CN111471041A - Synthetic method of oxazolidinone antibacterial drug intermediate - Google Patents
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Abstract
The invention discloses a synthetic method of an oxazolidinone antibacterial drug intermediate, which comprises the following steps: (1) acetate derivatives IV-1 and 2, 5-disubstituted pyridine IV-2 react in an organic solvent under the action of a metal reagent to obtain a compound IV-3; (2) carrying out reduction reaction on the compound IV-3 in an organic solvent in the presence of a reducing agent to obtain a compound IV-4; (3) reacting the compound IV-4 with methylamine solution to obtain a compound IV-5; (4) carrying out salt forming reaction on the compound IV-5 and chiral acid at the temperature of 20-100 ℃, recrystallizing the obtained salt, and dissociating under the action of alkali to obtain a compound III-4; (5) and carrying out cyclization reaction on the compound III-4 in the presence of a cyclization reagent to obtain the oxazolidinone antibacterial drug intermediate II-8. The method overcomes the defects of the prior art that explosive azide compounds and expensive metal catalysts are adopted, has mild and safe reaction conditions, easily purchased reagents, low cost, shortened reaction steps, avoids column chromatography and is beneficial to industrial production.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, and mainly relates to a synthesis method of an oxazolidinone antibacterial drug intermediate.
Background
The problem of bacterial resistance worldwide is becoming more serious due to abuse of antibiotics, and presents a great challenge for clinical anti-infective therapy, so that the development of antibacterial drugs with a completely new action mechanism is urgent. The oxazolidinone antibacterial drug has a brand new action mechanism different from the existing antibacterial drugs, has good antibacterial activity on various common clinical drug-resistant bacteria, and brings eosin for solving the problem of drug resistance clinically.
The patent report (Z L201210576376.8) discloses a novel tricyclic oxazolidinone antibacterial drug, and a representative compound of the tricyclic oxazolidinone antibacterial drug is shown in a formula I:
wherein M is H or pharmaceutically acceptable salts such as alkali metal, alkaline earth metal, basic amino acid and the like.
The in vivo anti-MRSA activity of the compound (M ═ Na) in the formula I is 2 times that of linezolid, and more importantly, the compound also has high antibacterial activity on linezolid drug-resistant bacteria, so that a powerful weapon is provided for clinically solving the problem of linezolid drug resistance. The compound of formula I (M ═ Na) has good water solubility, can be taken orally or injected for administration, and has excellent pharmacokinetic property, half-life and AUC, and in-vitro and in-vivo antibacterial activity superior to linezolid in rats and dogs. The literature (Journal of medicinal chemistry,2013,56,2642-2650) reports the synthesis of novel oxazolidinone antibacterial drugs in formula I as follows:
a key chiral intermediate II-8 (hereinafter referred to as an oxazolidinone antibacterial drug intermediate) is involved in the route, and the synthesis efficiency of the chiral intermediate has important influence on the whole route. The literature reports that the above synthetic route for intermediate II-8 has several disadvantages: (1) the reaction involves expensive metal catalyst, the production cost is too high; (2) the reaction involves explosive azide and needs to be carried out at high temperature, so that potential safety problems exist; (3) column chromatography is generally adopted in the post-treatment of the multi-step reaction, and the method is not suitable for industrial mass production.
Another synthesis method of the intermediate II-8 is reported in the patent (CN201610368999.4), and the reaction route is as follows:
however, the route still needs expensive metal catalysts, the production cost is too high, the chiral reduction reaction conditions are harsh, and the method is not suitable for industrial mass production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an improved synthesis method of an oxazolidinone antibacterial drug intermediate, which avoids the use of explosive azide and expensive metal catalysts, has higher safety and lower synthesis cost, and is suitable for industrial mass production.
