CN110938058A - Preparation method of oxazolidinone antibiotic intermediate - Google Patents
Preparation method of oxazolidinone antibiotic intermediate Download PDFInfo
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Abstract
The invention provides a preparation method of tedizolid phosphate intermediate compound 3-fluoro-4- (6- (2-methyltetrazol-5-yl) pyridine-3-yl) benzyl phenyl carbamate, which takes 5-bromo-2- (2-methyltetrazol-5-yl) pyridine as a raw material, firstly reacts with triisopropyl borate under the action of n-butyllithium to prepare a boric acid intermediate, then is coupled with 1, 2-difluoro-4-nitrobenzene, and finally is subjected to nitro reduction and amidation to prepare the required target. Compared with the prior art, the preparation method has the advantages of easily available raw materials, simple process, economy, environmental protection and suitability for industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a tedizolid phosphate intermediate.
Background
Tedizolid phosphate (Tedizolid phosphate) is an oxazolidinone antibiotic developed by the Carpess tailor-made drug company (Cubist), which is approved by the FDA on the market at 6/10.2014 under the trade name Sivextro, and is used for treating acute bacterial skin and skin structure infections caused by gram-positive bacteria such as Staphylococcus aureus and various Streptococcus and enterococcus faecalis. The tedizolid phosphate is an oxazolidinone antibiotic, can inhibit the synthesis of bacterial protein by combining with bacterial ribosome 50S subunit, plays an antibacterial role, is not easy to generate cross drug resistance with other antibiotics, and has better curative effect and higher safety compared with the first oxazolidinone antibiotic linezolid.
Tedizolid phosphate, which has the chemical name of ((5R) -3- (4- (6- (2-methyl-2H-tetrazol-5-yl) -3-pyridyl) -3-fluorophenyl) -2-oxo-5-oxazolidinyl) methyl phosphate, and has the structure shown in the formula (I):
for the synthesis of the compound of formula (I), the following synthesis process is disclosed in chinese patent CN 102177156A:
and examples 5 to 7 of the description specifically disclose the compounds of the above formula (I) (corresponding to the above reaction scheme wherein Het is 2-methyltetrazol-5-yl, X is Br, Y is BR3R4、R1a is F, R1b is H, R2Is Bz, R is H and R' is PO (OH)2) And (4) preparing. The method adopts Pd2(dba)3The corresponding intermediate (II) is synthesized by the catalytic Suzuki coupling reaction, the palladium catalyst is expensive, so the total cost is increased, and the adopted ligand tricyclohexylphosphine is particularly sensitive to oxygen, so the cost of the reaction reagent is high, the reaction condition is harsh, and the industrial amplification is not facilitated.
Chinese patent CN105367547A also discloses the preparation of the above intermediate (II) using a similar reaction route as described above, except that the X, Y group is inverted, and the Miyaura reaction and Suzuki reaction therein use a one-pot process:
however, this method still does not avoid the use of expensive palladium catalysts and corresponding ligands, and is also disadvantageous for industrial scale-up.
The technical problem to be solved by the invention is to overcome the defects of the prior art, and provide an improved preparation method of a tedizolid phosphate intermediate compound, which has the advantages of mild reaction conditions, simple and convenient operation, cheap and easily-obtained reagents, high reaction yield and suitability for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of a tedizolid phosphate intermediate compound 1, which has the advantages of easily available raw materials, simple process, economy, environmental protection and suitability for industrialization, aiming at the defects in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of tedizolid phosphate intermediate compound 1 comprises the following steps:
(1) reacting 5-bromo-2- (2-methyltetrazol-5-yl) pyridine (compound 2) serving as a raw material with triisopropyl borate in the presence of n-butyllithium to obtain an intermediate 2- (2-methyltetrazol-5-yl) pyridine-5-boric acid (compound 3);
(2) the intermediate compound 3 is treated with CuI/Cs in the presence of tetrabutylammonium bromide2CO3The system is catalyzed to react with 1, 2-difluoro-4-nitrobenzene to obtain an intermediate 5- (2-fluoro-4-nitrophenyl) -2- (2-methyltetrazol-5-yl) pyridine (compound 4);
(3) intermediate compound 4 in Fe/NH4Reducing in Cl system to obtain 3-fluoro-4- (6- (2-methyltetrazol-5-yl) pyridin-3-yl) aniline (compound 5);
(4) and carrying out substitution reaction on the intermediate compound 5 and CbzCl in the presence of alkali to obtain the target compound 1.
