CN112707862A - Preparation method of polycyclic pyridone compound - Google Patents
Preparation method of polycyclic pyridone compound Download PDFInfo
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- CN112707862A CN112707862A CN201911018439.6A CN201911018439A CN112707862A CN 112707862 A CN112707862 A CN 112707862A CN 201911018439 A CN201911018439 A CN 201911018439A CN 112707862 A CN112707862 A CN 112707862A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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Abstract
The invention relates to a preparation method of a polycyclic pyridone compound, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of reacting raw materials with diglycolamine to obtain an intermediate compound, or oxidizing and cyclizing the intermediate compound to obtain a cyclopyridone compound. The method uses the diglycolamine which is cheap and easy to obtain, can reduce reaction steps, simplify operation, reduce material cost, and is easy for industrial large-scale production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a heterocyclic-fused pyridone compound.
Background
BaloxavirMarvoxil (formerly S-033188, tradename Xofluza) is an innovative Cap-dependent endonuclease inhibitor, can inhibit transcription of influenza virus self mRNA, and is recognized by Japan as a pioneer (Sakigake) drug for preventing influenza A and influenza B. BaloxavirMarvoxil was first described in PCT patent WO2016175224 and has the following structural formula:
the compound 03 is an important intermediate for preparing the Baloxavir Marvoxil, while the compound 03 is prepared by a series of steps generally adopted by the compound I in the prior art,
for example, in patent application WO2019070059 and the like, 2- (2-aminoethoxy) -1, 1-dimethoxyethane is prepared through a plurality of reaction steps, and then reacts with compound I to obtain compound 03. The reaction steps involved in the methods have harsh reaction conditions, are not favorable for operation and implementation and are environment-friendly, or the reaction steps are more, the process is complex, the cost is high, and the method is not favorable for industrial production. Therefore, a simple, convenient, easy to operate and control, environment-friendly, low-cost and easy to industrially produce method is needed for preparing the intermediate of the BaloxavirMarvoxil.
Disclosure of Invention
The invention provides a preparation method of an intermediate for preparing BaloxavirMarvoxil, namely a compound 03. A method of preparing compound 03 comprising: in a reaction solvent, under the action of an oxidant, reacting the compound 02 at a second temperature, after the reaction is finished, carrying out secondary post-treatment, reacting the obtained product at a third temperature under the action of an acid, and after the reaction is finished, carrying out third post-treatment to prepare a compound 03
In some embodiments, the compound 02-1 is obtained by a second post-treatment in the aforementioned method, the obtained compound 02-1 is reacted under the action of acid at a third temperature, and after the reaction is completed, the compound 03 is obtained by a third post-treatment, as shown in the following formula:
the oxidizing agent may be at least one selected from 2-iodoxybenzoic acid (IBX), 2,6, 6-tetramethylpiperidineoxide/sodium hypochlorite (TEMPO/NaClO), sodium periodate, 2,6, 6-tetramethylpiperidineoxide/trichloroisocyanuric acid (TEMPO/TCCA), dess-martin oxidizing agent.
In some embodiments, the oxidizing agent is 2-iodoxybenzoic acid, which is more advantageous for obtaining the product. The inventor finds that different oxidants have a large influence on the obtaining of the compound 03, while the 2-iodoxybenzoic acid is more beneficial to the generation and the obtaining of the product, and other oxidants can also obtain the target product, but the impurities are more, and the yield of the target product is lower.
The feeding molar ratio of the oxidant to the compound 02 can be 10:1-0.5:1, or 5:1-1:1, or 2:1-1: 1. In some embodiments, the molar ratio of oxidant to compound 02 charged is from 1:1 to 2: 1.
The acid may be at least one selected from methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid. In some embodiments, the acid is methanesulfonic acid, which facilitates the target product and reduces the production of impurities.
The feeding molar ratio of the acid to the compound 02 can be 5:1-0.5:1, or 3:1-1:1, or 2:1-1: 1. In some embodiments, the molar ratio of acid to compound 02 charged is from 1.5:1 to 1:1. In some embodiments, the acid to compound 02 feed molar ratio is 1.5: 1.
In some embodiments, the aforementioned method is performed with or without the addition of water to the reaction system. In some embodiments, the acid contains a certain amount of water, or the acid and water are added to the reaction system simultaneously or sequentially.
