CN101906115A - Preparation method of beta-methyl carbapenem antibiotic intermediate - Google Patents
Preparation method of beta-methyl carbapenem antibiotic intermediate Download PDFInfo
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- CN101906115A CN101906115A CN 201010255356 CN201010255356A CN101906115A CN 101906115 A CN101906115 A CN 101906115A CN 201010255356 CN201010255356 CN 201010255356 CN 201010255356 A CN201010255356 A CN 201010255356A CN 101906115 A CN101906115 A CN 101906115A
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Abstract
The invention relates to a synthesis method of a beta-methyl carbapenem antibiotic intermediate shown as a following formula I, comprising the following step of: reacting a compound shown in the formula I with p-toluenesulfonyl azide in a water-insoluble solvent to obtain a mixture of p-toluenesulfonamide and the compound shown in the formula I; then dissolving the compound shown in the formula I in the mixture by using a solvent, filtering and removing the insoluble p-toluenesulfonamide, and concentrating to obtain a crude product of the compound shown in the formula I; and then recrystallizing to obtain a refined product of the compound shown in the formula I. The preparation method has the advantages of convenient operation, high reaction yield and product purity, low cost and easy industrial production.
Description
Technical field
The present invention relates to the synthetic field of chemicals, in particular to a kind of beta-methylcarbapenem antibiotics intermediates preparation.
Background technology
Beta-methylcarbapenem antibiotics (as: meropenem, biapenem, ertapenem etc.) is a class microbiotic of being a dark horse in recent years, it was come out the eighties in 20th century, be the widest class atypia β-Nei Xiananleikangshengsu of antimicrobial spectrum, can effectively treat with methicillin-resistant gold Portugal bacterium (MRSA) is the infection disease that the Resistant strain of representative causes.
Adopting the compound shown in the formula I in the disclosed synthetic beta-methylcarbapenem antibiotics method route in Japanese patent application JP6016680A is intermediate, compound shown in its Chinese style I is by the compound shown in the formula II and the dodecyl sulfonyl azide is reacted, generate by product simultaneously to the dodecyl benzsulfamide, mixed solvent through ethyl acetate and normal hexane carries out recrystallization again, obtains the compound shown in the purer formula I.
Because compound is to the generation of mole such as the compound shown in dodecyl benzsulfamide and the formula I, through the material balance analysis, it is about 60% to contain the compound shown in the formula I in the material that obtains after the reaction, contains dodecyl benzsulfamide about 40%.Obviously be efficiently to remove the dodecyl benzsulfamide by a recrystallization, thereby can not obtain conforming with the compound shown in the formula I of ideal specification of quality, with the beta-methylcarbapenem antibiotics of preparation high standard.Can pass through repeatedly recrystallization if obtain the compound shown in the high-quality formula I, but can cause yield to reduce, cost raises; Also can pass through column chromatography for separation, but this is also very expensive.High price to the dodecyl sulfonyl azide also makes cost increase in addition.
So be necessary to invent efficient, the cost effective method of the compound shown in a kind of preparation formula I, to be suitable for suitability for industrialized production.
Summary of the invention
Therefore, the object of the present invention is to provide a kind of synthetic method, avoided the above-mentioned shortcoming that exists in the prior art, can obtain the product of high standard, high yield, lower cost suc as formula the beta-methylcarbapenem antibiotics intermediate shown in the I.
Method of the present invention comprises the steps:
A. compound and p-toluene sulfonyt azide shown in the formula II react in a kind of and the immiscible solvent of water, obtain the mixture of the compound shown in para toluene sulfonamide and the formula I;
B. use the compound shown in the formula I in a kind of dissolution with solvents mixture, insoluble para toluene sulfonamide is removed by filter, obtain the crude product of the compound shown in the formula I after concentrating;
C. with polar solvent with the crude product recrystallization, obtain the highly finished product of the compound shown in the formula I.
According to a preferred embodiment of the invention, in above-mentioned steps a, described and the immiscible solvent of water are one or more the mixture in chloroform, methylene dichloride, ethylene dichloride, the toluene, are preferably methylene dichloride or toluene.
