CN111943885A - Synthetic method of Laolatinib intermediate 2-amino-5-bromo-3-hydroxypyridine - Google Patents
Synthetic method of Laolatinib intermediate 2-amino-5-bromo-3-hydroxypyridine Download PDFInfo
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Abstract
The invention relates to synthesis of an important intermediate 2-amino-5-bromo-3-hydroxypyridine of antitumor drug Lauratinib (Lorlatinib, PF-06463922). Taking 2-amino-3-hydroxypyridine as an initial raw material, and finally synthesizing 2-amino-5-bromo-3-hydroxypyridine through 3 steps of ring closing, bromination, hydrolysis and the like, wherein in the ring closing step, bis (trichloromethyl) carbonate (BTC) and N, N' -Carbonyldiimidazole (CDI) are used in combination; in the bromination step, 2-hydroxy-2-methyl-1-phenyl-1-acetone is used as a photoinitiator, and liquid bromine is used as a brominating agent.
Description
Technical Field
The invention relates to synthesis of 2-amino-5-bromo-3-hydroxypyridine, in particular to a synthesis method of 2-amino-5-bromo-3-hydroxypyridine by adopting steps of ring closure, photocatalytic bromination, hydrolysis and the like.
Background
Laolatinib (Lorlatinib, PF-06463922), named in English: (R) -26-amino-55-fluoro-11, 4, 7-trimethy-6-oxo-11H-3-oxa-7-aza-2 (3,5) -pyridina-1(4,3) -pyrazoli-5 (1,2) -benzacycloctyphane-15-carbonitrile, CAS number: 1454846-35-5, formula: c21H19FN6O2Molecular weight: 406.4. lorlatinib is a third-generation inhibitor of ALK (anaplastic lymphoma kinase). First generation ALK inhibitorZotinib (Crizotinib), an ATP-competitive multi-target protein kinase inhibitor, was approved by the FDA in the united states in 2016 for the treatment of advanced (metastatic) non-small cell lung cancer (NSCLC) patients carrying mutations in the ROS-1 gene. Unfortunately, most patients develop resistance to criptotritib within 12 months after treatment and develop acquired resistance mutations. In recent years, a plurality of second-generation ALK inhibitors with good curative effect and low toxicity have been continuously emerged: ceritinib, Alectonib, Brigatinib. Refractory tumors, however, quickly develop resistance to these new inhibitors. In the face of drug resistance of the criptotiib and second generation ALK inhibitors, scientists began to develop third generation ALK inhibitors, i.e., drugs that are still therapeutically effective in patients with NSCLC who develop central nervous system metastases and are resistant to criptotiib and second generation ALK inhibitors. The third generation ALK inhibitors were lorelatinib, developed by the company pyroxene. 27 Rizeri, 4.4.2017, the FDA awards the name of Lorlatinib 'breakthrough drug' as a new generation ALK/ROS1 tyrosine kinase inhibitor for the second-line treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC).
The synthesis of loratinib and the synthesis method of intermediate thereof are reported in many documents, but the synthesis routes mainly include the following two routes. Synthetic route one (ref: johnson tw, richardson pf, Bailey S, et al. Journal of Medicinal Chemistry, 2014, 57(11): 4720-.
Reaction scheme 1
Synthesis scheme II (ref: Duan S, Li B, Dugger R W, et al, Organic Process Research & Development, 2017, 21 (9)) As shown in reaction scheme 2, Compound 6 (5-fluoro-3-methylisobenzofuran-1 (3H) -one) is amidated with pyrazole Compound 7 to give Compound 8, which is further reacted with amino-protected, hydroxy-activated Compound 9 (derivative of 2-amino-5-bromo-3-hydroxypyridine), to give the macrocyclic compound Lorlatinib via several steps. Wherein the compound 9 is 2-amino-5-bromo-3-hydroxypyridine which is subjected to radical protection of amino and hydroxyl (reaction formula 3).
Reaction formula 2
Reaction formula 3
Furthermore, documents CN 109232607A, EP 3415518 a1, WO 2018137679 a1 and the like also successively disclose methods for synthesizing loratinib. However, in almost all publications reporting the synthesis method of loratinib, 2-amino-5-bromo-3-hydroxypyridine is one of the important intermediates of loratinib, and therefore, the research on the synthesis of loratinib is of great significance.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an easy-to-operate and high-efficiency preparation method of a Lalatinib intermediate 2-amino-5-bromo-3-hydroxypyridine.
The invention is realized by the following steps: 2-amino-3-hydroxypyridine is used as an initial raw material, and subjected to ring closing, bromination, hydrolysis and other 3 steps of reactions to finally synthesize the 2-amino-5-bromo-3-hydroxypyridine.
