CN112778332A - Synthesis method of baroxavir pivoxil intermediate polycyclic carbamoylpyridone - Google Patents
Synthesis method of baroxavir pivoxil intermediate polycyclic carbamoylpyridone Download PDFInfo
- Publication number
- CN112778332A CN112778332A CN202011642486.0A CN202011642486A CN112778332A CN 112778332 A CN112778332 A CN 112778332A CN 202011642486 A CN202011642486 A CN 202011642486A CN 112778332 A CN112778332 A CN 112778332A
- Authority
- CN
- China
- Prior art keywords
- dihydropyridine
- benzyloxy
- oxo
- carboxamide
- hydroxyethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a synthesis method of a baroxavir ester intermediate polycyclic carbamoylpyridone, which comprises the step of carrying out ring closure on 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide and chloroacetaldehyde under the action of alkali to obtain the baroxavir ester intermediate polycyclic carbamoylpyridone in one step. Compared with the prior art, the method disclosed by the invention has the advantages that 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide and chloroacetaldehyde are subjected to ring closure under the action of alkali to obtain the polycyclic carbamoylpyridone, the traditional multi-step synthesis is improved into a one-pot method, the reaction operation is obviously simplified, and the method has the advantages of high production efficiency, low cost, small pollution and suitability for industrial production.
Description
Technical Field
The invention relates to baloxavir disoproxil, in particular to a synthesis method of a baloxavir disoproxil intermediate polycyclic carbamoylpyridone, belonging to the technical field of pharmaceutical chemistry.
Background
Baloxavir (baloxavir marboxil) is a novel anti-influenza drug developed by japan salt wild pharmacy (Shionogi). The Baroswarriol ester acts on endonuclease of polymerase acidic protein necessary for transcription of influenza virus genome, and can inhibit influenza virus from obtaining CAP structure at 5' end of host mRNA from host cell, so as to inhibit transcription of influenza virus self mRNA, and has strong inhibitory activity to influenza A and B viruses. Since there is no protease with a similar mechanism in the host cell, this drug theoretically has no effect on the host cell. Baloxavir disoproxil was first marketed in japan on 23/2 in 2018 and then approved by the U.S. FDA on 24/10 in 2018. The structural formula of the baroxavir disoproxil is as follows:
polycyclic carbamoylpyridone is an important intermediate for synthesizing baroxavir pivoxil, and in patent WO2019/196891A1, morpholinone is adopted as a starting material, is subjected to Alloc protection, DIBAL-H reduction and methylation to obtain 3-methoxy morpholine-4-allyl carboxylate, is coupled with 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-ethyl carboxylate, and is subjected to ring closure under the action of palladium to obtain the polycyclic carbamoylpyridone compound. The reaction formula is as follows:
the synthesis method has long steps and complicated operation, some steps need to be controlled to be anhydrous and anaerobic, the reaction conditions are harsh, the raw materials are expensive, and the method uses reagents which are not favorable for environmental protection requirements and is not favorable for large-scale production.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a synthesis method of a baroxavir pivoxil intermediate polycyclic carbamoylpyridone.
Except for special description, the parts are parts by weight, and the percentages are mass percentages.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a synthetic method of a baloxavir dipivoxil intermediate polycyclic carbamoylpyridone is characterized by comprising the following steps: the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide and chloroacetaldehyde are subjected to a ring closure reaction under the action of alkali to prepare the baroxavir ester intermediate polycyclic carbamoylpyridone.
The reaction route is as follows:
in the above method, the base is an inorganic base or an organic base.
Further, the alkali is selected from one or a combination of more of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium tert-butoxide and potassium tert-butoxide; still further, the base is selected from sodium bicarbonate.
In the above process, the molar ratio of 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to chloroacetaldehyde is 1 (1.0-2.0), preferably 1 (1.2-1.5). The molar ratio of 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to base is 1 (1.0-3.0), preferably 1 (1.2-2.0).