A synthetic method of an oxazolidinone antibacterial drug intermediate comprises the following steps:
(1) acetate derivatives IV-1 and 2, 5-disubstituted pyridine IV-2 react in an organic solvent under the action of a metal reagent to obtain a compound IV-3;
(2) carrying out reduction reaction on the compound IV-3 in an organic solvent in the presence of a reducing agent to obtain a compound IV-4;
(3) reacting the compound IV-4 with methylamine solution to obtain a compound IV-5;
(4) carrying out salt forming reaction on the compound IV-5 and chiral acid (HA) at the temperature of 20-100 ℃, recrystallizing the obtained salt, and dissociating under the action of alkali to obtain a compound III-4;
(5) carrying out cyclization reaction on the compound III-4 in the presence of a cyclization reagent to obtain an oxazolidinone antibacterial drug intermediate II-8;
in the formula R1Selected from chlorine, bromine, iodine, -OSO2R4Wherein R is4Selected from unsubstituted or substituted C1-C6Straight or branched alkyl, unsubstituted or substituted C3-C6Cycloalkyl, unsubstituted or substituted C6-C14Aryl or unsubstituted or substituted 5-14 membered heteroaryl, wherein said substitution is by one or more groups selected from halogen, nitro, C1-C6Alkyl is substituted by a substituent; the heteroaryl group comprises 1-3 heteroatoms selected from N, O, S; r2Is selected from C1-C6Straight or branched alkyl of (2), C3-C6Cycloalkyl, benzyl (i.e. -CH)2-phenyl); r3Selected from fluorine, chlorine, bromine, iodine.
In the step (1), preferably, the acetate derivative IV-1 is selected from ethyl chloroacetate, methyl chloroacetate, ethyl bromoacetate, propyl chloroacetate, butyl chloroacetate, amyl chloroacetate, benzyl chloroacetate, ethyl bromoacetate, and methyl bromoacetate; more preferably, the acetate derivative IV-1 is ethyl chloroacetate. Preferably, the 2, 5-disubstituted pyridine IV-2 is 2, 5-dibromopyridine, 5-bromo-2-iodopyridine or 5-bromo-2-chloropyridine; more preferably, the 2, 5-disubstituted pyridine IV-2 is 2, 5-dibromopyridine. Preferably, the metal reagent is an organic lithium reagent or a Grignard reagent; more preferably, the metal reagent is n-butyllithium. The organic solvent is toluene or dichloromethane; more preferably, the organic solvent is toluene; preferably, the reaction temperature is from 0 to-78 ℃; preferably, the reaction time is from 1 to 12 hours.
In the step (2), preferably, the reducing agent is sodium borohydride, lithium borohydride, borane, aluminum isopropoxide or lithium aluminum hydride; more preferably, the reducing agent is sodium borohydride. The organic solvent is one or a mixture of more than two of methanol, ethanol, isopropanol and tetrahydrofuran; preferably, the reaction temperature is from-20 to 30 ℃; preferably, the reaction time is from 0.5 to 8 hours.
In the step (3), preferably, the methylamine solution is methylamine alcohol solution or methylamine water solution; more preferably, the methylamine solution is an aqueous methylamine solution. Preferably, the reaction temperature is from 0 to 80 ℃; preferably, the reaction time is from 0.5 to 12 hours.
In the step (4), preferably, the chiral acid is selected from L-tartaric acid, D-tartaric acid, L- (-) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid, (-) -di-p-toluoyl-L-tartaric acid, (-) -di-pivaloyl-L-tartaric acid, D- (-) -quinic acid, D-camphoric acid, D- (+) -malic acid, (S) - (+) -O-acetyl-L-mandelic acid, (-) -O-acetyl-D-mandelic acid, D (+) -10-camphorsulfonic acid, L- (-) -camphorsulfonic acid, D-aspartic acid, L-aspartic acid, D- (-) -mandelic acid or L- (+) -mandelic acid, more preferably, the chiral acid is D- (-) -mandelic acid, and the solvent used for recrystallization is selected from one or more than one of acetonitrile, tetrahydrofuran, methanol, isopropanol, ethanol and water, and preferably, the reaction is carried out at a temperature of 1-hour to 12 ℃.
In the step (5), preferably, the cyclizing reagent is N, -carbonyldiimidazole, phosgene or triphosgene; more preferably, the cyclizing reagent is N, N, -carbonyldiimidazole. Preferably, the reaction temperature is from 0 to 80 ℃; preferably, the reaction time is from 1 to 12 hours.
Compared with the prior art, the invention has the following advantages: the invention provides a method for splitting an oxazolidinone antibacterial drug intermediate, which overcomes the defects of the prior art that an explosive azide compound and an expensive metal catalyst are adopted, has mild and safe reaction conditions, easily purchased reduction reagent and low cost, shortens reaction steps, avoids column chromatography, is more beneficial to industrial mass production, and has good application prospect.