Reaction formula 4
The first step, a ring closure reaction step (reaction formula 4): dissolving 2-amino-3-hydroxypyridine in Tetrahydrofuran (THF), completely dissolving the Tetrahydrofuran (THF), stirring for a period of time, adding N, N' -Carbonyldiimidazole (CDI), gradually dissolving CDI solid, stirring at room temperature for 1.5 hours after dissolving to obtain a yellow-brown clear solution, cooling to 0 ℃ in a ice salt bath, adding bis (trichloromethyl) carbonate (BTC) in batches, heating to reflux for about 1 hour after the addition is finished, filtering after the reaction is finished, washing a filter cake with water, and drying to obtain a light yellow powder crude product of 3H-oxazole [4,5-b ] pyridin-2-one, wherein the crude product can be directly used in the next bromination reaction without purification, and the molar yield of the crude product is 92-98%.
Reaction formula 5
The second step, photocatalytic bromination reaction step (equation 5): dissolving the crude product of oxazole [4,5-b ] pyridine-2 (3H) -ketone obtained in the ring closing step in an anhydrous solvent N, N-Dimethylformamide (DMF), adding the mixture into a quartz glass three-necked bottle, adding a catalytic amount of photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone, irradiating the reaction bottle by using a 23W ultraviolet lamp with a standard lampshade, controlling the temperature of the reaction solution to be 0-5 ℃, slowly dropwise adding a DMF solution of liquid bromine, and after dropwise adding, continuing to perform a light reaction for 1-2 hours at the temperature of 0-5 ℃; and after the thin-layer chromatography monitoring reaction is completed, pouring the reaction liquid into a certain amount of ice-water mixture, stirring, filtering, washing a filter cake with water, and drying to obtain a yellow solid crude 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one product, wherein the crude product can be directly used in the next hydrolysis reaction without purification, and the molar yield of the crude product in the photocatalytic bromination single-step reaction is 85-97%.
Reaction formula 6
A third step, a hydrolysis reaction step (reaction formula 6): and (2) adding the 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-one intermediate obtained in the step of photocatalytic bromination reaction into a three-necked bottle, adding a 10% sodium hydroxide aqueous solution in percentage by mass, and heating to reflux for reaction. Monitoring the reaction process by thin-layer chromatography, cooling to room temperature when the reaction raw material 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone is completely converted, dropwise adding 5% dilute hydrochloric acid to adjust the pH value of the solution to 6-7, extracting with ethyl acetate for three times, collecting an organic layer, adding anhydrous magnesium sulfate into the organic layer for drying, and concentrating under reduced pressure to obtain a gray brown solid crude product of 2-amino-5-bromo-3-hydroxypyridine, wherein the molar yield of the crude product of the single-step hydrolysis reaction is 88-95%, the relative content of liquid chromatography is 90-94%, and the purity of the product can be further improved by adopting column chromatography purification.
In the method for the step of photocatalytic bromination, the anhydrous solvent N, N-Dimethylformamide (DMF) may be any one of aprotic polar solvents such as Dimethylsulfoxide (DMSO), sulfolane, N-methylpyrrolidone (NMP), and N, N-Dimethylacetamide (DMC).
In the step of the photocatalytic bromination reaction, the amount of the photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone is 0.01-20% of the mass fraction of the raw material of oxazole [4,5-b ] pyridine-2 (3H) -ketone in the step of the reaction, and the optimal amount is 0.1-5%.
The invention has a technical characteristic that: the ring closing step combines the use of Bis Trichloromethyl Carbonate (BTC) and N, N' -Carbonyldiimidazole (CDI), thereby not only avoiding the defect that the conventional method needs to use highly toxic phosgene as a cyclization reagent, but also improving the reaction yield and the product quality.
The invention also has the technical characteristics that: the method has the advantages that the method is environment-friendly and economical compared with the prior art.
The invention also has the technical characteristics that: the 2-hydroxy-2-methyl-1-phenyl-1-acetone is used as a photoinitiator to catalyze the bromination reaction, so that the reaction selectivity is improved, the reaction can be carried out at a lower temperature, the energy consumption is saved, and the method has potential industrial application value.
Therefore, the invention has good economic benefit and social benefit.
The invention is characterized in that: (1) avoiding using virulent phosgene as a cyclization reagent; (2) BTC and CDI are combined for use, so that the reaction rate is obviously improved compared with that of BTC or CDI used alone; (3) the reaction efficiency is improved by adopting a photocatalysis method.
