CN110590618A - Preparation method of avibactam intermediate - Google Patents
Preparation method of avibactam intermediate Download PDFInfo
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- CN110590618A CN110590618A CN201910834688.6A CN201910834688A CN110590618A CN 110590618 A CN110590618 A CN 110590618A CN 201910834688 A CN201910834688 A CN 201910834688A CN 110590618 A CN110590618 A CN 110590618A
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- avibactam
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
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Abstract
The invention discloses a preparation method of an avibactam intermediate, wherein a compound I and trimethyl sulfoxide iodide react in the presence of alkali to prepare a compound II; the structures of the compound I and the compound II are as follows: r is one of methyl, ethyl, benzyl, tertiary butyl and allyl; the alkali is one or more of magnesium hydroxide, lithium hydroxide and calcium hydroxide. The preparation method of the avibactam intermediate uses pyroglutamic acid ester with double protection as a raw material to react with trimethyl sulfoxide iodide in the presence of alkali to obtain the avibactam intermediate, avoids the defects of potential safety hazard, strict reaction condition requirement, strict process control requirement and the like of strong alkali in the prior art, and has the advantages of mild reaction condition, simple operation, high safety, less reaction impurities and the like.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an avibactam intermediate.
Background
Abamebactam (avibactam) is a novel beta-lactamase inhibitor with a non-beta-lactam structure, and is combined with a broad-spectrum cephalosporin ceftazidime (ceftazidime) to treat complex intraperitoneal infection (cIAI) and complex urinary tract infection (cUTI), and the combination is approved by FDA at present and sold on the market under the name of Avycaz. Combinations with other antibiotics (e.g., ceftaroline fosamil, thiaximo monoamides, etc.) are under clinical investigation. Compared with 3 beta-lactamase inhibitors on the market, clavulanic acid, sulbactam and tazobactam, the abamectin has stronger effect and wider range, and has obvious inhibition effect on A, C and part D beta-lactamase.
The abamectin has a diazabicyclooctane framework, has a structure different from that of a classical beta-lactamase inhibitor, can be recovered by reverse reaction, and has a long-acting enzyme inhibition effect. In addition, the classical beta-lactamase inhibitor has no or weak inhibition effect on C-class enzyme, but the abamectin has obvious effect of inhibiting the C-class enzyme and wider enzyme inhibition spectrum. Abamebactam is clinically applied in the form of sodium salt, the chemical name of the Abamebactam is sulfuric acid mono [ (1R,2S,5R) -2-aminocarbonyl-7-oxo-1, 6-azabicyclo [3.2.1] oct-6-yl ester sodium salt, and the specific structure is as follows:
there are many reports on the synthesis of avibactam, such as CN103649051B, CN106699756A, US2012323010A1, EP2657234A1, etc. All use strong bases such as sodium hydrogen, potassium tert-butoxide and the like, have high requirements on reaction moisture, need dehydration treatment of a solvent, difficult process control and more reaction impurities.
Patent document CN 108822014 a discloses a method for synthesizing an avibactam intermediate, which uses carbonate as alkali to perform reaction, but the carbonate is weak in alkalinity, so the reaction time is long, the use amount of the alkali is high, the post-treatment is complicated, and the preparation cost is high. In addition, when carbonate is used as alkali for reaction, bubbles which are difficult to control are easily generated during industrial scale-up experiments, the safety of the industrial process is reduced, and the post-treatment difficulty is increased.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of an avibactam intermediate. The method has the advantages of mild conditions, high safety, simple operation, high reaction purity, less impurities and easy industrial production.
A preparation method of an avibactam intermediate comprises the steps of reacting a compound I with trimethyl sulfoxide iodide in the presence of alkali to prepare a compound II;
the structures of the compound I and the compound II are as follows:
r is one of methyl, ethyl, benzyl, tertiary butyl and allyl; further preferred is an ethyl group or a benzyl group.