The reaction solvent can be at least one selected from acetonitrile, water, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, alcohols with 1-6 carbon atoms, such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, n-pentanol, n-hexanol, cyclohexanol and the like, dichloromethane, ethyl acetate, ethyl formate, isopropyl acetate, tert-butyl ether, DMF, DMAc and DMSO. In some embodiments, the reaction solvent is dichloromethane. In some embodiments, the reaction solvent is acetonitrile.
The reaction solvent may be used in an amount of 1ml to 30ml, or 3ml to 30ml, or 5ml to 30ml, or 1ml to 20ml, or 5ml to 15ml per gram of compound 02. In some embodiments, the reaction solvent is used in an amount of 5ml to 20ml per gram of compound 02.
The second temperature or the third temperature may be-10 ℃ to 100 ℃. In some embodiments, the second temperature or the third temperature may be from 0 ℃ to 100 ℃. In some embodiments, the second temperature or the third temperature may be from 40 ℃ to 100 ℃. In some embodiments, the second temperature or the third temperature may be from 50 ℃ to 90 ℃. In some embodiments, the second or third temperature is from 60 ℃ to 80 ℃.
The reaction time for the reaction of the compound 02 with the oxidizing agent may be determined depending on the remaining amount of the compound 02, and is generally within 0.5 to 8 hours.
The aforementioned second post-treatment may include: cooling to room temperature, filtering, washing the filter cake with reaction solvent such as acetonitrile or DCM, mixing filtrates, and evaporating to dryness under reduced pressure or directly feeding into the next reaction.
After the second post-treatment, the reaction time of the resultant may be determined according to the remaining amount thereof, and is generally within 0.5 to 12 hours.
The aforementioned third post-treatment may include: cooling the reaction liquid to room temperature, removing the solvent, mixing the obtained crude product with sodium hydroxide and water, stirring at room temperature or at 0-10 ℃, filtering, washing a filter cake with water, and drying to obtain the compound 03.
The above compound 02 can be prepared using compound 01. A method of making compound 02 comprising: optionally in a first reaction solvent, optionally in the presence of an alkaline agent, at a first temperature, reacting the compound 01 with diglycolamine, and after the reaction is finished, carrying out post-treatment to prepare the compound 02
Wherein R is hydrogen, substituted or unsubstituted C1-C8(1 carbon-8 carbon) alkyl, substituted or unsubstituted C3-C10(3 carbon-10 carbon) cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, and the like, optionally substituted with halogen, or haloalkyl.
In some embodiments, R is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, or substituted or unsubstituted aryl. In some embodiments, R is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl. In some embodiments, R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl. In some embodiments, R is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, or naphthyl, these groups optionally substituted with a halogen such as fluorine, chlorine, bromine, or iodine.
In some embodiments, R is hydrogen. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is tert-butyl. In some embodiments, R is phenyl. In some embodiments, R is benzyl.
In the reaction of the compound 01 with diglycolamine, the reaction solvent may not be added, and the first reaction solvent may be added. The first reaction solvent may be at least one of ethyl acetate, toluene, 2-methyltetrahydrofuran, tetrahydrofuran, alcohols with 1-6 carbon atoms such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, n-pentanol, n-hexanol, cyclohexanol and the like, dichloromethane, DMF, DMAc, DMSO, and water. In some embodiments, the first reaction solvent is dichloromethane. In some embodiments, the first reaction solvent is tetrahydrofuran, which facilitates the reaction as compared to other solvents.
In some embodiments, no reaction solvent is added to the reaction of compound 01 with diglycolamine.
The first reaction solvent may be used in an amount of 0.01ml to 10ml, or 0.1ml to 10ml, or 0.5ml to 5ml per gram of compound 01. In some embodiments, the first reaction solvent is used in an amount of 0.1ml to 5ml per gram of compound 01.
In the reaction of the compound 01 with diglycolamine, an alkaline agent may or may not be added.
In some embodiments, a basic reagent is added, which may be at least one of 1, 8-diazabicycloundecen-7-ene (DBU), triethylamine, DIPEA, pyridine, dimethylamine, diisopropylamine, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium phosphate. In some embodiments, the basic agent is at least one of 1, 8-diazabicycloundecen-7-ene (DBU), triethylamine, DIPEA, pyridine, dimethylamine, diisopropylamine. In some embodiments, the alkaline agent is DBU, which is more advantageous for the product.