According to a preferred embodiment of the invention, in above-mentioned steps a, the mol ratio of the compound shown in described p-toluene sulfonyt azide and the formula II is 1: 1～1.2: 1, is preferably 1.05: 1.
According to another preferred embodiment of the present invention, wherein in above-mentioned steps a, add organic bases, as triethylamine.
According to another preferred embodiment of the present invention, in above-mentioned steps b, described solvent is one or more the mixture in chloroform, methylene dichloride, the toluene, is preferably methylene dichloride or toluene.
According to another preferred embodiment of the present invention, in above-mentioned steps c, described polar solvent is one or more the mixture in methyl alcohol, ethanol, Virahol, the ethyl acetate, is preferably ethanol or Virahol.
The inventive method is easy and simple to handle, the product purity height, and steady quality, the reaction yield height, cost is low, is easy to suitability for industrialized production.
Description of drawings
Fig. 1 makes the beta-methylcarbapenem antibiotics intermediate shown in the formula I according to the inventive method
1The H-NMR spectrogram.
Fig. 2 makes the beta-methylcarbapenem antibiotics intermediate shown in the formula I according to the inventive method
13The C-NMR spectrogram.
Fig. 3 is the mass spectrum that makes the beta-methylcarbapenem antibiotics intermediate shown in the formula I according to the inventive method.
Fig. 4 is the infared spectrum that makes the beta-methylcarbapenem antibiotics intermediate shown in the formula I according to the inventive method.
Embodiment
Now the invention will be further elaborated by following examples, but the present invention is not limited to this.
The compound shown in the used formula II all is to be initial self-control according to the JP6016680A disclosed method with 4-BMA among the following embodiment, chromatographic purity:＞95% (HPLC).P-toluene sulfonyt azide is available from safe hundred million Fine Chemical Co., Ltd in Lianyun Harbour, purity＞98%.
In reaction flask, add compound 71.9g (0.150mol), 300ml toluene and the 16.8g triethylamine shown in the formula II, slowly drip p-toluene sulfonyt azide 35.4g (0.179mol) in 2 ℃ then.Drip to finish, be warming up to 7 ℃ stir insulation reaction 1.5h after, add water 200ml, transfer pH 2～3, static layering with dilute hydrochloric acid.Water 50ml methylbenzene extraction merges organic phase.Organic phase is successively used 50ml saturated potassium hydrogen carbonate solution and 50ml water washing.
Organic layer is concentrated into dried, adds 120ml toluene and stir, in 0 ℃ of filtration, filter cake merges diafiltration liquid with ice toluene 50ml washing, is concentrated into dried.
Add 220ml ethanol in residue, stirring heats up makes it to dissolve fully, slowly is cooled to 0 ℃ of stirring and crystallizing 1.5h then.Filter, filter cake is iced washing with alcohol with 30ml, and vacuum-drying gets the compound 68g shown in the formula I, chromatographic purity: 99.5% (HPLC).
In reaction flask, add compound 71.9g (0.150mol), 300ml methylene dichloride and the 16.8g triethylamine shown in the formula II, slowly drip p-toluene sulfonyt azide 31.1g (0.158mol) in 3 ℃ then.Drip to finish, be warming up to 8 ℃ stir insulation reaction 1.5h after, add water 200ml, transfer pH 2～3, static layering with dilute hydrochloric acid.Water 50ml dichloromethane extraction merges organic phase.Organic phase is successively used 60ml saturated potassium hydrogen carbonate solution and 60ml water washing.
Organic layer is concentrated into dried, adds the 120ml methylene dichloride and stir, in 0 ℃ of filtration, filter cake merges diafiltration liquid with ice methylene dichloride 50ml washing, is concentrated into dried.
Add the 280ml Virahol in residue, stirring heats up molten clear, slowly is cooled to 0 ℃ of stirring and crystallizing 1.5h then.Filter, filter cake is iced washed with isopropyl alcohol with 20ml, and vacuum-drying gets the compound 68g shown in the formula I, chromatographic purity: 99% (HPLC).
