CN113717200B - Preparation method of Barosavir intermediate - Google Patents
Preparation method of Barosavir intermediate Download PDFInfo
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- CN113717200B CN113717200B CN202111067413.8A CN202111067413A CN113717200B CN 113717200 B CN113717200 B CN 113717200B CN 202111067413 A CN202111067413 A CN 202111067413A CN 113717200 B CN113717200 B CN 113717200B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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Abstract
The invention provides a preparation method of a baroxavir intermediate. According to the invention, organic magnesium alkoxide and magnesium chloride are used as reaction reagents, and a liquid Grignard reagent which is easy to inactivate and is inflammable in the prior art is replaced by a solid and stable magnesium alkoxide reagent, so that the applicability and safety of industrial production are greatly improved under the condition of ensuring the reaction efficiency and the product purity.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a Barosavir intermediate.
Background
The original research company of mabalovir is salt-wilderness pharmaceutical corporation, and 2017 salt-wilderness corporation authorizes market development to roche except japan and taiwan, china. Listed in japan in 2018, 10 in 2018 and 4 in china, and approved for sale in the united states in 2021. Approved indications are: is suitable for patients with simple influenza A and influenza B of 12 years old or above, including healthy patients and patients with high risk of influenza complications.
The intermediate I of the mabarosavir, which has the chemical name of (R) -7- (hexyloxy) -3,4,12, 12a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-diketone, is a key intermediate for preparing a novel anti-influenza medicament, namely the mabarosavir, and has the following structure:
the structure of the practical application is p-toluenesulfonate, and the structure is as follows:
at present, the preparation method of the intermediate I or II of the mabulaosavir disclosed in the literature comprises the following steps:
the method comprises the following steps: CN109311911A discloses reacting a compound of formula 1-A with R in the presence of a sodium and/or magnesium salt 2 The alcohol of-OH reacts to obtain the compound of the formula I, and the reaction formula is as follows:
R 1 is hydrogen or a protecting group other than unsubstituted alkyl, R 2 Is unsubstituted alkyl.
Examples of the sodium salt and/or the magnesium salt indicated in the patent include sodium hydroxide, sodium hydride, sodium isopropoxide, sodium t-amylate, isopropyl magnesium chloride, cyclohexyl magnesium chloride and the like, with sodium t-amylate and isopropyl magnesium chloride being preferred, and isopropyl magnesium chloride being particularly preferred. And specific examples using isopropyl magnesium chloride, cyclohexyl magnesium chloride and sodium tert-amylate, all in the form of tetrahydrofuran solution (example 5, step 1).
The inventor of the present patent application conducts experimental research on the salt disclosed in the patent, and finds that when isopropyl magnesium chloride is selected, flammable and explosive propane gas with the same equivalent weight as isopropyl magnesium chloride is generated in the reaction process, necessary safety measures need to be taken in the processes of scale-up production and industrial production to reduce safety risks, and higher requirements are provided for equipment for implementing production, tail gas treatment and electrostatic explosion prevention. Meanwhile, isopropyl magnesium chloride is a high-activity substance, the separation and inactivation of active ingredients exist in long-time room-temperature storage, high requirements are put on material storage, and centralized treatment is carried out after overdue or waste treatment needs mild quenching, otherwise violent heat release is easy to occur, and explosion and deflagration risks are caused.
Cyclohexyl magnesium chloride is similar in nature to isopropyl magnesium chloride, with the same risks mentioned above. When sodium tert-amylate is selected, the safety is higher than that of the two reagents, but the characteristic impurities generated by the reaction are higher, and the impurities are difficult to remove, so that the product purity is seriously influenced.
The second method comprises the following steps: CN111386276A discloses a chiral starting material, a compound of formula 1-B, is obtained by a photo-initiated free radical reaction or a reduction decarboxylation reaction catalyzed by nickel, cobalt and palladium under an oxygen-free condition, wherein the reaction process is as follows:
the method discloses that the reaction scale of the embodiment is milligram, nitrogen bubbling is required for 15 minutes for degassing in the reaction process, and the post-treatment needs to be purified by a silica gel column. The scheme needs anaerobic conditions for scale-up production, the reaction conditions are harsh, and the industrial production cost is high.