The reaction equation is as follows:
further, in the above reaction step (1), the molar ratio of the compound 2 to triisopropyl borate is 1: (1-1.4); the molar ratio of the compound 2 to n-butyllithium is 1: (2-2.5); the reaction is carried out at-78 deg.C to-70 deg.C, and the reaction solvent is selected from tetrahydrofuran, 1, 4-dioxane, etc.
In the above reaction step (2), the molar ratio of the compound 3 to 1, 2-difluoro-4-nitrobenzene is 1: (0.7-1.1) and the compound 3 is mixed with CuI, TBAB and Cs2CO3In a molar ratio of 1: (0.35-0.45): (0.1-0.2): (1.5-2); the reaction is carried out at the temperature of 145-150 ℃, and the reaction solvent is selected from DMSO, DMF or a mixed solvent of the DMSO and the DMF.
In the reaction step (3), the reduction is carried out by fixing iron powder and ammonium chloride, and the molar ratio of the compound 4 to the iron powder and ammonium chloride solids is 1: (5-7): (4-6); the reaction is carried out at 75-85 ℃, and the reaction solvent is selected from a mixed solvent of ethanol and water. After the reaction is completed, concentrating the reaction solution to be dry, and putting the reaction solution into the next reaction without further purification.
In the above reaction step (4), the base is selected from alkali metal carbonates or alkali metal bicarbonates, preferably sodium carbonate; the molar ratio of the base to the CbzCl to the compound 4 in the step (3) is (1.8-2.5): (1.1-1.3): 1; the reaction is carried out at a temperature ranging from-10 ℃ to 0 ℃.
Compared with the prior art, the preparation method of the tedizolid phosphate intermediate compound 1 has the advantages of easily available raw materials, simple process, economy, environmental protection and suitability for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be noted that, for those skilled in the art, without departing from the inventive concept of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be considered as the protection scope of the present invention.
The experimental procedures, in which specific conditions are not specified, in the following examples were carried out according to conventional conditions or according to conditions recommended by the manufacturers. In the preparation examples described below, the NMR was determined by means of a Bruker model AV III 400 NMR spectrometer with chemical shifts in ppm.
Example 1.2- (2-methyltetrazol-5-yl) pyridin-5-BPreparation of acid (Compound 3)
5-bromo-2- (2-methyltetrazol-5-yl) pyridine (compound 2, 20g, 0.083mol), THF (200mL), and triisopropyl borate (17.17g, 0.091mol, 1.1 equiv.) were added to a 500mL three-necked reaction flask with an addition funnel and nitrogen gas inlet adapter under a nitrogen atmosphere, and the mixture was cooled to-72 ℃. N-butyllithium (15.3ml, 0.183mol, 2.2 eq) was added portionwise to the addition funnel, dropwise over about 2 hours, with the temperature controlled to not exceed-65 ℃. After completion of the reaction as confirmed by HPLC, the reaction solution was quenched with 100ml of 20% (w/w) aqueous ammonium chloride solution. When the reaction mixture had warmed to room temperature (two-phase separation), the THF layer was separated and concentrated to dryness under reduced pressure. The crude product was slurried with 30mL of dichloromethane at room temperature, filtered off with suction, washed with a little dichloromethane and dried in vacuo to give 12.81g of compound 3 in 75.3% yield. MS M/z 206[ M +1 ]]+。
EXAMPLE 2 preparation of 5- (2-fluoro-4-nitrophenyl) -2- (2-methyltetrazol-5-yl) pyridine (Compound 4)