The alkali is one or more of magnesium hydroxide, lithium hydroxide and calcium hydroxide. More preferably, magnesium hydroxide or lithium hydroxide. When the alkali is used for reaction, the byproduct is water, the reaction temperature can be directly room temperature or the temperature close to room temperature, and the reaction time is short.
Preferably, the reaction temperature is 20 to 40 ℃. Further preferably 25 to 35 ℃.
Preferably, the reaction time is 1 to 3 hours.
Preferably, the molar ratio of the compound I to the base is 1 (1-2). Further preferably 1 (1-1.5).
Preferably, the molar ratio of the compound I to the trimethyl sulfoxide iodide is 1 (1-3). Further preferably 1 (1-1.5).
Preferably, the solvent is one of dimethyl sulfoxide, dimethylformamide and dioxane.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses a preparation method of an avibactam intermediate, which takes pyroglutamic acid ester with double protection as a raw material to react with trimethyl sulfoxide iodide in the presence of alkali to obtain the avibactam intermediate.
Detailed Description
Example 1:
a preparation method of an avibactam intermediate comprises the following steps of reacting a compound I with trimethyl sulfoxide iodide in a solvent in the presence of alkali to obtain a compound II:
the operation is as follows:
adding 25g (78mmol) of compound I, 100ml of dimethyl sulfoxide, 21.1g (96mmol) of trimethyl sulfoxide iodide and 2.5g (104mmol) of lithium hydroxide into a reaction bottle, keeping the temperature at 30 ℃ until the reaction is completed (about 2 hours), adding 20ml of pure water, 60ml of saturated ammonium chloride and 200ml of EA, separating phases, extracting the aqueous phase once by 50ml of EA, combining organic phases, washing the organic phases for 2 times by saturated saline, reducing the pressure to be dry, crystallizing by isopropyl ether, filtering, drying to obtain 30.9g of compound II, and obtaining the yield: 96 percent, content: 97 percent.
Example 2:
a preparation method of an avibactam intermediate comprises the following steps of reacting a compound I with trimethyl sulfoxide iodide in a solvent in the presence of alkali to obtain a compound II:
the operation is as follows:
putting 20.4g (78mmol) of compound I, 100ml of dimethyl sulfoxide, 21.1g (96mmol) of trimethyl sulfoxide iodide and 2.5g (104mmol) of lithium hydroxide into a reaction bottle, keeping the temperature at 30 ℃ until the reaction is completed (about 1.5 hours), adding 20ml of pure water, 60ml of saturated ammonium chloride and 100ml of EA, carrying out phase separation, extracting the aqueous phase once by 50ml of EA, combining the organic phase, washing for 2 times by saturated saline, reducing the pressure to dryness, crystallizing by isopropyl ether, carrying out suction filtration and drying to obtain 26.1g of compound II, and obtaining the yield: 94%, content: 97 percent.
Example 3:
a preparation method of an avibactam intermediate comprises the following steps of reacting a compound I with trimethyl sulfoxide iodide in a solvent in the presence of alkali to obtain a compound II:
the operation is as follows:
100ml of dimethyl sulfoxide, 21.1g (96mmol) of trimethyl sulfoxide iodide, 25g (78mmol) of a compound I and 5.0g (85.8mmol) of magnesium hydroxide are put into a reaction bottle, the temperature is kept at 30 ℃ until the reaction is completed (about 2.5 hours), 20ml of pure water, 60ml of saturated ammonium chloride and 100 EA100ml are added, phase separation is carried out, an aqueous phase is extracted once by 50ml of EA, an organic phase is combined, saturated saline is used for washing for 2 times, the pressure is reduced to dryness, isopropyl ether is used for crystallization, suction filtration and drying are carried out, and 31.2g of a compound II31, the content: 96%, yield: 97 percent.