In some embodiments, an alkaline agent is added, and the molar ratio of the alkaline agent to compound 01 charged can be 0.01:1 to 2:1, or 0.01:1 to 1.5:1, or 0.05:1 to 1.5:1, or 0.1:1 to 1.5: 1. In some embodiments, the molar ratio of the alkaline agent to compound 01 charged is 0.1:1 to 1.5: 1.
In some embodiments, no alkaline agent is added to the reaction of compound 01 with diglycolamine.
In the reaction of the above compound 01 with diglycolamine, a condensing agent is optionally added.
In some embodiments, no condensing agent is added to the reaction of compound 01 with diglycolamine as described above.
In some embodiments, in the reaction of compound 01 and diglycolamine, a condensing agent is added, and the condensing agent may be one or more of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-Hydroxybenzotriazole (HOBT), O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (TBTU), N' -Carbonyldiimidazole (CDI).
In some embodiments, the condensing agent is a 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-Hydroxybenzotriazole (HOBT) mixture.
The feeding molar ratio of the compound 01 to the diglycolamine can be 1:1-1:10, or 1:1-1:5, or 1:1-1: 2. In some embodiments, the compound 01 and diglycolamine are fed in a molar ratio of 1:1.5 to 1: 4.5.
The first temperature may be 0 ℃ to 100 ℃, or 30 ℃ to 80 ℃, or 50 ℃ to 100 ℃, or 50 ℃ to 80 ℃. In some embodiments, the first temperature is from 30 ℃ to 60 ℃. In some embodiments, the first temperature is from 30 ℃ to 80 ℃.
In the reaction of the compound 01 and diglycolamine, whether the reaction is finished can be judged according to the residual amount of the compound 01, and the reaction time is generally 0.5 to 28 hours. In some embodiments, compound 01 is reacted with diglycolamine for a reaction time of from 0.5 hours to 24 hours.
After the reaction of the compound 01 and diglycolamine is finished, post-treatment is carried out, wherein the post-treatment comprises the following steps: adding water into a reaction system at room temperature, optionally adding an acid reagent such as glacial acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoromethanesulfonic acid and the like, stirring, extracting by using an extraction solvent, combining organic phases, washing by using saturated sodium bicarbonate or potassium bicarbonate, washing by using water, drying the organic phases by using anhydrous sodium sulfate, filtering, and removing the solvent to obtain a compound 02; the extraction solvent may be ethyl acetate, isopropyl acetate, methyl acetate, or a combination thereof.
In some embodiments, after the reaction of compound 01 with diglycolamine is completed, a post-treatment is performed, the post-treatment comprising: cooling the reaction system to room temperature, adding water into the reaction system, adding an acid reagent such as glacial acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoromethanesulfonic acid and the like, stirring, extracting with an extraction solvent, combining organic phases, washing the organic phases with saturated sodium bicarbonate or potassium bicarbonate, washing with water, drying the organic phases with anhydrous sodium sulfate, filtering, and removing the solvent to obtain a compound 02; the extraction solvent may be ethyl acetate, isopropyl acetate, methyl acetate, or a combination thereof.
In some embodiments, after the reaction of compound 01 with diglycolamine is completed, a post-treatment is performed, the post-treatment comprising: filtering the reaction system, adding water into the reaction system at room temperature, stirring, extracting with an extraction solvent, combining organic phases, washing the organic phases with saturated sodium bicarbonate or potassium bicarbonate, washing with water, drying the organic phases with anhydrous sodium sulfate, filtering, and removing the solvent to obtain a compound 02; the extraction solvent may be ethyl acetate, isopropyl acetate, methyl acetate, or a combination thereof.
The method of the invention uses the diglycolamine which is cheap and easy to obtain, and does not need to use the 2- (2-aminoethoxy) -1, 1-dimethoxyethane, can reduce reaction steps, simplify operation, reduce material cost and is easy for industrial amplification production.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.
In the invention, the room temperature refers to the ambient temperature and is 20-30 ℃, or 25-28 ℃.