The third method comprises the following steps: WO2021007506A1 discloses that the conversion of compounds of formula 1-C to compounds of formula I can be achieved using lithium or potassium alkoxides, liHMDS, KHMDS instead of isopropyl magnesium chloride, but no specific examples are given. The inventor of the present invention conducts experiments by using the salts disclosed in the patent, and finds that partial salts cannot obtain final products, and the yield and purity of the products obtained by partial salts are low.
The method comprises the following steps: CN109912624A discloses that a compound of formula 1-D is used as a starting material, an intermediate compound of formula 1-E is generated under the action of a chiral resolution reagent S-tetrahydrofuran formic acid, and the intermediate compound of formula 1-E is hydrolyzed and salified under the conditions of methanol and DUB to finally obtain a compound of formula II. The key process of the route is the synthesis of the intermediate 1-D, the chiral purity of the compound has direct influence on the chiral purity of the target intermediate, and the chiral purity of the intermediate 1-D is not given in the literature. Moreover, the process uses starting materials 1-C that are currently not commercially available and require custom production.
The invention aims to provide a preparation method of a Barosavir intermediate suitable for industrial production.
Disclosure of Invention
Through a large amount of researches, the inventor finds that a preparation method which has higher yield and purity and is suitable for industrial production is obtained by changing the salt used in the reaction conditions.
The invention provides a preparation method of a Barosavir intermediate, which comprises the following steps:
a. reacting n-hexanol and magnesium tert-butoxide at a reaction temperature, removing generated tert-butanol, cooling to room temperature, adding tetrahydrofuran, magnesium chloride and a compound of formula SM into a reaction system, and stirring for reaction;
b. after the reaction in the step (1) is finished, adding an organic acid aqueous solution into the system, and extracting to obtain an organic phase;
c. and (3) concentrating the organic phase obtained in the step (2) to remove the solvent, adding p-toluenesulfonic acid monohydrate and tetrahydrofuran into the system, concentrating to remove the solvent under stirring, and adding a crystallization solvent to perform crystallization to obtain the compound shown in the formula II.
Further, the preparation method of the baroxavir intermediate, wherein the organic acid in the step b is selected from citric acid, succinic acid, glutaric acid, disodium ethylene diamine tetraacetate and the like, preferably citric acid and disodium ethylene diamine tetraacetate, and more preferably citric acid.
Further, the preparation method of the baroxavir intermediate has the advantage that the molar ratio of n-hexanol to the compound of the formula SM is in the range of 16-20.
Further, the preparation method of the baroxavir intermediate is characterized in that the molar ratios of the magnesium tert-butoxide and the magnesium chloride to the compound of the formula SM are respectively in the ranges of 0.8-1.25 and 0.4-1.25.
Further, the preparation method of the baroxavir intermediate has the advantages that the molar ratio of n-hexanol to the compound of the formula SM is 16, and the molar ratios of magnesium tert-butoxide and magnesium chloride to the compound of the formula SM are respectively 0.8 and 0.6.
Further, the preparation method of the baroxavir intermediate is characterized in that the solvent used in the crystallization process in the step c is selected from methyl tert-butyl ether, n-hexane, cyclohexane, n-heptane and octane, preferably methyl tert-butyl ether and n-heptane, and more preferably n-heptane.
Further, the preparation method of the barusavir intermediate has 2 extraction processes in the step b.
Further, the preparation method of the baroxavir intermediate is characterized in that the organic solution is tetrahydrofuran.
Further, the preparation method of the baroxavir intermediate has the advantage that the reaction temperature in the step a is 45-55 ℃.
The invention has the beneficial effects that:
1. the invention uses organic magnesium alkoxide and magnesium chloride as reaction reagents, and replaces a Grignard reagent which is in a liquid form, easy to inactivate and inflammable in the prior art (method I in the background technology) with a solid and stable magnesium alkoxide reagent, thereby greatly improving the applicability and safety of industrial production under the condition of ensuring the reaction efficiency and product purity.
2. According to the invention, the organic acid aqueous solution is used for extraction in the step b, so that on one hand, the residue of magnesium salt can be reduced through the complexation reaction of the magnesium salt; on the other hand, the high-proportion removal of characteristic impurities can be realized by adjusting the pH value of the solution, and the product quality is improved.
3. The invention has the advantages of mild reaction conditions, stable reaction reagent, insensitivity to air and water and convenience for large-scale industrial production.
Detailed Description
The preparation method of the baroxavir intermediate provided by the present invention is described in detail by some examples, but the present invention is not limited to the following examples. Any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Example 1: selection of salts
(1) N-hexanol (50g, 0.49mol, 16980) and salt 1 (6.5g, 38mmol,1.25eq; if salt 2 is absent, the amount of salt 1 is 76 mol) are reacted at 45 ℃ to 55 ℃ for 60min, the generated tert-butanol is removed, the reaction system is cooled to room temperature, tetrahydrofuran (70ml, 7.0v/m), salt 2 (3.64g, 38mmol, 1.25eq), R-7- (benzyloxy) -3,4,12, 12A-tetrahydro-1H- [1,4] oxazine [3,4-C ] pyrido [2,1-F ] [1,2,4] triazine-6, 8 dione (SM, 10g,30.5mmol, 1.0eq) are added to the reaction system, and the reaction is stirred at room temperature for 4H.
(2) After the reaction is finished, adding a citric acid aqueous solution 1 into a reaction system, extracting, separating to remove a lower aqueous phase, adding a citric acid aqueous solution 2 into an upper organic layer, extracting, separating to remove a lower aqueous phase, concentrating the organic phase to remove a solvent, adding p-toluenesulfonic acid monohydrate (5.8g, 30.5mmol, 1.0eq) and tetrahydrofuran (40ml, 4.0v/m) into the system after the concentration is finished, concentrating to remove the tetrahydrofuran under stirring, adding n-heptane (250ml, 25.0v/m) into the system at the temperature of 45-55 ℃ for crystallization, filtering after the crystallization is finished, obtaining a target product II, and calculating the molar yield.
Note: "/" is not added or detected.
Through screening, the reaction conversion rate is lower under the condition of no magnesium chloride reaction. After magnesium chloride is added, the conversion rate of each reaction is improved, the highest conversion rate of a magnesium tert-butoxide/magnesium chloride system is adopted, and the highest molar yield can reach 80-90%. Although the salt is selected from sodium tert-butoxide and sodium tert-amylate, the alkalinity is enough, so that the reaction molar yield is up to 70-80%, the reaction system has more side reactions, the content of the generated characteristic impurity 1 is up to 0.5-1.0%, and the product purity is seriously influenced.
Example 2: salt proportion
(1) N-hexanol and magnesium tert-butoxide were reacted at 45 ℃ to 55 ℃ for 60min, the resulting tert-butanol was removed, the temperature was lowered to room temperature, tetrahydrofuran (70ml, 7.0 v/m), magnesium chloride, R-7- (benzyloxy) -3,4,12, 12A-tetrahydro-1H- [1,4] oxazine [3,4-C ] pyrido [2,1-F ] [1,2,4] triazine-6, 8-dione (SM, 1g, 30.5mmol, 1.0eq) were added to the reaction system, and the reaction was stirred at room temperature for 4 hours.
(2) After the reaction is finished, adding a citric acid aqueous solution 1 into a reaction system, extracting, separating to remove a lower aqueous phase, adding a citric acid aqueous solution 2 into an upper organic layer, extracting, separating to remove a lower aqueous phase, concentrating the organic phase to remove a solvent, adding p-toluenesulfonic acid monohydrate (5.8g, 30.5mmol, 1.0eq) and tetrahydrofuran (40ml, 4.0v/m) into the system after the concentration is finished, concentrating to remove the tetrahydrofuran under stirring, adding n-heptane (250ml, 25.0v/m) into the system at the temperature of 45-55 ℃ for crystallization, filtering after the crystallization is finished, obtaining a target product II, and calculating the molar yield.
As can be seen from the data in the table, when the molar ratio of n-hexanol to SM is in the range of 16-20, the molar yield reaches 71% -90% when the molar ratio of magnesium tert-butoxide and magnesium chloride to SM is in the ranges of 0.8-1.25 and 0.4-1.25, respectively.
Example 3: influence of the extraction Process
(1) N-hexanol (50g, 0.49mol, 16eq) and magnesium tert-butoxide (4.16g, 24.3mmol, 0.8eq) were reacted at 45 ℃ to 55 ℃ for 60min, the resulting tert-butanol was removed, the temperature was lowered to room temperature, tetrahydrofuran (70ml, 7.0 v/m), magnesium chloride (1.75g, 18.2mmol, 0.6eq), R-7- (benzyloxy) -3,4,12, 12A-tetrahydro-1H- [1,4] oxazine [3,4-C ] pyrido [2,1-F ] [1,2,4] triazine-6, 8 dione (SM, 10g,30.5mmol, 1.0eq) were added to the reaction system, and the reaction was stirred at room temperature for 4 hours.
(2) After the reaction in the step (1) was completed, an aqueous citric acid solution (citric acid: 3.51g,18.3mmol,0.6eq; water: 2.0 v/m) was added to the reaction system, followed by extraction and separation to remove the lower aqueous phase and obtain an organic phase.
(3) And (3) concentrating the organic phase obtained in the step (2) to remove the solvent, adding p-toluenesulfonic acid monohydrate (5.8g, 30.5mmol, 1.0eq) and tetrahydrofuran (40ml, 4.0v/m) into the system after concentration, concentrating to remove the tetrahydrofuran under stirring, adding n-heptane (250ml, 25.0v/m) into the system at the temperature of 45-55 ℃ for crystallization after concentration is finished, filtering after crystallization is finished to obtain a target product II, and calculating the molar yield and the characteristic impurity content.
When the content of citric acid in the citric acid aqueous solution is more than 0.5 equivalent, the requirement of removing the magnesium salt can be met.
The data in the table show that the extraction times in the step (2) have obvious influence on the content level of the characteristic impurities of the product, and the extraction process for 2 times has little influence on the molar yield of the product under the condition of obviously reducing the content level of the characteristic impurities 2.
Claims (3)
1. A preparation method of a baroxavir intermediate comprises the following specific steps:
a. reacting n-hexanol and magnesium tert-butoxide at 45-55 ℃, removing generated tert-butanol, cooling to room temperature, adding tetrahydrofuran, magnesium chloride and a compound of formula SM into a reaction system, and stirring for reaction;
b. after the reaction in the step a is finished, adding a citric acid aqueous solution into the system, and extracting to obtain an organic phase;
c. concentrating the organic phase obtained in the step b to remove the solvent, adding p-toluenesulfonic acid monohydrate and tetrahydrofuran into the system, concentrating to remove the solvent under stirring, and adding n-heptane for crystallization to obtain a compound shown in the formula II;
wherein the molar ratios of the magnesium tert-butoxide and the magnesium chloride in the step a to the compound of the formula SM are respectively in the ranges of 0.8-1.25 and 0.4-1.25; the molar ratio of n-hexanol to the compound of formula SM is in the range of 16-20;
2. the process for preparing a baroxavir intermediate as claimed in claim 1, wherein the molar ratio of n-hexanol to the compound of formula SM is 16, and the molar ratios of magnesium tert-butoxide, magnesium chloride to the compound of formula SM are 0.8 and 0.6, respectively.
3. The process for preparing a baroxavir intermediate as claimed in claim 1, wherein the extraction in step b is performed 2 times.
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| CN109311911A (en) * | 2016-06-20 | 2019-02-05 | 盐野义制药株式会社 | It is used to prepare the method for replacing polycyclic pyridines ketone derivatives and its crystal |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109311911A (en) * | 2016-06-20 | 2019-02-05 | 盐野义制药株式会社 | It is used to prepare the method for replacing polycyclic pyridines ketone derivatives and its crystal |
Non-Patent Citations (2)
| Title |
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| Nenavath Parvathalu等.Reversible chemoselective transetherification of vinylogous esters using Fe-catalyst under additive free conditions.《Org. Biomol. Chem.》.2019,第17卷第3258-3266页. * |
| 戎欠欠.醇镁化合物的合成研究.《中国优秀硕士学位论文全文数据库全文数据库工程科技I辑B014-38》.2007, * |
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