Detailed description of the invention
Specific embodiments of the present invention are illustrated by reference to the following examples, which are intended to illustrate the invention and not to limit it in any way.
EXAMPLE 1 Synthesis of Compound II-3
Dissolving 2, 5-dibromopyridine II-2(25.00g,0.12mol) in dry toluene (1000ml), cooling to-78 ℃, dropwise adding n-butyllithium (56.00ml,0.14mol,2.5M n-hexane solution), stirring for 2 hours after the addition is finished, dropwise adding ethyl chloroacetate V-1(13.73M L, 0.13mol, dissolving in 20ml toluene), stirring for 2 hours after the dropwise addition is finished, adding 10% ammonium chloride solution for quenching reaction, raising to room temperature, adding water for dilution, separating a toluene layer, extracting an aqueous phase once with ethyl acetate, combining organic phases, sequentially washing with water and saturated common salt solution, drying with anhydrous sodium sulfate, filtering, concentrating, and recrystallizing with ethanol-water (10/1 in volume ratio) to obtain 14.53g of white-like solid with the yield of 52%.1H NMR(600MHz,CDCl3)8.73(d,J＝2.1Hz,1H),8.02(dd,J＝8.4, 2.2Hz,1H),7.99(dd,J＝8.3,0.9Hz,1H),5.06(s,2H).
EXAMPLE 2 Synthesis of Compound V-2
Dissolving II-3(25g,107.33mmol) in methanol (250ml), cooling to 0 deg.C, adding sodium borohydride (4.87g,128.80mmol) in batches, removing ice water bath, reacting at room temperature for 2h, reacting completely, cooling, slowly adding saturated ammonium chloride solution to quench reaction, evaporating methanol, extracting water phase twice with ethyl acetate, washing organic phase with water and saturated salt solution sequentially, and removing waterDrying with sodium sulfate, filtering, concentrating to obtain thick crude product V-2, and directly feeding into the next step for reaction without purification.1H NMR(400MHz,CDCl3)8.65(s,1H), 7.88(d,J＝8.6Hz,1H),7.38(d,J＝8.3Hz,1H),4.96(t,J＝5.4Hz,1H),3.90–3.85 (m,1H),3.85–3.77(m,1H).
EXAMPLE 3 Synthesis of Compound IV-5
The crude product from the previous step was dissolved in ethanol (260m L), aqueous methylamine solution (260m L) was added, the reaction was carried out at 40 ℃ for 3h, concentration was carried out, the pH was adjusted to 6 with 1N HCl solution, extraction was carried out three times with dichloromethane, the organic phase was discarded, then the aqueous phase was adjusted to pH 12 with 1N sodium hydroxide solution, extraction was carried out with dichloromethane until no product was produced, the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 19.7g of white solid with a yield of 80% from two steps.1H NMR(400MHz,CDCl3)8.60(d,J＝2.3Hz,1H), 7.82(dd,J＝8.4,2.4Hz,1H),7.37(d,J＝8.4Hz,1H),4.77(dd,J＝7.9,3.8Hz,1H), 2.99(dd,J＝12.2,3.8Hz,1H),2.77(dd,J＝12.1,7.9Hz,1H),2.46(s,3H).
EXAMPLE 4 Synthesis of Compound III-4
Dissolving IV-5(8g,34.78mmol) in acetonitrile (100ml), heating to 70 deg.C, adding D-mandelic acid (2.64g,17.39mmol), reacting at 70 deg.C for 3h, and concentrating to obtain white solid; adding the obtained white solid into acetonitrile (50ml) and water (2ml), heating to 70 ℃, preserving heat for 3h, then slowly cooling to 4 ℃, and separating out 5.7g of white solid; 5.7g of the solid was added to acetonitrile (50ml) and water (2ml), and the above operation was repeated to obtain 3.8g of a white solid. 3.8g of white solid was dissolved in water, the pH was adjusted to 12 with 1N sodium hydroxide solution, extraction was carried out twice with methylene chloride, and concentration was carried out to obtain 2.45g of white solid, yield 31%, ee value 97%.1H NMR(400MHz,CDCl3)8.62(dd,J＝2.3,0.7Hz,1H),7.85(dd,J＝8.3,2.3Hz, 1H),7.39(d,J＝8.4Hz,1H),4.81(dd,J＝7.9,3.9Hz,1H),3.02(dd,J＝12.1,3.9 Hz,1H),2.80(dd,J＝12.1,7.9Hz,1H),2.49(s,3H).