In the present invention, when referring to numerical values, there is a deviation of ± 10% for each numerical value, whether about or about used.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, min means minute, g means g, ml means ml, DMF means N, N-dimethylformamide, DMSO means dimethyl sulfoxide, DMAc means dimethylacetamide, DBU means 1, 8-diazabicycloundecen-7-ene, DIPEA means N, N-diisopropylethylamine, THF means tetrahydrofuran, DCM means dichloromethane, EA means ethyl acetate, Bn means benzyl, BOC or Boc means t-butyloxycarbonyl; TLC for thin layer chromatography; v/v represents a volume ratio; CDCl3Represents deuterated chloroform;1h NMR represents nuclear magnetic resonance hydrogen spectrum;
LC-MS: liquid phase-mass spectrometry;
in the present invention, the reaction is considered to be completed when the remaining amount of the raw materials is less than 2%, 1% or 0.5% of the charged amount thereof during the reaction.
EXAMPLE 1 preparation of Compound 02
A 50mL single-neck flask was charged with 1.00g of compound I, 0.562g of diglycolamine, 1.50g of HATU, 1.10g of DIPEA (diisopropylethylamine), and 10mL of DMF, reacted at room temperature for 6 hours after completion of the addition, followed by TLC detection (ethyl acetate: n-hexane: 2:1, v/v) at 2 hours and 6 hours, respectively, and no compound 02 was produced, and discarded.
EXAMPLE 2 preparation of Compound 02
Adding 10.00g of compound I, 10.8g of diglycolamine, 407mg of DBU and 8mL of tetrahydrofuran into a 250mL single-neck bottle, heating to 60 ℃ after adding, reacting for 24 hours, detecting by TLC (ethyl acetate: n-hexane: 2:1, v/v) until no compound I remains, and stopping the reaction;
cooling the reaction system to room temperature, adding 30mL of water and 3.83g of glacial acetic acid, uniformly stirring, extracting with ethyl acetate for 3 times, each time with 30mL, combining ethyl acetate phases, sequentially washing with 50mL of saturated sodium bicarbonate and 50mL of water, drying the organic phase with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a yellow solid, namely a compound 02: 11.00g, yield 92%. And (3) detecting the obtained product:
LC-MS:[M+1]＝448.21；
1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.7Hz,1H),7.35(d,J＝6.2Hz,2H),7.30–7.11(m,4H),6.15(d,J＝7.6Hz,1H),5.05(s,2H),3.82(s,2H),3.69(dd,J＝21.6,3.6Hz,3H),3.54(t,J＝4.7Hz,3H),3.23(s,2H),1.48(d,J＝15.9Hz,9H)。
EXAMPLE 3 preparation of Compound 02
Adding 10.00g of compound 4, 12.20g of diglycolamine and 391mg of DBU into a 250mL single-neck bottle, heating to 60 ℃ after the addition is finished, reacting for 20 hours, and stopping the reaction by TLC (detection by ethyl acetate: n-hexane ═ 2:1, v/v) when no compound 4 remains;
cooling the reaction system to room temperature, adding 50mL of water and 3.68g of glacial acetic acid, uniformly stirring, extracting with ethyl acetate for 3 times (30 mL each time), combining ethyl acetate phases, sequentially washing with 50mL of saturated sodium bicarbonate and 50mL of water, drying an organic phase with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a yellow solid compound 02: 10.01g, yield 88%, and mass spectrum confirmed compound 02.
EXAMPLE 4 preparation of Compound 02
A 100mL single-neck flask was charged with 5.00g of compound 5, 2.20g of diglycolamine, 2.70g of EDCI, 1.9g of HOBT and 25mL of dichloromethane, reacted at 30 ℃ for 24 hours after completion of the addition, and checked by TLC (ethyl acetate: methanol 10:1, v/v) to stop the reaction without the compound 5 remaining;
filtering to remove insoluble substances, adding 50mL of water into the crude product, extracting the water phase with ethyl acetate for 3 times, each time extracting by 30mL, combining the organic phases, washing by 30mL of saturated sodium bicarbonate water solution and 30mL of saturated brine, drying the obtained organic phase by anhydrous sodium sulfate, filtering, and carrying out rotary drying under reduced pressure to obtain a yellow solid compound 02: 4.60g, yield 75%; mass spectrum confirmed to be compound 02.