In reaction flask, add compound 71.9g (0.150mol), 350ml chloroform and the 16.8g triethylamine shown in the formula II, slowly drip p-toluene sulfonyt azide 29.5g (0.150mol) in 0 ℃ then.Drip to finish, be warming up to 5 ℃ stir insulation reaction 1.5h after, add water 250ml, transfer pH 2～3, static layering with dilute hydrochloric acid.Water 60ml chloroform extraction merges organic phase.Organic phase is successively used 50ml saturated potassium hydrogen carbonate solution and 50ml water washing.
Organic layer is concentrated into dried, adds the 150ml chloroform and stir, in 0 ℃ of filtration, filter cake merges diafiltration liquid with ice chloroform 60ml washing, is concentrated into dried.
Add the 320ml ethyl acetate in residue, stirring heats up molten clear, slowly is cooled to 0 ℃ of stirring and crystallizing 1.5h then.Filter, filter cake washs with 30ml glacial acetic acid ethyl ester, and vacuum-drying gets the compound 65g shown in the formula I, chromatographic purity: 99.0% (HPLC).
In reaction flask, add compound 71.9g (0.150mol), 300ml methylene dichloride and the 16.8g triethylamine shown in the formula II, slowly drip p-toluene sulfonyt azide 31.1g (0.158mol) in 1 ℃ then.Drip to finish, be warming up to 10 ℃ stir insulation reaction 1.5h after, add water 200ml, transfer pH 2～3, static layering with dilute hydrochloric acid.Water 50ml dichloromethane extraction merges organic phase.Organic phase is successively used 60ml saturated potassium hydrogen carbonate solution and 60ml water washing.
Organic layer is concentrated into dried, adds 120ml toluene and stir, in 0 ℃ of filtration, filter cake merges diafiltration liquid with ice toluene 50ml washing, is concentrated into dried.
Add 200ml methyl alcohol in residue, stirring heats up molten clear, slowly is cooled to 0 ℃ of stirring and crystallizing 1.5h then.Filter, filter cake is iced methanol wash with 20ml, and vacuum-drying gets the compound 67g shown in the formula I, chromatographic purity: 98.8% (HPLC).
The sample nuclear magnetic resonance spectrum that the foregoing description 1-4 makes is measured with Varian 400MHz instrument, and mass spectrum is measured with Thermo Finnigan LCQ Advantage type mass spectrograph, and infrared spectra is measured with NicoletAvatar 370 Fourier transformation infrared spectrometers.
The comparative example
In reaction flask, add compound 71.9g (0.150mol), 300ml methylene dichloride and the 16.8g triethylamine shown in the formula II, slowly drip in 2 ℃ then dodecyl sulfonyl azide 55.4g (0.158mol).Drip to finish, be warming up to 7 ℃ stir insulation reaction 1.5h after, add water 200ml, transfer pH 2～3, static layering with dilute hydrochloric acid.Water 50ml dichloromethane extraction merges organic phase.Organic phase is successively used 60ml saturated potassium hydrogen carbonate solution and 60ml water washing.
Organic layer is concentrated into dried, (v/v=10: 9), stirring heats up makes it to dissolve fully, slowly is cooled to 0 ℃ of stirring and crystallizing 1.5h then to add 140ml ethyl acetate/normal hexane mixed solution in residue.Filter, (v/v=10: 9) washing, vacuum-drying gets the compound 49.2g shown in the formula I to filter cake, chromatographic purity: 90% (HPLC) with 20ml glacial acetic acid ethyl ester/normal hexane mixed solution.
By embodiments of the invention and comparative example are compared, can find that the compound shown in the formula I that the present invention makes all is being higher than the comparative example aspect yield and the chromatographic purity.
Although the foregoing description describes in detail technical scheme of the present invention, but technical scheme of the present invention is not limited to above embodiment, under the situation that does not break away from thought of the present invention and aim, any change that technical scheme of the present invention is done all will fall into claims of the present invention institute restricted portion.
Claims (10)
1. synthetic method suc as formula the beta-methylcarbapenem antibiotics intermediate shown in the I is characterized in that described method comprises:
A. compound shown in the formula II and p-toluene sulfonyt azide are reacted in a kind of and the immiscible solvent of water, obtain the mixture of the compound shown in para toluene sulfonamide and the formula I;
B. use the compound shown in the formula I in a kind of dissolution with solvents mixture, insoluble para toluene sulfonamide is removed by filter, obtain the crude product of the compound shown in the formula I after concentrating;
C. with polar solvent with the crude product recrystallization, obtain the highly finished product of the compound shown in the formula I.