EXAMPLE 5 Synthesis of Compound II-8
III-4(2g,8.7mmol) was dissolved in THF (15ml), 4-dimethylaminopyridine (225mg,1.74mmol) and CDI (2.24g,13.0mmol) were added and reacted at room temperature for 5h, ethyl acetate was added and KHSO was added successively4The solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from ethyl acetate-n-heptane (volume ratio 1/10) to give 1.6g of a white solid, yield 73%, ee value: 99.5 percent.1H NMR(600 MHz,Chloroform-d)8.64(d,J＝2.2Hz,1H),7.89(dd,J＝8.4,2.3Hz,1H),7.45 (d,J＝8.3Hz,1H),5.51(dd,J＝9.1,6.0Hz,1H),4.00(t,J＝9.0Hz,1H),3.71(dd,J ＝8.9,6.0Hz,1H),2.91(s,3H).
EXAMPLE 6 Synthesis of Compound V-4
Dissolving 2, 5-dibromopyridine II-2(25.00g,0.12mol) in dry toluene (1000ml), cooling to-78 ℃, dropwise adding n-butyllithium (56.00ml,0.14mol,2.5M n-hexane solution), stirring for 2 hours after the addition is finished, dropwise adding ethyl methylsulfonyloxyacetate V-3(23.66g,0.13mol, dissolving in 20ml toluene), stirring for 2 hours after the dropwise addition is finished, adding 10% ammonium chloride solution for quenching reaction, raising to room temperature, adding water for dilution, separating a toluene layer, extracting an aqueous phase once with ethyl acetate, combining organic phases, washing with water and saturated common salt solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and recrystallizing with ethanol-water (volume ratio 10/1) to obtain an off-white solid of 16.87g and yield of 48%.1H NMR(600MHz,CDCl3)8.71(d,J＝2.1Hz,1H),8.03(dd,J＝8.4,2.2Hz,1H),7.96(dd,J＝8.3,0.9Hz,1H),5.92(s,2H),3.36(s,3H).
EXAMPLE 7 Synthesis of Compound V-5
Dissolving V-4(15g,51.2mmol) in methanol (250ml), cooling to 0 ℃, adding sodium borohydride (2.9g,76.8mmol) in batches, removing the ice water bath, reacting at room temperature for 2h, reacting completely, slowly adding saturated ammonium chloride solution under cooling to quench the reaction, evaporating the methanol, extracting the water phase twice with ethyl acetate, washing the organic phase with water and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a viscous crude product V-5, and directly feeding the crude product V-5 to the next step for reaction without purification.1H NMR(400MHz,CDCl3)8.63(s,1H), 7.86(d,J＝8.6Hz,1H),7.35(d,J＝8.3Hz,1H),4.98(t,J＝5.4Hz,1H),3.92–3.88 (m,1H),3.87–3.80(m,1H),3.35(s,3H).