EXAMPLE 5 preparation of Compound 03
Adding 6.0g of compound 02, 7.5g of 2-iodoxybenzoic acid and 60mL of acetonitrile serving as solvents into a 250mL single-mouth bottle, heating to 80 ℃ after the addition of the solvents, reacting for about 3 hours, and stopping the reaction after TLC detects that the raw material point disappears; cooling the reaction solution to room temperature, filtering, washing a filter cake once by using 6mL of acetonitrile, and combining filtrates; transferring the obtained filtrate (mainly the filtrate of the compound 02-1) to a 250mL single-neck bottle, adding 1.32mL methanesulfonic acid and 9mL water under stirring at room temperature, heating to 60 ℃ after adding, reacting for 6 hours, detecting by TLC (dichloromethane: methanol 20:1, v/v) that all the raw material points (the compound 02-1) disappear, and stopping the reaction;
cooling the reaction solution to room temperature, removing the solvent under reduced pressure, adding 20mL of 30% aqueous sodium hydroxide solution (mass fraction) into the crude product, stirring at room temperature to generate a large amount of solid, filtering after 2 hours, washing the filter cake with 20mL of water, and drying at 60 ℃ in vacuum to obtain a yellow solid compound 03: 3.5g, yield 80%. And (3) detecting the obtained product:
LC-MS:[M+1]＝328.39；
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.6Hz,2H),7.41–7.30(m,3H),6.33(d,J＝7.7Hz,1H),5.63(d,J＝13.1Hz,1H),5.35(d,J＝9.8Hz,1H),5.04(d,J＝9.9Hz,1H),4.55–4.41(m,1H),4.03–3.87(m,2H),3.80(dd,J＝11.5,4.5Hz,1H),3.56(dd,J＝12.0,9.3Hz,1H),2.99–2.91(m,1H),2.83(td,J＝13.3,4.4Hz,1H)。
EXAMPLE 6 preparation of Compound 03
Adding 6.0g of compound 02, 7.5g of 2-iodoxybenzoic acid and 60mL of acetonitrile serving as solvents into a 250mL single-mouth bottle, heating to 80 ℃ after the addition of the solvents, reacting for about 3 hours, detecting by TLC (dichloromethane: methanol ═ 20:1, v/v), and stopping the reaction when a raw material point disappears; cooling the reaction liquid to room temperature, filtering, washing a filter cake once with 6mL of acetonitrile, combining filtrates, transferring to a 250mL single-neck bottle, adding 1.32mL of methanesulfonic acid while stirring at room temperature, heating to 60 ℃ after the addition, reacting for 4 hours, detecting by TLC (dichloromethane: methanol is 20:1, v/v) when all the raw material points (compound 02-1) disappear, and stopping the reaction;
cooling the reaction solution to room temperature, removing the solvent under reduced pressure, adding 20mL of 30% aqueous sodium hydroxide solution into the crude product, stirring at room temperature to generate a large amount of solid, filtering after 2 hours, washing the filter cake with 20mL of water, and drying at 60 ℃ in vacuum to obtain a yellow solid compound 03: 3.9g, yield 89%; mass spectrum confirmed to be compound 03.
EXAMPLE 7 preparation of Compound 03
Adding 6.0g of compound 02, 8.5g of dess-martin oxidant and 60mL of dichloromethane serving as solvents into a 250mL single-neck bottle, reacting at 30 ℃ for 8 hours after the addition is finished, detecting by TLC (dichloromethane: methanol is 20:1, v/v), and stopping the reaction when the raw material point disappears; filtering, washing a filter cake once by using 6mL of dichloromethane, combining filtrates, transferring to a 250mL single-mouth bottle, carrying out reduced pressure spin-drying, adding 50mL of acetonitrile, 1.32mL of methanesulfonic acid and 6mL of water at room temperature, raising the temperature to 60 ℃ after adding, reacting for 6 hours, detecting by TLC (dichloromethane: methanol ═ 20:1, v/v) when all raw material points (compound 02-1) disappear, and stopping the reaction;
cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, adding 20mL of 30% sodium hydroxide aqueous solution into the crude product, stirring at room temperature to generate a solid, cooling to 0 ℃, stirring for 2 hours, filtering, washing a filter cake with 20mL of water, and drying at 60 ℃ in vacuum to obtain 2.5g of a yellow solid with a yield of 57%; mass spectrum confirmed to be compound 03.