The invention discloses a synthesis method of a baroxavir pivoxil intermediate polycyclic carbamoylpyridone, which is characterized by comprising the following steps: adding 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide, chloroacetaldehyde and organic solvent into a reaction bottle, controlling the temperature to be-40-100 ℃, adding alkali after reacting for 0.5-10 hours, continuing to react for 0.5-10 hours, terminating the reaction, filtering, concentrating, purifying and drying to obtain the polycyclic carbamoylpyridone.
The organic solvent is selected from one or a combination of more of dichloromethane, trichloromethane, 1, 4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 2-dimethyl-2-imidazolone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, isopropyl acetate, 2-butanone, N-methylpyrrolidone and 1, 2-dichloroethane, and tetrahydrofuran is preferred. Further, the weight ratio of the organic solvent to the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide is 1-30 times.
A synthetic method of a baroxavir dipivoxil intermediate polycyclic carbamoylpyridone is characterized by comprising the following steps: adding 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide, chloroacetaldehyde and an organic solvent into a reaction bottle, controlling the temperature to be 40-60 ℃, adding alkali after reacting for 2-4 hours, continuing to react for 2-4 hours, terminating the reaction, filtering, concentrating, purifying and drying to obtain the intermediate polycyclic carbamoylpyridone of the baroxavir disoproxil; the alkali is sodium bicarbonate; the solvent is tetrahydrofuran, and the weight ratio of the solvent to the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide is 1-30 times; the molar ratio of the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to chloroacetaldehyde is 1 (1.2-1.5); the molar ratio of the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to the base is 1 (1.2-2.0).
Has the advantages that:
the invention provides a synthesis method of a baroxavir ester intermediate polycyclic carbamoylpyridone, which comprises the step of carrying out ring closure on 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide and chloroacetaldehyde under the action of alkali to obtain the baroxavir ester intermediate polycyclic carbamoylpyridone in one step. Compared with the prior art, the method disclosed by the invention has the advantages that 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide and chloroacetaldehyde are subjected to ring closure under the action of alkali to obtain the polycyclic carbamoylpyridone, the traditional multi-step synthesis is improved into a one-pot method, the reaction operation is obviously simplified, and the method has the advantages of high production efficiency, low cost, small pollution and suitability for industrial production.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure. The raw materials and reagents used in the invention are all commercial products.
Example 1
Adding 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide (1.0g, 3.30mmol), chloroacetaldehyde (0.39g, 4.95mmol) and tetrahydrofuran (20ml) into a dry and clean reaction bottle, stirring and heating to 60 ℃ for reaction for 4h, adding sodium bicarbonate (0.55g, 6.59mmol) for reaction for further 2h, monitoring the reaction completion by a TLC point plate, cooling the system to room temperature, filtering the reaction solution, collecting the filtrate, concentrating under reduced pressure, and purifying to obtain a white solid of 0.84g and the yield of 78%.
Characterization data for white solids are as follows:1H-NMR(600MHz,DMSO-d6)δ:3.21(dd,J＝12.0,9.8Hz,1H),3.47–3.66(m,4H),3.85(dd,J＝12.1,3.0Hz,1H),4.91(dd,J＝5.8,2.9Hz,2H),5.02(d,J＝10.6Hz,1H),5.22(d,J＝10.6Hz,1H),6.23(d,J＝7.6Hz,1H),7.31(dt,J＝27.4,7.2Hz,3H),7.46(d,J＝7.1Hz,2H),7.63(d,J＝7.6Hz,1H),7.66(d,J＝1.5Hz,1H).13C-NMR(151MHz,DMSO-d6)δ:173.83,155.11,147.80,140.03,137.35,131.10,128.43,128.01,127.73,115.59,72.45,71.17,58.75,48.02,40.18.ESI-MS[M+H]+＝328.1.