EXAMPLE 8 Synthesis of Compound IV-5
The crude product obtained in example 7 was dissolved in ethanol (150m L), aqueous methylamine (150m L) was added, the reaction was carried out at 40 ℃ for 3h, the mixture was concentrated, the pH was adjusted to 6 with 1N HCl solution, the mixture was extracted three times with dichloromethane, the organic phase was discarded, the aqueous phase was adjusted to pH 12 with 1N sodium hydroxide solution, the mixture was extracted with dichloromethane until no product was obtained, the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 9.2g of a white solid in 78% yield in two steps.1H NMR(400MHz,CDCl3)8.60(d,J＝2.3Hz, 1H),7.82(dd,J＝8.4,2.4Hz,1H),7.37(d,J＝8.4Hz,1H),4.77(dd,J＝7.9,3.8Hz, 1H),2.99(dd,J＝12.2,3.8Hz,1H),2.77(dd,J＝12.1,7.9Hz,1H),2.46(s,3H)。
Claims (6)
1. A synthetic method of an oxazolidinone antibacterial drug intermediate is characterized by comprising the following steps:
(1) acetate derivatives IV-1 and 2, 5-disubstituted pyridine IV-2 react in an organic solvent under the action of a metal reagent to obtain a compound IV-3;
(2) carrying out reduction reaction on the compound IV-3 in an organic solvent in the presence of a reducing agent to obtain a compound IV-4;
(3) reacting the compound IV-4 with methylamine solution to obtain a compound IV-5;
(4) carrying out salt forming reaction on the compound IV-5 and chiral acid at the temperature of 20-100 ℃, recrystallizing the obtained salt, and dissociating under the action of alkali to obtain a compound III-4;
(5) carrying out cyclization reaction on the compound III-4 in the presence of a cyclization reagent to obtain an oxazolidinone antibacterial drug intermediate II-8;
in the formula R1Selected from chlorine, bromine, iodine, -OSO2R4Wherein R is4Selected from unsubstituted or substituted C1-C6Straight or branched alkyl, unsubstituted or substituted C3-C6Cycloalkyl, unsubstituted or substituted C6-C14Aryl or unsubstituted or substituted 5-14 membered heteroaryl, wherein said substitution is by one or more groups selected from halogen, nitro, C1-C6Alkyl is substituted by a substituent; the heteroaryl group comprises 1-3 heteroatoms selected from N, O, S; r2Is selected from C1-C6Straight or branched alkyl of (2), C3-C6Cycloalkyl, benzyl; r3Selected from fluorine, chlorine, bromine, iodine.
2. The method of synthesis of claim 1, wherein:
in the step (1), the acetate derivative IV-1 is selected from ethyl chloroacetate, methyl chloroacetate, ethyl bromoacetate, propyl chloroacetate, butyl chloroacetate, pentyl chloroacetate, benzyl chloroacetate, ethyl bromoacetate and methyl bromoacetate; preferably, the acetate derivative IV-1 is ethyl chloroacetate;
in the step (1), the 2, 5-disubstituted pyridine IV-2 is 2, 5-dibromopyridine, 5-bromo-2-iodopyridine or 5-bromo-2-chloropyridine; preferably, the 2, 5-disubstituted pyridine IV-2 is 2, 5-dibromopyridine;
in the step (1), the metal reagent is an organic lithium reagent or a Grignard reagent; preferably, the metal reagent is n-butyl lithium;
in the step (1), the organic solvent is toluene or dichloromethane; preferably, the organic solvent is toluene.
3. The method of synthesis of claim 1, wherein:
in the step (2), the reducing agent is sodium borohydride, lithium borohydride, borane, aluminum isopropoxide or lithium aluminum hydride; preferably, the reducing agent is sodium borohydride; the organic solvent is one or a mixture of more than two of methanol, ethanol, isopropanol and tetrahydrofuran.
4. The method of synthesis of claim 1, wherein: in the step (3), the methylamine solution is methylamine alcohol solution or methylamine water solution; preferably, the methylamine solution is an aqueous methylamine solution.
5. The method of synthesis of claim 1, wherein:
in the step (4), the chiral acid is selected from L-tartaric acid, D-tartaric acid, L- (-) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid, (-) -di-p-toluoyl-L-tartaric acid, (-) -di-pivaloyl-L-tartaric acid, D- (-) -quinic acid, D-camphoric acid, D- (+) -malic acid, (S) - (+) -O-acetyl-L-mandelic acid, (-) -O-acetyl-D-mandelic acid, D (+) -10-camphorsulfonic acid, L- (-) -camphorsulfonic acid, D-aspartic acid, L-aspartic acid, D- (-) -mandelic acid or L- (+) -mandelic acid, preferably, the chiral acid is D- (-) -mandelic acid;
in the step (4), the solvent used for recrystallization is selected from one or more of acetonitrile, tetrahydrofuran, methanol, isopropanol, ethanol and water;
in the step (4), the alkali is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
6. The method of synthesis of claim 1, wherein: in the step (5), the cyclization reagent is N, N' -carbonyldiimidazole, phosgene or triphosgene; preferably, the cyclisation agent is N, N' -carbonyldiimidazole.
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