CN108822014B - Synthetic method of avibactam intermediate - Google Patents
Synthetic method of avibactam intermediate Download PDFInfo
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- CN108822014B CN108822014B CN201810563927.4A CN201810563927A CN108822014B CN 108822014 B CN108822014 B CN 108822014B CN 201810563927 A CN201810563927 A CN 201810563927A CN 108822014 B CN108822014 B CN 108822014B
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Abstract
The invention discloses a synthetic method of an avibactam intermediate, belonging to the technical field of pharmaceutical chemistry synthesis. The synthesis method provided by the invention has the advantages that pyroglutamic acid ester with amino protecting group and trimethyl sulfoxide iodide react in a reaction solvent under the action of carbonate to prepare the intermediate of abamectin, so that the problems of large potential safety hazard, difficult process control and more impurities in the strong base process method in the prior art are solved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a synthetic method of an avibactam intermediate.
Background
Abamebactam (NXL104), chemically known as ((2S, 5R) -2-aminocarbonyl-7-oxo-1, 6-diazabicyclo [3, 2, 1] oct-6-yl) sulfuric acid monoester, is a non- β -lactam β -lactamase inhibitor developed by Novexel (Novexel corporation). Abamebactam belongs to diazabicyclooctanone compounds, and does not have significant antibacterial activity per se, but acts by inhibiting β -lactamase. Abamebactam can inhibit type A (including ESBL and KPC), partial C and partial D β -lactamase. Abamebactam, and therefore, when used in combination with penicillins, cephalosporins and carbapenems antibiotics, has broad-spectrum antibacterial activity, particularly has significant complexity for the activity of Escherichia coli containing the broad-spectrum β -lactamase and Klebsiella pneumoniae, Escherichia coli containing the hyperphostromactam, and broad-spectrum Escherichia coli containing ampC lactamase, β -superfused as a broad-spectrum antibiotic, has no significant activity for the Escherichia coli containing ampC, MRE, MRA, MRE MRA, MRA MRE, MRE, MRE, MRE MR.
Unlike semi-synthetic β -lactamase inhibitors such as clavulanic acid, sulbactam, tazobactam and the like, the avibactam is chemically synthesized, the structure of the avibactam is complex, the development of a simple and efficient synthesis method is very urgent, at present, the synthesis of the avibactam basically takes L-pyroglutamic acid with a protective group as a raw material, five-membered ring of the pyroglutamic acid is subjected to ring opening and then ring closing to form a six-membered ring required by the avibactam, II is an important intermediate, the II can construct a basic skeleton of the avibactam through reactions such as deprotection, ring closing, reduction and the like, a plurality of patents disclose subsequent reaction steps, the synthesis of the II basically uses I and trimethyl sulfoxide iodide for reaction, the reaction needs to use strong base to react with the trimethyl sulfoxide to generate the thiofolide, the documents use strong bases such as sodium hydride, potassium tert-butoxide and the like (U.S. Pat. No. 2012323010A1, EP2657234A1, CN 201029765) and the strong base process method has the following problems that (1) the requirements on equipment and operation are high, the generation of strong base, the strong base of strong base, the hydrogen-potassium hydride, the potential of the strong base, the hydrogen-potassium hydride, the strong base, the potential of the strong base, the hydrogen-potassium ion.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the synthetic method of the avibactam intermediate, which has the advantages of mild reaction conditions, simple operation, high safety of process operation, high yield and high product purity, and is suitable for industrial production.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a synthetic method of an avibactam intermediate is characterized in that a compound I and trimethyl sulfoxide iodide react in a reaction solvent under the action of carbonate to prepare a compound II, and the chemical reaction formula is as follows:
wherein, P is tert-butyloxycarbonyl or benzyloxycarbonyl; r is one of benzyl, methyl, ethyl, tertiary butyl and allyl.
In a preferred embodiment of the present invention, the carbonate is one of potassium carbonate, sodium carbonate and cesium carbonate, and preferably potassium carbonate.
As a preferred embodiment of the present invention, the reaction solvent is dimethyl sulfoxide or N, N-dimethylformamide, preferably dimethyl sulfoxide.
In a preferred embodiment of the present invention, the molar ratio of trimethyl sulfoxide iodide to compound I is 1.0 to 3.0: 1, preferably 1.7-2.2: 1.
in a preferred embodiment of the present invention, the molar ratio of the carbonate to the compound I is 2 to 8: 1, preferably 3-5: 1.
in a preferred embodiment of the present invention, the volume-to-mass ratio of the reaction solvent to the compound I is 10 to 50mL/g, preferably 20 to 30 mL/g.
In a preferred embodiment of the present invention, the reaction temperature of the reaction is 30 to 60 ℃, preferably 45 to 55 ℃; the reaction time is 10-30 h, preferably 16-24 h.
As a preferred embodiment of the present invention, the present invention further comprises the steps of: and in the post-treatment process, firstly adding a saturated ammonium chloride solution, adding purified water for dilution, adding an organic solvent for extraction, adding a drying agent for drying, and then concentrating under reduced pressure to obtain an avibactam intermediate.
Compared with the prior art, the invention has the beneficial effects that:
the synthesis method of the avibactam intermediate disclosed by the invention has the following advantages that weak base carbonate is adopted to replace strong base:
(1) the carbonate is cheap, and the process cost is low; the carbonate is safe and does not need special storage;
(2) the carbonate belongs to weak base, has low requirement on moisture, does not need to remove water from a solvent, and has low requirement on equipment and operation;
(3) the carbonate has relatively weak activity, does not react with functional groups such as ester groups and the like, has few byproducts and high product purity, and does not need additional purification steps.
The synthesis method disclosed by the invention avoids the problems of large potential safety hazard, difficult process control and more impurities existing in a strong alkali process method in the prior art, is mild in reaction condition, simple to operate, high in process operation safety, high in yield and high in product purity, and is suitable for industrial production.
Drawings
FIG. 1 is a liquid chromatogram of the product synthesized according to the method of the invention of example 1;
FIG. 2 is a liquid chromatogram of the product of example 6 synthesized according to the prior art;
FIG. 3 is a liquid phase spectrum of N-Boc-pyroglutamic acid benzyl ester as a starting material in examples 1, 2, 3 and 6.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
A synthetic method of an avibactam intermediate is characterized in that a compound I and trimethyl sulfoxide iodide react in a reaction solvent under the action of carbonate to prepare a compound II, and the chemical reaction formula is as follows:
adding saturated ammonium chloride solution, adding purified water for dilution, adding an organic solvent for extraction, adding a drying agent for drying, and then carrying out reduced pressure concentration to obtain the avibactam intermediate.
Wherein, P is tert-butyloxycarbonyl or benzyloxycarbonyl; r is one of benzyl, methyl, ethyl, tertiary butyl and allyl. The carbonate is one of potassium carbonate, sodium carbonate and cesium carbonate, preferably potassium carbonate. The reaction solvent is dimethyl sulfoxide or N, N-dimethylformamide, and dimethyl sulfoxide is preferred. The molar ratio of trimethyl sulfoxide iodide to the compound I is 1.0-3.0: 1, preferably 1.7-2.2: 1. the molar ratio of the carbonate to the compound I is 2-8: 1, preferably 3-5: 1. the volume-to-mass ratio of the reaction solvent to the compound I is 10-50 mL/g, preferably 20-30 mL/g. The reaction temperature of the reaction is 30-60 ℃, and preferably 45-55 ℃; the reaction time is 10-30 h, preferably 16-24 h.