referring to the above examples, the inventors conducted a search for reaction conditions for cyclizing 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide with chloroacetaldehyde to synthesize polycyclic carbamoylpyridone, and the results are shown in Table 1. The results show that when 1.2 equivalents of NaHCO were used respectively3、Na2CO3、NaOtBu and Et3N as catalyst and other conditions were unchanged (table 1, entries 1,2,4,5), the reaction gave moderate and above yields, with trace yields of product when NaOH was used as catalyst (table 1, entry 3), and lower yields without catalyst (table 1, entry 6), indicating that the catalyst plays a crucial role in the reaction system; the yield did not increase significantly when 2.0 equivalents of catalyst were used (table 1, entry 7). In addition, increasing the amount of chloroacetaldehyde from 1.2 equivalents to 2.0 equivalents did not result in any further improvement in product yield (Table 1)Entry 8). On the basis, the influence of the reaction temperature is considered, the reaction at different temperatures of-15-60 ℃ is tried, the conversion rate is increased, and the temperature is increased to be beneficial to the reaction. Specifically, the yield of the target product was low at-15 ℃ and moderate at-60 ℃ by increasing the temperature (Table 1, entries 9-11). Therefore, 60 ℃ was selected as the optimum temperature for the reaction system (Table 1, entry 1). In addition, the screening of the reaction solvent showed that tetrahydrofuran was the best solvent for the reaction, while other solvents such as ethyl acetate, dichloromethane, acetonitrile and DMF gave lower yields (table 1, entries 13-16). Finally, the optimal conditions for the reaction are determined, at 60 ℃ with NaHCO3(1.2 equiv) is used as a catalyst, and chloroacetaldehyde (1.2 equiv) reacts in tetrahydrofuran for 6h, so that the reaction yield is up to 80%. The reaction route is as follows:
TABLE 1 screening of reaction conditionsa。
aThe reaction was carried out using 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide (1mmol) and chloroacetaldehyde (1.2 equiv.).
bIsolated in yield.
cTrace yield.
Claims (10)
1. A synthetic method of a baloxavir dipivoxil intermediate polycyclic carbamoylpyridone is characterized by comprising the following steps: 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide and chloroacetaldehyde are subjected to ring closure reaction under the action of alkali to obtain the compound; the reaction route is as follows:
the alkali is inorganic alkali or organic alkali.
2. The method of claim 1, wherein: the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide and calcium hydroxide; the organic base is selected from one or two of sodium tert-butoxide or potassium tert-butoxide.
3. The method of claim 1, wherein: the inorganic base is selected from sodium bicarbonate.
4. The method of any one of claims 1-3, wherein: the molar ratio of 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to chloroacetaldehyde is 1 (1.0-2.0), preferably 1 (1.2-1.5).
5. The method of any one of claims 1-3, wherein: the molar ratio of 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to base is 1 (1.0-3.0), preferably 1 (1.2-2.0).
6. The method according to any one of claims 1 to 5, characterized by the following steps: adding 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide, chloroacetaldehyde and organic solvent into a reaction bottle, controlling the temperature to be-40-100 ℃, adding alkali after reacting for 0.5-10 hours, continuing to react for 0.5-10 hours, terminating the reaction, filtering, concentrating, purifying and drying to obtain the polycyclic carbamoylpyridone.
7. The method of claim 6, wherein: the organic solvent is selected from one or a combination of more of dichloromethane, trichloromethane, 1, 4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 2-dimethyl-2-imidazolone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, isopropyl acetate, 2-butanone, N-methylpyrrolidone and 1, 2-dichloroethane.
8. The method of claim 6, wherein: the organic solvent is tetrahydrofuran.
9. The method of claim 6 or 7, wherein: the weight ratio of the organic solvent to the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide is 1-30 times.