2. method according to claim 1 is characterized in that, is one or more mixture in chloroform, methylene dichloride, ethylene dichloride, the toluene with the immiscible solvent of water described in the step a.
3. method according to claim 2 is characterized in that, is methylene dichloride or toluene with the immiscible solvent of water described in the step a.
4. method according to claim 1 is characterized in that, the mol ratio of the compound shown in p-toluene sulfonyt azide described in the step a and the formula II is 1: 1～1.2: 1.
5. method according to claim 4 is characterized in that, the mol ratio of the compound shown in p-toluene sulfonyt azide described in the step a and the formula II is 1.05: 1.
6. method according to claim 1 is characterized in that, adds organic bases in step a, as triethylamine.
7. method according to claim 1 is characterized in that, solvent described in the step b is one or more the mixture in chloroform, methylene dichloride, the toluene.
8. method according to claim 7 is characterized in that, solvent described in the step b is methylene dichloride or toluene.
9. method according to claim 1 is characterized in that, polar solvent described in the step c is one or more the mixture in methyl alcohol, ethanol, Virahol, the ethyl acetate.
10. method according to claim 9 is characterized in that, polar solvent described in the step c is ethanol or Virahol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690282A (en) * | 2011-07-07 | 2012-09-26 | 深圳市海滨制药有限公司 | Crystal-form 1beta methylcarbapenem antibiotic intermediate and preparation method thereof |
| CN103214507A (en) * | 2013-04-10 | 2013-07-24 | 浙江九洲药业股份有限公司 | Preparation method of nitrogen heterocyclic compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62255494A (en) * | 1986-04-25 | 1987-11-07 | Nippon Redarii Kk | (1r)-1-substituted-2-oxocarbapenem-3-carboxylic acid derivative |
| JP3479720B2 (en) * | 1992-07-08 | 2003-12-15 | 武田薬品工業株式会社 | Method for producing carbapenems |
| CN101500992A (en) * | 2006-08-15 | 2009-08-05 | 明治制果株式会社 | Method for producing 1-methylcarbapenem production intermediate |
-
2010
- 2010-08-13 CN CN 201010255356 patent/CN101906115B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62255494A (en) * | 1986-04-25 | 1987-11-07 | Nippon Redarii Kk | (1r)-1-substituted-2-oxocarbapenem-3-carboxylic acid derivative |
| JP3479720B2 (en) * | 1992-07-08 | 2003-12-15 | 武田薬品工業株式会社 | Method for producing carbapenems |
| CN101500992A (en) * | 2006-08-15 | 2009-08-05 | 明治制果株式会社 | Method for producing 1-methylcarbapenem production intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 《中国药物化学杂志》 20080430 陈晓芳等 帕尼培南关键中间体2-酮碳青霉烷-3-羧酸对硝基苄酯的合成改进 119-122 1-10 第18卷, 第2期 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690282A (en) * | 2011-07-07 | 2012-09-26 | 深圳市海滨制药有限公司 | Crystal-form 1beta methylcarbapenem antibiotic intermediate and preparation method thereof |
| CN103214507A (en) * | 2013-04-10 | 2013-07-24 | 浙江九洲药业股份有限公司 | Preparation method of nitrogen heterocyclic compound |
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Owner name: ZHEJIANG HISOAR CHUANNAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: ZHEJIANG HAIXIANG PHARMACEUTICAL CO., LTD. Effective date: 20121203 Owner name: ZHEJIANG HAIXIANG PHARMACEUTICAL CO., LTD. Effective date: 20121203 |
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Effective date of registration: 20121203 Address after: 317016 chemical raw material base of Taizhou, Zhejiang, Donghai Park, No. 23 Donghai Fifth Avenue Patentee after: Zhejiang Hisoar Pharmaceutical Co., Ltd. Patentee after: Zhejiang Hisoar Pharmaceutical Co., Ltd. Address before: 318000, No. 100, Sha Wai Road, Jiaojiang District, Zhejiang, Taizhou Patentee before: Zhejiang Hisoar Pharmaceutical Co., Ltd. |