Detailed Description
Example 1: synthesis of 3H-oxazole [4,5-b ] pyridin-2-one
Dissolving 2-amino-3-hydroxypyridine (4.0 g, 36.3 mmol) in THF (120 mL), stirring for a period of time, adding CDI (8.8 g, 54.3 mmol), gradually dissolving CDI solid, stirring at room temperature for 1.5H, adding BTC (6.5 g, 21.9 mmol) in batches under ice bath condition, heating to reflux, reacting for 1H, filtering, washing filter cake with water, and drying to obtain light yellow powder 3H-oxazole [4,5-b ] 4]4.75g of pyridin-2-one in 96.1% yield, which was used directly in the next bromination without purification. The intermediate structure is required to be identified, column chromatography is adopted for further separation and purification,1H NMR (400 MHz, DMSO) 12.43 (s, 1H), 8.04 (dd, J = 5.3, 1.2 Hz, 1H), 7.64 (dd, J = 7.9, 1.2 Hz, 1H), 7.11 (dd, J = 7.9, 5.3 Hz, 1H).
example 2: synthesis of 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one
Oxazole [4,5-b ] obtained in the ring closing step]Adding a pyridine-2 (3H) -ketone crude product (2.50 g, 18.35 mmol) and 30 mL of anhydrous N, N-Dimethylformamide (DMF) into a quartz glass three-necked bottle in sequence, then adding 25 mg of photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone, irradiating the reaction bottle by using a 23W ultraviolet lamp with a standard lamp shade, controlling the temperature of the reaction solution to be 0-5 ℃, slowly dropwise adding a DMF solution containing liquid bromine (2.94 g, 18.35 mmol), and after dropwise adding, continuing to perform a photoreaction reaction for 1.5 hours at 0-5 ℃; after the reaction is monitored by thin-layer chromatography to be complete, pouring the reaction liquid into a certain amount of ice-water mixture, stirring, filtering, washing a filter cake with water, and drying to obtain yellow solid 6-bromo-3H-oxazolo [4,5-b ]]3.93g of pyridine-2-ketone crude product, 86.4 percent of molar yield of the photocatalytic bromination single-step reaction crude product and 93.7 percent of relative content of liquid chromatogram. The crude product can be used directly in the next hydrolysis without purification. The intermediate structure is required to be identified, column chromatography is adopted for further separation and purification,1H NMR (400 MHz, DMSO) 12.65 (s, 1H), 8.17 (s, 1H), 8.00 (t, J = 16.4 Hz, 1H)。
example 3: synthesis of 2-amino-5-bromo-3-hydroxypyridine
6-bromine-3H-oxazolo [4,5-b ] prepared according to the photocatalytic bromination reaction method]The pyridin-2-one intermediate (5.0 g, 23.3 mmol) was added to a three-necked flask, 40 mL of aqueous sodium hydroxide solution with a mass percentage concentration of 10% was added, and the mixture was heated and refluxed for 14 hours. Monitoring the reaction process by thin-layer chromatography, and waiting for the reaction of the raw material 6-bromo-3H-oxazolo [4,5-b]Completely converting pyridine-2-ketone, cooling to room temperature, dropwise adding 5% dilute hydrochloric acid to adjust the pH value of the solution to 6-7, extracting with ethyl acetate for three times, collecting an organic layer, adding anhydrous magnesium sulfate into the organic layer for drying, and concentrating under reduced pressure to obtain a gray brown solid crude product of 2-amino-5-bromo-3-hydroxypyridine 3.96g, wherein the hydrolysis single-step reaction molar yield is 90%, the relative content of a liquid chromatogram is 94%, and the method can adopt column chromatography (elution and elution)Ethyl acetate as an agent: petroleum ether =3: 1) purification further improves product purity.1H NMR (400 MHz, DMSO) 10.05 (s, 1H), 7.47 (s, 1H), 6.92 (s, 1H), 5.74 (s, 2H)。
Example 4: synthesis of 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one
Adding a crude product of oxazole [4,5-b ] pyridine-2 (3H) -ketone (2.50 g, 18.35 mmol) prepared by the method in example 1 and 30 mL of anhydrous N, N-Dimethylformamide (DMF) into a quartz glass three-necked bottle in sequence, then adding 0 mg of photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone, irradiating the reaction bottle by adopting a 23W ultraviolet lamp with a standard lampshade, controlling the temperature of the reaction solution to be 0-5 ℃, slowly dropwise adding a DMF solution containing liquid bromine (2.94 g, 18.35 mmol), and after dropwise adding, continuing to perform an illumination reaction for 3 hours at 0-5 ℃; after the reaction is monitored by thin-layer chromatography completely, the reaction liquid is poured into a certain amount of ice-water mixture, stirred and filtered, filter cakes are washed by water and dried to obtain 3.87g of a yellow solid 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one crude product, the molar yield of the photocatalytic bromination single-step reaction crude product is 85.1 percent, and the relative content of liquid chromatography is 76.2 percent. The crude product has low purity, and cannot be directly used in the next hydrolysis reaction without purification, and column chromatography (eluent ethyl acetate: petroleum ether =4: 1) is adopted to obtain 2.51g of light yellow solid 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one product, the molar yield of the photocatalytic bromination single-step reaction crude product is 55.2%, and the relative content of liquid chromatography is 96.7%.
