri-benzoyl Erythromycin A 9-oxime is a raw material, prepares 6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 with reference to the method for embodiment 7 ", 9-tri-benzoyl Erythromycin A 9-oxime.
Embodiment 11
6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 ", the preparation of 9-triacetyl Erythromycin A 9-oxime
With 2 ', 4 ", 9-triacetyl Erythromycin A 9-oxime is a raw material, prepares 6-O-[3-(3-quinolyl)-2-propylene-1-yl]-2 ', 4 with reference to the method for embodiment 7 ", 9-triacetyl Erythromycin A 9-oxime.
By means of above description and the for example clear the present invention of embodiment.More than describe and should illustrate as non-limiting, because for a person skilled in the art, many variations of making in view of the above are conspicuous.Should think that all these variations should be included within the scope and essence of accompanying claims.
Can be to the combination of the inventive method described herein, operation and layout are replaced, and do not deviate from inventive concept and the scope that is limited claim.
Claims (10)
1.6-O-the preparation method of substituted erythromycin derivatives (V), this method are that under the highly basic effect, formula (VI) erythromycin derivatives compound and 3-(3-quinolyl)-2-propylene-1-halides is reacted:
Wherein, R represents 1-isopropoxy cyclohexyl, benzoyl-, ethanoyl or trimethyl silicon based; R
1Be meant benzoyl-, ethanoyl or trimethyl silicon based.
2. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 1 (V) is characterized in that: said highly basic comprises potassium tert.-butoxide and sodium methylate.
3. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 1 (V) is characterized in that: temperature of reaction is at-15 ℃-35 ℃.
4. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 3 (V) is characterized in that: temperature of reaction is at-15 ℃-25 ℃.
5. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 1 (V) is characterized in that: said 3-(3-quinolyl)-2-propylene-1-halides is 3-(3-quinolyl)-2-propylene-1-bromo-derivative, 3-(3-quinolyl)-2-propylene-1-iodo thing or 3-(3-quinolyl)-2-propylene-1-chloro thing.
6. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 1 (V) is characterized in that: said 3-(3-quinolyl)-2-propylene-1-halides prepares through following method: with formula III compound 3-(3-quinolyl)-2-propylene-1-alcohol and halide reaction
Wherein, X represents bromine, chlorine or iodine.
7. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 6 (V) is characterized in that: said halogenide is selected from phosphorus tribromide, phosphorus triiodide, phosphorus trichloride, N-bromo-succinimide, N-iodo succimide and N-chlorosuccinimide.
8. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 6 (V) is characterized in that: the temperature of reaction of preparation 3-(3-quinolyl)-2-propylene-1-halides is at-15 ℃-35 ℃.
9. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 8 (V) is characterized in that: the temperature of reaction of preparation 3-(3-quinolyl)-2-propylene-1-halides is at-15 ℃-10 ℃.
10. the preparation method of the substituted erythromycin derivatives of 6-O-as claimed in claim 6 (V) is characterized in that: during preparation 3-(3-quinolyl)-2-propylene-1-halides, when halogenide is N-halogenated succinimide imide, add dimethyl sulphide.
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Citations (5)
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|---|---|---|---|---|
| CN1224427A (en) * | 1996-05-07 | 1999-07-28 | 艾博特公司 | 6-0-substd. erythromycins and method for making them |
| CN1237183A (en) * | 1996-09-04 | 1999-12-01 | 艾博特公司 | 6-0-substituted ketolides having antibacterial activity |
| US6046171A (en) * | 1997-10-29 | 2000-04-04 | Abbott Laboratories | 6,11-bridged erythromycin derivatives |
| WO2002096922A1 (en) * | 2001-05-30 | 2002-12-05 | Abbott Laboratories | An arylation method for the functionalization of o-allyl erythromycin derivatives |
| CN1216064C (en) * | 1999-06-24 | 2005-08-24 | 艾博特公司 | Process for preparing 6-o-alkenyl-substituted erythromycin derivatives |
-
2011
- 2011-05-06 CN CN2011101173305A patent/CN102766181A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1224427A (en) * | 1996-05-07 | 1999-07-28 | 艾博特公司 | 6-0-substd. erythromycins and method for making them |
| CN1237183A (en) * | 1996-09-04 | 1999-12-01 | 艾博特公司 | 6-0-substituted ketolides having antibacterial activity |
| US6046171A (en) * | 1997-10-29 | 2000-04-04 | Abbott Laboratories | 6,11-bridged erythromycin derivatives |
| CN1216064C (en) * | 1999-06-24 | 2005-08-24 | 艾博特公司 | Process for preparing 6-o-alkenyl-substituted erythromycin derivatives |
| WO2002096922A1 (en) * | 2001-05-30 | 2002-12-05 | Abbott Laboratories | An arylation method for the functionalization of o-allyl erythromycin derivatives |
Non-Patent Citations (3)
| Title |
|---|
| FRANCO BELLESIA，等: "Some Anomalous Products from the Attempted Halogenation of Unsaturated Alcohols by the Complex from Dimethyl Sulphide and N-Halogenosuccinimide", 《J.C.S.PERKIN I》, 1 January 1979 (1979-01-01), pages 851 - 855 * |
| HONG FU，等: "Synthesis and in vitro antibiotic activity of 16-membered 9- O-arylalkyloxime macrolides", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 16, no. 5, 1 March 2006 (2006-03-01), pages 1259 - 1266 * |
| 周忠华，等: "《赛红霉素的合成工艺》", 《华西药学杂志》, vol. 26, no. 1, 15 February 2011 (2011-02-15), pages 20 - 23 * |
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