Example 4:
a preparation method of an avibactam intermediate comprises the following steps of reacting a compound I with trimethyl sulfoxide iodide in a solvent in the presence of alkali to obtain a compound II:
the operation is as follows:
100ml of dimethyl sulfoxide, 20.4g (78mmol) of a compound I, 21.1g (96mmol) of trimethyl sulfoxide iodide and 5.0g (85.8mmol) of magnesium hydroxide are put into a reaction bottle, the reaction is kept at 30 ℃ until the reaction is completed (about 3 hours), 20ml of pure water, 60ml of saturated ammonium chloride and 100 EA100ml are added, the phases are separated, the aqueous phase is extracted once by 50ml of EA, the organic phase is combined, the organic phase is washed for 2 times by saturated saline, the pressure is reduced to dryness, the isopropyl ether is used for crystallization, the suction filtration and the drying are carried out, and 26.4g of a compound II is obtained, the yield is 95 percent: 97 percent.
Comparative example 1:
comparative experiments were carried out using the reaction conditions of example 1, with respect to the reaction time, the type of base and the amount of base added:
from the above comparative example, it can be seen that, when participating in the reaction of carbonate as a base, the reaction time, the reaction temperature and the molar ratio have a large influence on the final yield, and when similar yields are obtained, the reaction time and the molar amount are much greater than those of the present invention, and the reaction temperature is higher than that of the present invention; when the reaction is carried out by using potassium tert-butoxide as a base, more impurities are generated.
Claims (6)
1. A preparation method of an avibactam intermediate is characterized in that a compound I and trimethyl sulfoxide iodide react in the presence of alkali to prepare a compound II;
the structures of the compound I and the compound II are as follows:
r is one of methyl, ethyl, benzyl, tertiary butyl and allyl;
the alkali is one or more of magnesium hydroxide, lithium hydroxide and calcium hydroxide.
2. The preparation method of the avibactam intermediate according to claim 1, wherein the reaction temperature is 20-40 ℃.
3. The preparation method of the avibactam intermediate according to claim 1, wherein the reaction time is 1-3 hours.
4. The preparation method of the avibactam intermediate according to claim 1, wherein the molar ratio of the compound I to the base is 1 (1-2).
5. The preparation method of the avibactam intermediate according to claim 1, wherein the molar ratio of the compound I to the trimethyl sulfoxide iodide is 1 (1-3).
6. The method for preparing the avibactam intermediate according to claim 1, wherein the solvent is one or more of dimethyl sulfoxide, dimethylformamide and dioxane.
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| CN201910834688.6A CN110590618A (en) | 2019-09-05 | 2019-09-05 | Preparation method of avibactam intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115504913A (en) * | 2021-06-23 | 2022-12-23 | 上海雨程生物科技有限公司 | Synthetic method of avibactam sodium intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010126820A2 (en) * | 2009-04-30 | 2010-11-04 | Merck Sharp & Dohme Corp. | Preparation of alkyl esters of n-protected oxo-azacycloalkylcarboxylic acids |
| WO2014152996A1 (en) * | 2013-03-14 | 2014-09-25 | Cubist Pharmaceuticals, Inc. | Crystalline form of a beta-lactamase inhibitor |
| CN108822014A (en) * | 2018-06-04 | 2018-11-16 | 珠海联邦制药股份有限公司 | A kind of synthetic method of AVM hereinafter Batan intermediate |
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- 2019-09-05 CN CN201910834688.6A patent/CN110590618A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010126820A2 (en) * | 2009-04-30 | 2010-11-04 | Merck Sharp & Dohme Corp. | Preparation of alkyl esters of n-protected oxo-azacycloalkylcarboxylic acids |
| WO2014152996A1 (en) * | 2013-03-14 | 2014-09-25 | Cubist Pharmaceuticals, Inc. | Crystalline form of a beta-lactamase inhibitor |
| CN108822014A (en) * | 2018-06-04 | 2018-11-16 | 珠海联邦制药股份有限公司 | A kind of synthetic method of AVM hereinafter Batan intermediate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115504913A (en) * | 2021-06-23 | 2022-12-23 | 上海雨程生物科技有限公司 | Synthetic method of avibactam sodium intermediate |
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