EXAMPLE 8 preparation of Compound 03
1.0g of compound 02 and 20mL of dichloromethane are added into a 100mL single-neck flask, 623mg of TCCA is added after the temperature is reduced to 0 ℃, 94mg of sodium bicarbonate and 3.5mg of TEMPO are added after the addition, and the temperature is increased to 15 ℃ after the addition to react for 6 hours to stop the reaction. After filtration, the filter cake was washed once with 3mL of dichloromethane, the filtrates were combined, transferred to a 100mL single-neck flask, dried under reduced pressure, 15mL of acetonitrile and 319mg of methanesulfonic acid and 1mL of water were added at room temperature, and after completion of the addition, the temperature was raised to 60 ℃ to react for 3 hours, and the reaction was stopped by TLC (dichloromethane: methanol ═ 20:1, v/v) when all the starting material spots (compound 02-1) disappeared.
Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, adding 10mL of 30% sodium hydroxide aqueous solution into the crude product, stirring at room temperature to generate a solid, cooling to 0 ℃, stirring for 2 hours, filtering, washing a filter cake with 10mL of water, and drying at 60 ℃ in vacuum to obtain 208mg of a yellow solid with the yield of 28%; mass spectrum confirmed to be compound 03.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of preparing compound 03 comprising: in a reaction solvent, under the action of an oxidant, reacting the compound 02 at a second temperature, after the reaction is finished, carrying out secondary post-treatment, reacting the obtained product at a third temperature under the action of an acid, and after the reaction is finished, carrying out third post-treatment to prepare a compound 03
2. The method of claim 1, further comprising: optionally in a first reaction solvent, optionally in the presence of an alkaline agent, at a first temperature, reacting the compound 01 with diglycolamine, and after the reaction is finished, carrying out post-treatment to prepare the compound 02
Wherein R is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
3. The method of claim 1, wherein the oxidizing agent is selected from at least one of 2-iodoxybenzoic acid, TEMPO/NaClO, sodium periodate, TEMPO/DCCA, dess-martin oxidizing agent; the acid is at least one selected from methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid.
4. The method according to claim 1, wherein the reaction solvent is at least one selected from acetonitrile, water, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, alcohols with 1-6 carbon atoms, dichloromethane, ethyl acetate, ethyl formate, isopropyl acetate, tert-butyl ether, DMF, DMAc and DMSO.
5. The method of claim 1, wherein the second temperature or the third temperature is from-10 ℃ to 100 ℃.
6. The method of claim 1, wherein the second post-processing comprises: cooling to room temperature, filtering, washing a filter cake with a reaction solvent, and combining filtrates; the third post-treatment comprises: cooling the reaction liquid to room temperature, removing the solvent, mixing the obtained crude product with sodium hydroxide and water, stirring, filtering, washing a filter cake with water, and drying to obtain the compound 03.
7. The method according to claim 2, wherein a first reaction solvent is added, and the first reaction solvent is at least one of ethyl acetate, toluene, 2-methyltetrahydrofuran, tetrahydrofuran, alcohols with 1-6 carbon atoms, dichloromethane, DMF, DMAc, DMSO and water; or, adding an alkaline reagent, wherein the alkaline reagent is one of DBU, triethylamine, DIPEA, pyridine, dimethylamine, diisopropylamine, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium carbonate, cesium carbonate and potassium phosphate; or, in the reaction, a condensing agent is added, wherein the condensing agent is one or more of 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, 1-hydroxybenzotriazole, O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate and N, N ' -carbonyl diimidazole.
8. The method of claim 2, wherein the first temperature is between 0 ℃ and 100 ℃.
9. The method of claim 2, comprising: adding water and optionally an acid reagent into the reaction system at room temperature, stirring, extracting by using an extraction solvent, combining organic phases, washing the organic phases by using saturated sodium bicarbonate or potassium bicarbonate, washing by using water, drying the organic phases by using anhydrous sodium sulfate, filtering, and removing the solvent to obtain the compound 02.
10. The method of claim 2, wherein R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl.
Priority Applications (1)
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| CN111484508A (en) * | 2019-01-29 | 2020-08-04 | 北京四环制药有限公司 | Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof |
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| CN111484508B (en) * | 2019-01-29 | 2022-11-25 | 北京四环制药有限公司 | Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof |
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