To a reaction flask, under nitrogen, was added compound 3(12.50g, 0.061mol), 1, 2-difluoro-4-nitrobenzene (7.48g, 0.047mol, 0.77 eq), CuI (4.48g, 0.024mol, 0.39 eq), tetrabutylammonium bromide TBAB (3.03g, 0.009mol, 0.15 eq), cesium carbonate (30.62g, 0.094mol, 1.54 eq), and DMSO (120 mL). The mixture was heated and stirred between 145 ℃ and 150 ℃ until the substrate concentration no longer changed as monitored by HPLC. The reaction solution is cooled to room temperature, filtered, the filtrate is poured into 300mL of ether for extraction, an organic layer is separated, the mixture is washed by saturated saline solution and dried by anhydrous sodium sulfate, and the mixture is decompressed and concentrated to be dry to obtain a crude product. The crude product is further pulped with ethanol (30ml), filtered and the filter cake is dried in vacuum to obtain 12.85g of compound 4 with the yield of 70.2%. MS M/z 301[ M +1 ]]+。
Example 3.3-fluoro-4- (6- (2-methyltetrazole-)Preparation of 5-yl) pyridin-3-yl) aniline (Compound 5)
Compound 4(12.49g, 0.042mol), ethanol (120ml) and water (40ml) were added to the reaction flask, and then ammonium chloride solid (13.48g, 0.252mol, 6 equivalents) and iron powder (11.73g, 0.210mol, 5 equivalents) were added to the reaction flask. The reaction mixture was heated to 80 ℃ for reaction until the reaction was complete as monitored by HPLC. Cooling to room temperature, filtering the reaction solution, and concentrating the filtrate under reduced pressure to dryness. To the resulting residue was added water (50ml), followed by extraction with ethyl acetate (100 ml. times.2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated again to dryness under reduced pressure. The product obtained was used in the next step without isolation.
Example 4.3-fluoro-4- (6- (2-methyltetrazol-5-yl) pyridin-3-yl) phenylcarbamic acid benzyl ester (Compound
1) Preparation of
Tetrahydrofuran (100ml) was added to the crude product obtained in example 3, then solid sodium bicarbonate (7.06g, 0.084mol, 2 equivalents) was added to the reaction system, after cooling to 0 ℃ with stirring, CbzCl (7.5ml, 0.052mol, 1.24 equivalents) was added slowly thereto, and the reaction was continued at 0 ℃ until the reaction was complete as monitored by HPLC. After extraction with 50ml of ethyl acetate, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (mobile phase: dichloromethane: methanol ═ 100:1) to give 14.1g of compound 1 (total yield in two steps 83.02%) with an HPLC purity of 98.6%. MS M/z 406[ M +1 ]]+。
Claims (10)
1. A preparation method of tedizolid phosphate intermediate compound 1 is characterized by comprising the following steps:
(1) reacting 5-bromo-2- (2-methyltetrazol-5-yl) pyridine (compound 2) serving as a raw material with triisopropyl borate in the presence of n-butyllithium to obtain an intermediate 2- (2-methyltetrazol-5-yl) pyridine-5-boric acid (compound 3);
(2) the intermediate compound 3 is treated with CuI/Cs in the presence of tetrabutylammonium bromide2CO3The system is catalyzed to react with 1, 2-difluoro-4-nitrobenzene to obtain an intermediate 5- (2-fluoro-4-nitrophenyl) -2- (2-methyltetrazol-5-yl) pyridine (compound 4);
(3) intermediate compound 4 in Fe/NH4Reducing in Cl system to obtain 3-fluoro-4- (6- (2-methyltetrazol-5-yl) pyridin-3-yl) aniline (compound 5);
(4) carrying out substitution reaction on the intermediate compound 5 and CbzCl in the presence of alkali to obtain a target compound 1;
the reaction equation is as follows:
2. the production method according to claim 1, wherein in the reaction step (1), the molar ratio of the compound 2 to triisopropyl borate is 1: (1-1.4); the molar ratio of the compound 2 to n-butyllithium is 1: (2-2.5).
3. The process according to claim 1, wherein the reaction is carried out at a temperature in the range of-78 ℃ to-70 ℃ and the reaction solvent is selected from tetrahydrofuran and 1, 4-dioxane.
4. The production method according to claim 1, wherein in the reaction step (2), the molar ratio of the compound 3 to 1, 2-difluoro-4-nitrobenzene is 1: (0.7-1.1) and the compound 3 is mixed with CuI, TBAB and Cs2CO3In a molar ratio of 1: (0.35-0.45): (0.1-0.2): (1.5-2).
5. The preparation method according to claim 1, wherein the reaction is carried out at a temperature of 145-150 ℃ and the reaction solvent is selected from DMSO, DMF or a mixture thereof.
6. The method of claim 1, wherein in the reacting step (3), the reduction is performed using iron powder and ammonium chloride fixation, and the molar ratio of the compound 4 to the iron powder and ammonium chloride solids is 1: (5-7): (4-6).
7. The method according to claim 1, wherein the reaction is carried out at 75 to 85 ℃ and the reaction solvent is selected from a mixed solvent of ethanol and water.
8. The method according to claim 7, wherein the reaction mixture is concentrated to dryness after completion of the reaction, and then subjected to the next reaction without further purification.
9. The production method according to claim 1, wherein in the reaction step (4), the base is selected from an alkali metal carbonate or an alkali metal bicarbonate, preferably sodium carbonate.
10. The process according to claim 1, wherein the molar ratio of the base, CbzCl, relative to compound 4 in step (3) is (1.8-2.5): (1.1-1.3): 1; the reaction is carried out at a temperature ranging from-10 ℃ to 0 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248471A (en) * | 2021-07-05 | 2021-08-13 | 南京桦冠生物技术有限公司 | Preparation method of zolamide drug intermediate and intermediate thereof |
| CN113354620A (en) * | 2021-07-05 | 2021-09-07 | 南京桦冠生物技术有限公司 | Efficient preparation method of tedizolid intermediate and intermediate thereof |
| CN114105946A (en) * | 2020-08-26 | 2022-03-01 | 浙江苏泊尔制药有限公司 | A kind of tedizolid phosphate intermediate and preparation method thereof |
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| CN102177156A (en) * | 2008-10-10 | 2011-09-07 | 特留斯治疗学公司 | Methods for preparing oxazolidinones and compositions containing them |
| CN106632298A (en) * | 2015-11-03 | 2017-05-10 | 上海科胜药物研发有限公司 | Preparation method of tedizolid and intermediate of tedizolid |
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| CN102177156A (en) * | 2008-10-10 | 2011-09-07 | 特留斯治疗学公司 | Methods for preparing oxazolidinones and compositions containing them |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105946A (en) * | 2020-08-26 | 2022-03-01 | 浙江苏泊尔制药有限公司 | A kind of tedizolid phosphate intermediate and preparation method thereof |
| CN113248471A (en) * | 2021-07-05 | 2021-08-13 | 南京桦冠生物技术有限公司 | Preparation method of zolamide drug intermediate and intermediate thereof |
| CN113354620A (en) * | 2021-07-05 | 2021-09-07 | 南京桦冠生物技术有限公司 | Efficient preparation method of tedizolid intermediate and intermediate thereof |
| CN113248471B (en) * | 2021-07-05 | 2021-09-21 | 南京桦冠生物技术有限公司 | Preparation method of zolamide drug intermediate and intermediate thereof |
| WO2023279773A1 (en) * | 2021-07-05 | 2023-01-12 | 南京桦冠生物技术有限公司 | Efficient preparation method for tedizolid intermediate, and intermediate |
| JP2023539539A (en) * | 2021-07-05 | 2023-09-15 | ナンジン チェンピオン バイオテクノロジー カンパニー リミテッド | Efficient method for preparing tedizolid intermediate and its intermediate |
| JP7405967B2 (en) | 2021-07-05 | 2023-12-26 | ナンジン チェンピオン バイオテクノロジー カンパニー リミテッド | Efficient method for preparing tedizolid intermediate and its intermediate |
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