In the following examples, the HPLC method was as follows: a chromatographic column: c18150 × 4.5mm × 3.5 μm, mobile phase: acetonitrile (a) + 0.1% phosphoric acid water (B), flow rate: 1.0mL/min, detection wavelength: 210nm, column temperature: at 40 ℃. The gradient is shown in table 1:
TABLE 1 HPLC elution gradient
| Time (min) | A | |
| 0 | 95 | 5 |
| 7 | 55 | 45 |
| 20 | 30 | 70 |
| 22 | 10 | 90 |
| 25 | 10 | 90 |
| 26 | 95 | 5 |
| 30 | Stop | - |
Example 1:
into a 3L three-necked flask, 900mL of dimethyl sulfoxide, 55.2g (2.0eq, 250.9mmol) of trimethyl sulfoxide iodide, 70.0g (4.0eq, 506.9mmol) of potassium carbonate and 40.0g (1.0eq, 125.4mmol) of benzyl N-Boc-pyroglutamate were charged and heated to 50 ℃ for reaction for 23 hours. After that, heating was stopped, 500mL of a saturated aqueous ammonium chloride solution was added dropwise, and after completion of the addition, 500mL of purified water was added to dilute the solution, followed by extraction with ethyl acetate (500 mL. times.2). And (3) combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 49.5g of a light yellow solid product with the yield of 96% and the purity of 96.0%, wherein a liquid phase spectrogram is shown in a figure 1, the data of the liquid phase spectrogram is shown in a table 2, and ESI-MS m/z is as follows: 412.2([M+H]+)。
Table 2 liquid chromatogram data of the product of example 1
Example 2:
1000mL of dimethyl sulfoxide, 50.0(1.8eq, 227.3mmol) of trimethyl sulfoxide iodide, 61.0g (3.5eq, 441.7mmol) of potassium carbonate, and 40.0g (1.0eq, 125.4mmol) of benzyl N-Boc-pyroglutamate were charged in a 3L three-necked flask, and the mixture was heated to 45 ℃ for reaction for 20 hours. After the heating was stopped, 500mL of a saturated aqueous ammonium chloride solution was added dropwise, and 500mL of purified water was added thereto for dilution, followed by extraction with ethyl acetate (500 mL. times.2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 47.4g of a yellow solid product in 92% yield and 94.9% purity.
Example 3:
into a 3L three-necked flask, 900mL of dimethyl sulfoxide, 55.2g (2.0eq, 250.9mmol) of trimethyl sulfoxide iodide, 78.0g (4.5eq, 564.8mmol) of potassium carbonate, and 40.0g (1.0eq, 125.4mmol) of benzyl N-Boc-pyroglutamate were charged and heated to 55 ℃ for reaction for 25 hours. After the heating was stopped, 500mL of a saturated aqueous ammonium chloride solution was added dropwise, and 500mL of purified water was added thereto for dilution, followed by extraction with ethyl acetate (500 mL. times.2). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 49.1g of a yellow solid product, the yield is 95 percent, and the purity is 95.7 percent.
Example 4:
into a 3L three-necked flask, 1000mL of dimethyl sulfoxide, 77.0g (2.0eq, 350.0mmol) of trimethyl sulfoxide iodide, 97.0g (4.0eq, 702.4mmol) of potassium carbonate, and 50.0g (1.0eq, 175.3mmol) of N-Boc-pyroglutamic acid tert-butyl ester were charged and reacted at 50 ℃ for 21 hours. After the heating was stopped, 500mL of a saturated aqueous ammonium chloride solution was added dropwise, and 500mL of purified water was added thereto for dilution, followed by extraction with ethyl acetate (500 mL. times.2). Mixing organic phases, washing with saturated saline water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain yellow61.5g of a colored oil was obtained in 93% yield. ESI-MS m/z: 378.2([ M + H)]+)。
Example 5:
into a 3L three-necked flask, 1000mL of dimethyl sulfoxide, 75.2g (2.0eq, 341.8mmol) of trimethyl sulfoxide iodide, 95.0g (4.0eq, 687.9mmol) of potassium carbonate, and 50.0g (1.0eq, 171.6mmol) of ethyl N-Cbz-pyroglutamate were charged, and the mixture was heated to 50 ℃ and reacted for 21 hours. After the heating was stopped, 500mL of a saturated aqueous ammonium chloride solution was added dropwise, and then 500mL of purified water was added thereto for dilution, followed by extraction with ethyl acetate (500 mL. times.2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 64.5g of a yellow oil with a yield of 98%. ESI-MS m/z: 384.1([ M + H)]+)。
Example 6: synthesizing an avibactam intermediate according to the method disclosed in the prior art patent US2012323010A1
Under nitrogen protection, 200mL of anhydrous tetrahydrofuran, 39.7g (1.15eq, 180.5mmol) of trimethyl sulfoxide iodide, 19.3g (1.1eq, 172.0mmol) of potassium tert-butoxide, and 250mL of anhydrous dimethyl sulfoxide were sequentially added to a 2L three-necked flask, and the mixture was stirred at room temperature for 1 hour. Cooling to-10-15 deg.C, dropping 50.0g (1.0eq, 156.7mmol) of N-Boc-pyroglutamic acid benzyl ester anhydrous tetrahydrofuran solution (150mL) under the protection of nitrogen, and continuing to react at-10-15 deg.C until the liquid chromatogram detects that the raw materials have reacted completely. 250mL of a precooled saturated aqueous ammonium chloride solution was added, and the mixture was diluted with 150mL of ice water and extracted with ethyl acetate (500 mL. times.2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 61.2g of a yellow oil with a yield of 95% and a purity of 64.9%, as shown in FIG. 2, and as shown in Table 3.
Table 3 liquid chromatogram data of the product of example 6
Example 7:
the liquid chromatogram of the starting material, benzyl N-Boc-pyroglutamate, used in examples 1, 2, 3 and 6 is shown in FIG. 3, and the data of the liquid chromatogram is shown in Table 4.
TABLE 4 liquid chromatogram data of example 7N-Boc-benzyl pyroglutamate
As can be seen from fig. 1 to 3, the impurities of the product in example 6 are not derived from the raw material, N-Boc-pyroglutamic acid benzyl ester, and the avibactam intermediate prepared by the synthesis method of the present invention has high purity and low impurity content, so that compared with the prior art, the present invention has the advantages of greatly reduced impurity content, high process operation safety, high yield, high product purity, and suitability for industrial production. In the technical field of chemical synthesis, the purity of the synthesis of bulk drugs is of great importance. Impurities in the raw material medicaments not only affect the subsequent preparation and other processes, so that the quality standard of the medicaments cannot meet the requirements, but also cause serious adverse reactions of human bodies and harm to the health of the human bodies. The invention greatly improves the purity of the medicine and has outstanding contribution to ensuring the effectiveness and the safety of the medicine.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (9)
1. A synthetic method of an avibactam intermediate is characterized by comprising the following steps: reacting a compound I with trimethyl sulfoxide iodide in a reaction solvent under the action of carbonate to obtain a compound II, wherein the chemical reaction formula is as follows:
wherein the content of the first and second substances,
p is tert-butoxycarbonyl or benzyloxycarbonyl; r is one of benzyl, methyl, ethyl, tertiary butyl and allyl; the carbonate is one of potassium carbonate, sodium carbonate and cesium carbonate.
2. The method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the reaction solvent is dimethyl sulfoxide or N, N-dimethylformamide.
3. The method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the molar ratio of trimethyl sulfoxide iodide to the compound I is 1.0-3.0: 1.
4. the method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the molar ratio of trimethyl sulfoxide iodide to the compound I is 1.7-2.2: 1.
5. the method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the molar ratio of the carbonate to the compound I is 2-8: 1.
6. the method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the molar ratio of the carbonate to the compound I is 3-5: 1.
7. the method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the volume-mass ratio of the reaction solvent to the compound I is 10-50 mL/g.
8. The method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: the reaction conditions were as follows: the reaction temperature is 30-60 ℃, and the reaction time is 10-30 h.
9. The method for synthesizing an avibactam intermediate according to claim 1, wherein the method comprises the following steps: also comprises the following post-treatment steps: adding saturated ammonium chloride solution, adding purified water for dilution, adding an organic solvent for extraction, adding a drying agent for drying, and then carrying out reduced pressure concentration to obtain the avibactam intermediate.
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