Claims (3)
1. A synthetic method of 2-amino-5-bromo-3-hydroxypyridine is characterized in that 2-amino-3-hydroxypyridine is used as an initial raw material, and the 2-amino-5-bromo-3-hydroxypyridine is finally synthesized through 3 steps of reactions such as ring closing, photocatalytic bromination and hydrolysis:
the specific experimental operation steps are as follows:
step one, a ring closing reaction step: dissolving 2-amino-3-hydroxypyridine in Tetrahydrofuran (THF), stirring for a period of time, adding N, N '-Carbonyldiimidazole (CDI), gradually dissolving N, N' -Carbonyldiimidazole (CDI), stirring for 1.5 hours at room temperature, cooling to 0 ℃ with an ice salt bath, adding bis (trichloromethyl carbonate) (BTC) in batches, heating to reflux for about 1 hour after the addition is finished, filtering after the reaction is finished, washing a filter cake with water, and drying to obtain a light yellow powder crude product of 3H-oxazole [4,5-b ] pyridin-2-one, wherein the crude product can be directly used in the next bromination reaction without purification, and the molar yield of the crude product is 92-98%;
step two, photocatalytic bromination reaction: sequentially adding the crude product of oxazole [4,5-b ] pyridine-2 (3H) -ketone obtained in the ring closing step and an anhydrous solvent into a quartz glass three-necked bottle, then adding a catalytic amount of photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone, irradiating the reaction bottle by adopting a 23W ultraviolet lamp with a standard lampshade, controlling the temperature of the reaction liquid to be 0-5 ℃, slowly dropwise adding a DMF (dimethyl formamide) solution of liquid bromine, and after dropwise adding, continuing to perform a light reaction for 1-2 hours at the temperature of 0-5 ℃; after the thin-layer chromatography monitoring reaction is completed, pouring the reaction liquid into a certain amount of ice-water mixture, stirring, filtering, washing a filter cake with water, and drying to obtain a yellow solid crude 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one product, wherein the crude product can be directly used in the next hydrolysis reaction without purification, and the molar yield of the crude product in the photocatalytic bromination single-step reaction is 85-97%;
step three, hydrolysis reaction step: adding the 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one intermediate obtained in the photocatalytic bromination reaction step into a three-necked bottle, adding a 10% sodium hydroxide aqueous solution by mass percent, and heating to reflux reaction; monitoring the reaction process by thin-layer chromatography, cooling to room temperature when the reaction raw material 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone is completely converted, dropwise adding 5% dilute hydrochloric acid to adjust the pH value of the solution to 6-7, extracting with ethyl acetate for three times, collecting an organic layer, adding anhydrous magnesium sulfate into the organic layer for drying, and concentrating under reduced pressure to obtain a gray brown solid crude product of 2-amino-5-bromo-3-hydroxypyridine, wherein the molar yield of the crude product of the single-step hydrolysis reaction is 88-95%, the relative content of liquid chromatography is 90-94%, and the purity of the product can be further improved by adopting column chromatography purification;
2. the method according to claim 1, wherein the anhydrous solvent is any aprotic polar solvent such as N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), sulfolane, N-methylpyrrolidone (NMP) or N, N-Dimethylacetamide (DMC).
3. The experimental procedure as claimed in claim 1, wherein the photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-propanone is used in an amount of 0.01-20 wt%, preferably 0.1-5 wt%, based on the reaction raw material oxazolo [4,5-b ] pyridin-2 (3H) -one.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112724077A (en) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | Synthetic method of Laolatinib intermediate |
| WO2023112056A1 (en) | 2021-12-17 | 2023-06-22 | Pi Industries Ltd. | Novel substituted fused bicyclic pyridine carboxamide compounds for combating phytopathogenic fungi |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134410A (en) * | 2018-09-20 | 2019-01-04 | 沈阳药科大学 | The synthetic method of fluoro- 3- methyl isobenzofuran -1 (3H) -one of 5- |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109134410A (en) * | 2018-09-20 | 2019-01-04 | 沈阳药科大学 | The synthetic method of fluoro- 3- methyl isobenzofuran -1 (3H) -one of 5- |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724077A (en) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | Synthetic method of Laolatinib intermediate |
| CN112724077B (en) * | 2020-12-29 | 2023-07-11 | 武汉利昌医药科技有限公司 | Synthesis method of loratidine intermediate |
| WO2023112056A1 (en) | 2021-12-17 | 2023-06-22 | Pi Industries Ltd. | Novel substituted fused bicyclic pyridine carboxamide compounds for combating phytopathogenic fungi |
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