10. A synthetic method of a baroxavir dipivoxil intermediate polycyclic carbamoylpyridone is characterized by comprising the following steps: adding 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide, chloroacetaldehyde and an organic solvent into a reaction bottle, controlling the temperature to be 40-60 ℃, adding alkali after reacting for 2-4 hours, continuing to react for 2-4 hours, terminating the reaction, filtering, concentrating, purifying and drying to obtain polycyclic carbamoylpyridone; the alkali is sodium bicarbonate; the solvent is tetrahydrofuran, and the weight ratio of the solvent to the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide is 1-30 times; the molar ratio of the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to chloroacetaldehyde is 1 (1.2-1.5); the molar ratio of the 1-amino-3- (benzyloxy) -N- (2-hydroxyethyl) -4-oxo-1, 4-dihydropyridine-2-carboxamide to the base is 1 (1.2-2.0).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011642486.0A CN112778332B (en) | 2020-12-31 | 2020-12-31 | Synthesis method of baroxavir pivoxil intermediate polycyclic carbamoylpyridone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011642486.0A CN112778332B (en) | 2020-12-31 | 2020-12-31 | Synthesis method of baroxavir pivoxil intermediate polycyclic carbamoylpyridone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112778332A true CN112778332A (en) | 2021-05-11 |
| CN112778332B CN112778332B (en) | 2021-12-14 |
Family
ID=75755151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011642486.0A Active CN112778332B (en) | 2020-12-31 | 2020-12-31 | Synthesis method of baroxavir pivoxil intermediate polycyclic carbamoylpyridone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112778332B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912624A (en) * | 2019-04-11 | 2019-06-21 | 杭州科巢生物科技有限公司 | A kind of synthetic method of Ba Luoshawei ester key parent nucleus intermediate |
| WO2019196891A1 (en) * | 2018-04-11 | 2019-10-17 | 安帝康（无锡）生物科技有限公司 | Polycyclic carbamoylpyridone derivatives, pharmaceutical compositions and use thereof |
| CN111205304A (en) * | 2020-03-02 | 2020-05-29 | 南京法恩化学有限公司 | Preparation method of Barosavir intermediate |
| CN112079848A (en) * | 2020-09-24 | 2020-12-15 | 广东莱佛士制药技术有限公司 | Synthesis method of baroxavir key intermediate |
-
2020
- 2020-12-31 CN CN202011642486.0A patent/CN112778332B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019196891A1 (en) * | 2018-04-11 | 2019-10-17 | 安帝康（无锡）生物科技有限公司 | Polycyclic carbamoylpyridone derivatives, pharmaceutical compositions and use thereof |
| CN109912624A (en) * | 2019-04-11 | 2019-06-21 | 杭州科巢生物科技有限公司 | A kind of synthetic method of Ba Luoshawei ester key parent nucleus intermediate |
| CN111205304A (en) * | 2020-03-02 | 2020-05-29 | 南京法恩化学有限公司 | Preparation method of Barosavir intermediate |
| CN112079848A (en) * | 2020-09-24 | 2020-12-15 | 广东莱佛士制药技术有限公司 | Synthesis method of baroxavir key intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112778332B (en) | 2021-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102336754B (en) | Method for synthesizing entecavir and intermediate compound thereof | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN106279104A (en) | A kind of process modification method preparing succinum love song Ge Lieting | |
| CN112759558B (en) | Process for the preparation of triazine rings | |
| CN101012147A (en) | Method of preparing R-(+)-3-chlorophenylpropanol | |
| CN112778332B (en) | Synthesis method of baroxavir pivoxil intermediate polycyclic carbamoylpyridone | |
| CA3042923A1 (en) | A simple process for preparing avibactam | |
| KR20190046126A (en) | Improved process for preparing acotiamide | |
| CN110577482B (en) | Preparation method of amisulpride | |
| CN113024489A (en) | Preparation method of oseltamivir synthesis process impurity | |
| CN111349045A (en) | Synthetic method of lenvatinib and novel intermediate | |
| CN107663170B (en) | Method for preparing besifloxacin intermediate compound | |
| CN108623602A (en) | A method of prepare and purify and replaces Buddhist nun according to Shandong | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| EP2937331B1 (en) | A process for preparing an intermediate of vitamin b1 | |
| CN105294697B (en) | The synthetic method of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine | |
| CN109503511B (en) | Preparation method of dasatinib intermediate | |
| CN102924454A (en) | Synthetic method of entecavir | |
| CN104098509B (en) | A kind of method for preparing A type atazanavir sulfate | |
| CN106810485A (en) | A kind of Preparation Method And Their Intermediate of chiral boxidine alkanone | |
| CN107325078B (en) | Preparation method of cilostazol | |
| CN112679519B (en) | Polycyclic carbamoylpyridone analogs, their preparation and use | |
| CN109265455A (en) | A kind of preparation method of Dasatinib | |
| CN102491954B (en) | Preparation method of linezolid | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |